Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.NO.C([N:6]([CH2:9][CH3:10])CC)C.[Br:11][C:12]1[CH:13]=C(C=O)[S:15][C:16]=1[Cl:17].C1(=O)OC(=O)C2=CC=CC=C12>C(#N)C.C(OCC)(=O)C>[Br:11][C:12]1[CH:13]=[C:10]([C:9]#[N:6])[S:15][C:16]=1[Cl:17]
Reactant: CCN(CC)CC
Reactant: O=Cc1cc(Br)c(Cl)s1
Agent: Cl
Agent: NO
Agent: O=C1OC(=O)c2ccccc21
Solvent: CC#N
Solvent: CCOC(C)=O
Product: N#Cc1cc(Br)c(Cl)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
Hydroxylamine hydrochloride (Aldrich, 4.91 g, 70.66 mmol) and triethylamine (anhydrous, 11.2 mL, 80.36 mmol) were added to a 0° C. solution of 4-bromo-5-chloro-thiophene-2-carbaldehyde (Example 24: step a, 10.63 g, 47.14 mmol) in acetonitrile (anhydrous, 250 mL). The reaction mixture was warmed to room temperature and stirred for 1 hour. Phthalic anhydride was added and the reaction mixture was heated to 80° C. overnight. The mixture was cooled to room temperature, diluted with ethyl acetate (400 mL), and washed with aqueous citric acid, saturated NaHCO3, water, and brine. The organic layer was dried over magnesium sulfate, filtered, concentrated in vacuo, and purified by column chromatography (silica gel, 5% ethyl acetate/hexanes) to afford the title compound as a pale yellow solid (9.76 g, 93% yield). 1H-NMR (CDCl3): δ 7.47 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1([C:10]#[N:11])[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[CH2:3]1.N.[OH:13]S(O)(=O)=O>O>[NH2:1][C:2]1([C:10]([NH2:11])=[O:13])[CH2:7][CH2:6][CH2:5][C:4]([CH3:8])([CH3:9])[CH2:3]1
Reactant: O=S(=O)(O)O
Reactant: CC1(C)CCCC(N)(C#N)C1
Agent: N
Solvent: O
Product: CC1(C)CCCC(N)(C(N)=O)C1
Temperature: 0 °C

Procedure:
A solution of EXAMPLE 145A (4.6 g) in concentrated H2SO4 (9 mL) was heated to 70° C. for 20 minutes. The reaction mixture was cooled to about 0° C. in an ice bath and diluted with water. The pH of the solution was adjusted to pH 7-8 by addition of concentrated aqueous ammonia solution. The aqueous layer was extracted with methylene chloride (2×50 mL). The combined organic layers were washed with water (1×20 mL), dried over MgSO4, filtered, and concentrated to give the title compound, which was used in the next step without further purification.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]1[CH2:10][CH2:9][CH2:8][NH:7]1.[F:11][C:12]1[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1>>[F:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([N:7]2[CH2:8][CH2:9][CH2:10][CH:6]2[C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)(=[O:20])=[O:19])=[CH:14][CH:13]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: c1coc(C2CCCN2)c1
Product: O=S(=O)(c1ccc(F)cc1)N1CCCC1c1ccco1

Procedure:
The title compound, white solid, m.p. 69° C. and MS: m/e=295 (M+) was prepared in accordance with the general method of example 1e from (RS)-2-furan-2-yl-pyrrolidine and 4-fluoro-benzenesulfonyl chloride.
Reaction SMILES: CN(C)C=O.I[C:7]1[CH:8]=[N:9][N:10]([CH3:22])[C:11]=1[C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=1.[CH3:23][Si:24]([C:27]#[CH:28])([CH3:26])[CH3:25].C(N(CC)CC)C>C(OCC)(=O)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:22][N:10]1[C:11]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[C:7]([C:28]#[C:27][Si:24]([CH3:26])([CH3:25])[CH3:23])[CH:8]=[N:9]1
Reactant: C#C[Si](C)(C)C
Reactant: Cn1ncc(I)c1-c1ccc(C(F)(F)F)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cn1ncc(C#C[Si](C)(C)C)c1-c1ccc(C(F)(F)F)cc1
Temperature: 75 °C
Reaction time: 4 h
Yield: 83.8 %

Procedure:
Under a nitrogen atmosphere, copper(I) iodide (7 mg), bis(triphenylphosphine)palladium(II) dichloride (90 mg) and triphenylphosphine (34 mg) were added to a dimethylformamide (45 mL) solution that contained 4-iodo-1-methyl-5-[4-(trifluoromethyl)phenyl]-1H-pyrazole (4.51 g), trimethylsilylacetylene (2.26 g) and triethylamine (3.57 mL), and the obtained solution was then stirred at 75° C. for 4 hours. Thereafter, the reaction solution was diluted with ethyl acetate, and was then washed with water and a saturated saline. The organic layer was dried over anhydrous sodium sulfate, and was then concentrated under a reduced pressure. The residue was purified by column chromatography (silica gel 60N, hexane:ethyl acetate=85:15 to 70:30), so as to obtain the title compound (3.46 g).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:14][C:15]([F:18])([F:17])[F:16])[CH2:10][C:11]([OH:13])=[O:12])=[CH:5][C:4]=1[C:19]([F:22])([F:21])[F:20])#[N:2].[CH:23](O)([CH3:25])[CH3:24]>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:14][C:15]([F:16])([F:17])[F:18])[CH2:10][C:11]([O:13][CH:23]([CH3:25])[CH3:24])=[O:12])=[CH:5][C:4]=1[C:19]([F:21])([F:20])[F:22])#[N:2]
Reactant: N#Cc1ccc(N(CC(=O)O)CC(F)(F)F)cc1C(F)(F)F
Reactant: CC(C)O
Product: CC(C)OC(=O)CN(CC(F)(F)F)c1ccc(C#N)c(C(F)(F)F)c1

Procedure:
Synthesized according to example 3 N-[4-cyano-3-(trifluoromethyl)phenyl]-N-(2,2,2-trifluoroethyl)glycine and isopropanol: 1H NMR (300 MHz, CD3OD) δ 7.81-7.73 (m, 1H), 7.17-7.09 (m, 2H), 5.04 (sept, J=6.3 Hz, 1H), 4.38 (s, 2H, overlapped with 4.35), 4.35 (q, J=9.0 Hz, overlapped with 4.38, 2H), 1.23 (d, J=6.1 Hz, 6H).
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9]Br)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[P:13]([O:18]C)([O:16][CH3:17])[O:14][CH3:15]>>[C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][P:13](=[O:18])([O:16][CH3:17])[O:14][CH3:15])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COP(OC)OC
Reactant: CC(C)(C)c1ccc(CBr)cc1
Product: COP(=O)(Cc1ccc(C(C)(C)C)cc1)OC
Reaction time: 16 h
Yield: 95.2 %

Procedure:
4-t-Butylbenzyl bromide (19.16 g, 84 mmol) and trimethyl phosphite (10.46, 84 mmol) were heated at 120° C. under argon for 6 hours, after which a further 10.46 g trimethylphosphite was added and heating continued for a further 16 hours. The dimethyl methylphosphonate by-product was distilled off, leaving the desired dimethyl 4-t-butylbenzylphosphonate as a pale yellow oil (20.6 g, 80 mmol).
Reaction SMILES: [N:1]1([S:7]([C:10]2[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[NH:19]1[CH2:23][CH2:22][CH2:21][C@H:20]1[CH2:24][N:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1>>[N:1]1([S:7]([C:10]2[CH:11]=[CH:12][C:13]([C:14]([N:19]3[CH2:23][CH2:22][CH2:21][C@H:20]3[CH2:24][N:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)=[O:16])=[CH:17][CH:18]=2)(=[O:8])=[O:9])[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: O=C(O)c1ccc(S(=O)(=O)N2CCOCC2)cc1
Reactant: C1CN[C@H](CN2CCCC2)C1
Product: O=C(c1ccc(S(=O)(=O)N2CCOCC2)cc1)N1CCC[C@H]1CN1CCCC1
Yield: 35.8 %

Procedure:
The title compound is prepared from 4-(morpholine-4-sulfonyl)-benzoic acid (407 mg, 1.5 mmol) and (S)(+)-1-(2-pyrrolidinylmethyl)pyrrolidine (CAS 51207-66-0)(193 mg, 1.2 mmol) in a manner substantially similar to Procedure G to provide 175 mg (34%) of the title compound. MS (ES+) 408.3 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[C:14]([F:18])[C:15]([F:17])=[CH:16][C:11]=2[N:10]=[C:9]1[C:19]1[C:20]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29]C=2Cl)=[N:21][CH:22]=[CH:23][CH:24]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(CO)CCCC1>>[CH2:1]([N:8]1[C:12]2[CH:13]=[C:14]([F:18])[C:15]([F:17])=[CH:16][C:11]=2[N:10]=[C:9]1[C:19]1[C:20]([O:25][CH2:26][CH:27]2[CH2:29][CH2:30][CH2:31][CH2:32]2)=[N:21][CH:22]=[CH:23][CH:24]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Fc1cc2nc(-c3cccnc3OCc3ccccc3Cl)n(Cc3ccccc3)c2cc1F
Agent: OCC1CCCC1
Product: Fc1cc2nc(-c3cccnc3OCC3CCCC3)n(Cc3ccccc3)c2cc1F

Procedure:
The title compound was prepared in analogy to Example 1, from 1-benzyl-2-(2-chloro-pyridin-3-yl)-5,6-difluoro-1H-benzoimidazole (Example 6, intermediate) and cyclopentyl-methanol (CAS Reg. No. 3637-61-4). Light yellow powder (42%). MS (Turbo Spray): m/z=419.9 (M+H).
Reaction SMILES: C(Cl)(=O)C([Cl:4])=O.[CH:7]([CH:10]([CH2:14][CH2:15][C:16](=[O:18])[CH3:17])[C:11](O)=[O:12])([CH3:9])[CH3:8]>C1C=CC=CC=1>[CH:7]([CH:10]([CH2:14][CH2:15][C:16](=[O:18])[CH3:17])[C:11]([Cl:4])=[O:12])([CH3:9])[CH3:8]
Reactant: CC(=O)CCC(C(=O)O)C(C)C
Reactant: O=C(Cl)C(=O)Cl
Solvent: c1ccccc1
Product: CC(=O)CCC(C(=O)Cl)C(C)C
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 6.0 g (0.0468 mole) of oxalyl chloride in 4 ml of benzene was chilled to 0° C under a nitrogen atmosphere. A solution of 4.0 g (0.0234 mole) of 2-isopropyl-5-oxohexanoic acid in 4 ml of benzene was added and the solution was warmed to room temperature, and stirred at room temperature for 20 hours. Evaporation of the solvent under reduced pressure yielded a 2-isopropyl-5-oxohexanoyl chloride residue, and the residue was dissolved in 3 ml of benzene. A 3.1 g (0.0222 mole) quantity of 2-methoxy-4-methylphenol in 5 ml of benzene was added, and the solution was stirred for 20 hours. Ether was added and the solution was washed with water, aqueous saturated sodium chloride, and 5% potassium hydroxide. The organic layer was dried over anhydrous calcium chloride, and the solvent was removed under reduoed pressure to yield a liquid whioh was purified by Kugelrohr distillation bp 120°-125° C./0.04 mm Hg.
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH2:7][O:8][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10])=[CH:4][CH:3]=1.[Cu](C#N)[C:17]#[N:18]>>[Si:9]([O:8][CH2:7][C:5]1[S:6][C:2]([C:17]#[N:18])=[CH:3][CH:4]=1)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc(Br)s1
Reactant: N#C[Cu]C#N
Product: CC(C)(C)[Si](C)(C)OCc1ccc(C#N)s1

Procedure:
The crude product of the title compound was synthesized by conducting the similar reaction to that mentioned in Example 3 (3a) using [(5-bromo-2-thienyl)methoxy]t-butyldimethylsilane (2.4 g, 7.8 mmol) [reference literature: Tetrahedron, vol. 39, 2531 (1983)] and copper cyanide (1.3 g, 14 mmol). Subsequently, the crude product of the title compound thus obtained was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (1:50 to 1:7) as the eluent to afford the title compound (1.1 g) in a yield of 56% as a white crystalline solid.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([CH3:14])([CH3:13])[C:10](=[O:15])[C:9]=2[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]3[CH:33]=[CH:32][C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:25]=3)=[CH:18][CH:17]=2)=[CH:4][CH:3]=1.Cl.N([O-])=O.[Na+]>C(#N)C.O>[CH3:13][C:11]1([CH3:14])[C:10](=[O:15])[C:9]([C:16]2[CH:17]=[CH:18][C:19]([O:22][CH2:23][C:24]3[CH:33]=[CH:32][C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:25]=3)=[CH:20][CH:21]=2)=[C:8]([C:5]2[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=2)[O:12]1
Reactant: CC1(C)OC(c2ccc(N)cc2)=C(c2ccc(OCc3ccc4ccccc4n3)cc2)C1=O
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CC1(C)OC(c2ccccc2)=C(c2ccc(OCc3ccc4ccccc4n3)cc2)C1=O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 23.7 %

Procedure:
To a stirred solution of 5-(4-aminophenyl)-2,2-dimethyl-4-(4-(quinolin-2-ylmethoxy)phenyl)furan-3(2H)-one (80 mg, 0.18 mmol) in ACN: H2O (6 mL, 1:1) was added cone HCl (0.2 mL) at 0° C. under N2 atmosphere. The reaction mixture was stirred at 0° C. for 10 min. After being stirred for 5 min then added NaNO2 in water and stirred for 40 min at 0° C. The reaction mixture was stirred at 70° C. for 2h. After completion of starting material (by TLC), reaction mass was diluted with water and extracted with EtOAc (2×25 mL). Combined organic layers were washed with water (2×5 mL), brine and dried over anhydrous Na2SO4. After filtration and evaporation, the crude material was purified by silica gel column chromatography to afford 2,2-dimethyl-5-phenyl-4-(4-(quinolin-2-ylmethoxy)phenyl)furan-3(2H)-one (18 mg, 23%), as an off white solid, 1H NMR (400 MHz, CDCl3): δ 8.45 (d, J=8.5 Hz, 1 H), 8.10 (d, J=7.9 Hz, 1 H), 7.86 (d, J=8.4 Hz, 1 H), 7.75-7.62 (m, 3H), 7.52 (t, J=8.2 Hz, 1 H), 7.45 (d, J=8.5 Hz, 1 H), 7.32 (d, J=7.5 Hz, 2 H), 7.21 (d, J=7.4 Hz, 2 H), 7.03 (d, J=7.5 Hz, 2 H), 5.42 (s, 2 H), 1.51 (s, 6 H). MS: [M+Na]: m/z=444.1, [M+H]: m/z=422.1. HPLC: 98.72% (RT-2.83 min), Column: Acquity BEH-C-18, 50×2.1 mm, 1.7 um. Mobile Phase: 0.025% TFA in Water (A), ACN (B), Flow rate: 0.5 ml/min (Gradient).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Br:7][C:8]1[CH:9]=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=1.I[CH2:16][CH2:17][O:18][CH3:19].ClCCOC>CN(C)C=O>[Br:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:16][CH2:17][O:18][CH3:19])[CH:9]=1
Reactant: COCCI
Reactant: Oc1cccc(Br)c1
Agent: COCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCOc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 25.5 %

Procedure:
Anhydrous potassium carbonate (4.2 g, 30.4 mmol) was added to a stirred solution of 3-bromophenol (5.0 g, 28.9 mmol) in anhydrous dimethylformamide (100 ml). After 5 minutes, 1-iodo-2-methoxyethane (Annalen, 1967, 710, 59; 5.9 g, 31.8 mmol) was added and the reaction mixture stirred at room temperature for about 16 hours. At this point the mixture was heated at about 50° C. for approximately 72 hours, before 1-chloro-2-methoxyethane (1.8 ml, 19.8 mmol) was added and heating continued for a further 24 hours. The resulting mixture was evaporated under reduced pressure and the residue partitioned between ethyl acetate and water. The layers were separated and the aqueous layer was further extracted with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried (MgSO4) and concentrated to a red oil, which was purified by flash chromatography using hexane:ethyl acetate (3:1) as eluant, to furnish the title compound as a colourless oil (1.7 g, 25%). δ(CDCl3): 3.43 (s,3H), 3.74 (t,2H), 4.10 (t,2H), 6.87 (d,1H), 7.10 (m,3H).
Reaction SMILES: [N+](=[CH2:3])=[N-].[CH2:4]([O:11][C:12]1[CH:13]=[C:14]([C:19]([OH:25])([CH2:23][CH3:24])[C:20]([OH:22])=[O:21])[CH:15]=[C:16]([F:18])[CH:17]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>C(OCC)C>[CH2:4]([O:11][C:12]1[CH:13]=[C:14]([C:19]([OH:25])([CH2:23][CH3:24])[C:20]([O:22][CH3:3])=[O:21])[CH:15]=[C:16]([F:18])[CH:17]=1)[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: C=[N+]=[N-]
Reactant: CCC(O)(C(=O)O)c1cc(F)cc(OCc2ccccc2)c1
Solvent: CCOCC
Product: CCC(O)(C(=O)OC)c1cc(F)cc(OCc2ccccc2)c1

Procedure:
A solution of diazomethane in diethyl ether was added to a solution of (-)-2-(3-benzyloxy-5-fluorophenyl)-2-hydroxybutyric acid (2.24 g) in diethyl ether (35 ml) until the reaction mixture retained a yellow colouration. The mixture was evaporated to give methyl (-)-2-(3-benzyloxy-5-fluorophenyl)-2-hydroxybutyrate (2.27 g).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]([OH:9])=O)=[CH:5][O:4][N:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.ClN1C(=O)CCC1=O.[CH:37]1([CH2:40][N:41]2[C:49]3[N:48]=[C:47]([CH2:50][C:51]4[CH:56]=[CH:55][C:54]([NH:57][CH3:58])=[CH:53][CH:52]=4)[NH:46][C:45]=3[C:44](=[O:59])[N:43]([CH2:60][C:61]3[CH:66]=[CH:65][CH:64]=[CH:63][C:62]=3[F:67])[C:42]2=[O:68])[CH2:39][CH2:38]1>ClCCl>[CH:37]1([CH2:40][N:41]2[C:49]3[N:48]=[C:47]([CH2:50][C:51]4[CH:52]=[CH:53][C:54]([N:57]([CH3:58])[C:7]([C:6]5[C:2]([CH3:1])=[N:3][O:4][CH:5]=5)=[O:9])=[CH:55][CH:56]=4)[NH:46][C:45]=3[C:44](=[O:59])[N:43]([CH2:60][C:61]3[CH:66]=[CH:65][CH:64]=[CH:63][C:62]=3[F:67])[C:42]2=[O:68])[CH2:39][CH2:38]1
Reactant: Cc1nocc1C(=O)O
Reactant: CNc1ccc(Cc2nc3c([nH]2)c(=O)n(Cc2ccccc2F)c(=O)n3CC2CC2)cc1
Agent: O=C1CCC(=O)N1Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1nocc1C(=O)N(C)c1ccc(Cc2nc3c([nH]2)c(=O)n(Cc2ccccc2F)c(=O)n3CC2CC2)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 22 %

Procedure:
A mixture of 3-methyl-isoxazole-4-carboxylic acid (7.3 mg, 0.057 mmol) in dichloromethane (1.0 mL) cooled to 0° C. was treated with triphenylphosphine (17 mg, 0.063 mmol), and N-chlorosuccinimide (10 mg, 0.074 mmol). This mixture was stirred at 0° C. for 15 min and at 25° C. for 20 min. At this time, the reaction was treated with 3-cyclopropylmethyl-1-(2-fluoro-benzyl)-8-(4-methylamino-benzyl)-3,7-dihydro-purine-2,6-dione (50 mg, 0.11 mmol). The reaction was then stirred at 25° C. for 18 h. At this time, the reaction was diluted with dichloromethane (50 mL) and was washed with a saturated aqueous sodium bicarbonate solution (1×10 mL). The organics were dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by HPLC (15–60% acetonitrile/water (0.075% trifluoroacetic acid in both solvents) over 40 min). Fractions with the desired product were combined and concentrated in vacuo. The resulting residue was diluted with dichloromethane (100 mL) and was washed with a saturated aqueous sodium bicarbonate solution (25 mL). The aqueous layer was re-extracted with dichloromethane (1×50 mL). The combined organics were dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting solid was dried in vacuo for 24 h to afford 3-methyl-isoxazole-4-carboxylic acid {4-[3-cyclopropylmethyl-1-(2-fluoro-benzyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-ylmethyl]-phenyl}-methyl-amide (6.8 mg, 21.8%) as an off-white solid: EI-HRMS m/e calcd for C29H27N6O4 (M+) 542.2078, found 542.2077.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[S:5][C:6]=1Br.C([Li])CCC.CCCCCC.O>O1CCCC1>[Br:1][C:2]1[C:3]([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[S:5][CH:6]=1
Reactant: Fc1ccc(-c2sc(Br)c(Br)c2-c2ccncc2)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: Fc1ccc(-c2scc(Br)c2-c2ccncc2)cc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 99.7 %

Procedure:
4,5-Dibromo-2-(4-fluorophenyl)-3-(pyridin-4-yl)thiophene (13.88 g (33.6 mmol), prepared as described in 4)) was dissolved in tetrahydrofuran (140 ml). To the solution was added dropwise at −78° C. a solution of 1.59 M butyl lithium/hexane (23.3 ml, 37 mmol). The resulting mixture was stirred at −78° C. for 15 minutes. At the end of this time, water (24 ml) was added to the reaction mixture and it was allowed to warm to room temperature. The reaction mixture was partitioned between a saturated aqueous solution of ammonium chloride and ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate and the solvent was removed by distillation under reduced pressure. The residue (solid) was washed with diethyl ether, to give the title compound (11.20 g) as a pale brown powder (yield quantitative).
Reaction SMILES: C(O[CH:5]1[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:12][C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)(=O)C.[NH2:19][CH:20]1[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]1>C1C=CC=CC=1>[CH3:26][N:23]1[CH2:24][CH2:25][CH:20]([NH:19][CH:5]2[C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=3[O:12][C:13]3[C:18]2=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:21][CH2:22]1
Reactant: CN1CCC(N)CC1
Reactant: CC(=O)OC1c2ccccc2Oc2ccccc21
Solvent: c1ccccc1
Product: CN1CCC(NC2c3ccccc3Oc3ccccc32)CC1

Procedure:
A solution of 4.0 g. of 9-acetoxyxanthene and 1.9 g. of 4-amino-1-methylpiperidine in 100 ml. of dry benzene was refluxed for 24 hours. The cooled solution was then washed with 5% aqueous sodium carbonate solution and the organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue crystallized on triturating with hexane and was recrystallized from hexane to give N-(N-methyl-4-piperidinyl)-9-xanthenylamine, m.p. 96.5°-98° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])=[N:6][CH:7]=1.[Br-].[CH:19]1([Zn+])[CH2:21][CH2:20]1>C1COCC1.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>[CH:19]1([C:2]2[CH:3]=[CH:4][C:5]([C:8]([O:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[O:9])=[N:6][CH:7]=2)[CH2:21][CH2:20]1
Reactant: [Zn+]C1CC1
Reactant: O=C(OCc1ccccc1)c1ccc(Br)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)c1ccc(C2CC2)cn1
Temperature: 80 °C

Procedure:
To a solution of benzyl 5-bromopicolinate (876 mg, 3.0 mmol) in THF (10 mL) was added Pd(PPh3)4 (173 mg, 0.15 mmol) under N2. After addition of a solution of cyclopropylzinc bromide in THF (0.5 M, 10 mL), the mixture was heated at 80° C. for 3 hours and then cooled to room temperature. The reaction mixture was quenched with sat. NH4Cl (aq) and extracted with EtOAc (3×). The organic layer was washed with sat. NaHCO3(aq.), brine, and dried (MgSO4). The product benzyl 5-cyclopropylpicolinate (510 mg) was obtained by silica gel chromatography (elution with 0-15% EtOAc/Hex, then 15% EtOAc/Hex).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=3)=[CH:12][C:11]([C:21]([O:23]CC)=[O:22])=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].ClC1C=C(N2C(C3C=C(F)C=C(Cl)C=3)=CC(C(O)=O)=N2)C=CC=1F>>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=3)=[CH:12][C:11]([C:21]([OH:23])=[O:22])=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CCOC(=O)c1cc(-c2cccc(F)c2)n(-c2ccc(F)c(Cl)c2)n1
Agent: O=C(O)c1cc(-c2cc(F)cc(Cl)c2)n(-c2ccc(F)c(Cl)c2)n1
Product: O=C(O)c1cc(-c2cccc(F)c2)n(-c2ccc(F)c(Cl)c2)n1

Procedure:
The preparation of the title compound takes place starting from the compound of Example 46A in analogy to the synthesis of the compound of Example 71A. 550 mg (99% of theory) of the title compound are obtained.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH:16]1[CH:21]=[C:20]2[CH:22]=[CH:23][CH:24]=[C:25]([NH:26][C:27]([C:29]3[C:38]([OH:39])=[CH:37][C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[CH:30]=3)=[O:28])[C:19]2=[CH:18][CH:17]=1.O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1>[C:25]1([NH:26][C:27]([C:29]2[C:38]([O:39][C:2]3[C:11]4[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=4)[N:5]=[CH:4][CH:3]=3)=[CH:37][C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:30]=2)=[O:28])[C:19]2[C:20](=[CH:21][CH:16]=[CH:17][CH:18]=2)[CH:22]=[CH:23][CH:24]=1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: O=C(Nc1cccc2ccccc12)c1cc2ccccc2cc1O
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1
Solvent: O
Product: COc1cc2nccc(Oc3cc4ccccc4cc3C(=O)Nc3cccc4ccccc34)c2cc1OC
Temperature: 130 °C
Reaction time: 8 h
Yield: 17.3 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (111 mg), naphthol AS-BO (626 mg), and 4-dimethylaminopyridine (244 mg) were suspended in monochlorobenzene (2 ml), and the suspension was stirred at 130° C. overnight. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by chromatography on silica gel using ethyl acetate-hexane for development to give the title compound (43 mg, yield 17%).