Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:10][CH2:11][O:12][C:13]2[CH:45]=[CH:44][C:16]([CH2:17][CH:18]3[S:22][C:21](=[O:23])[N:20](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[C:19]3=[O:43])=[CH:15][CH:14]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H][H]>O1CCOCC1.[Pd]>[N:1]1([CH2:10][CH2:11][O:12][C:13]2[CH:14]=[CH:15][C:16]([CH2:17][CH:18]3[S:22][C:21](=[O:23])[NH:20][C:19]3=[O:43])=[CH:44][CH:45]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: [H][H]
Reactant: O=C1SC(Cc2ccc(OCCn3ccc4ccccc43)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Pd]
Solvent: C1COCCO1
Product: O=C1NC(=O)C(Cc2ccc(OCCn3ccc4ccccc43)cc2)S1
Reaction time: 2 h
Yield: 85.9 %

Procedure:
A solution of 2.05 g of 5-{4-[2-(indol-1-yl)-ethoxy]benzyl}-3-triphenylmethylthiazolidine-2,4-dione (prepared as described in Preparation 14) in 100 ml of dioxane was stirred in an atmosphere of hydrogen and in the presence of 3.1 g of 10% w/w palladium-on-charcoal, first at room temperature for 30 minutes, then at 60° C. for 2 hours and then at 80° C. for 3 hours. At the end of this time, the reaction mixture was filtered to remove the catalyst and the filtrate was concentrated by evaporation under reduced pressure. The concentrate was then purified by column chromatography through silica gel, using a 2:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 1.06 g of the title compound, melting at 42.3°-44.6° C.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[CH:8][C:9]([NH:11]C(=O)C)=[CH:10][C:5]=2[O:4][C:3]=1[C:15](=[O:23])[C:16]1[CH:21]=[CH:20][C:19](C)=[CH:18][CH:17]=1.[ClH:24].C(OC(=O)C)C>CO>[NH2:11][C:9]1[CH:8]=[CH:7][C:6]2[C:2]([CH3:1])=[C:3]([C:15]([C:16]3[CH:21]=[CH:20][C:19]([Cl:24])=[CH:18][CH:17]=3)=[O:23])[O:4][C:5]=2[CH:10]=1
Reactant: CC(=O)Nc1ccc2c(C)c(C(=O)c3ccc(C)cc3)oc2c1
Reactant: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1c(C(=O)c2ccc(Cl)cc2)oc2cc(N)ccc12
Temperature: 25 °C

Procedure:
3.1 g (10 mmol) of N-[3-methyl-2-(4-methyl-benzoyl)benzofuran-6-yl]-acetamide were suspended in 40 ml methanol. 20 ml 2.6N HCl were added with stirring. The reaction mixture was heated to reflux. After 1 hour a clear solution was obtained. After 3 hours reflux the solution was cooled to room temperature and ethylacetate was added. The organic layer was washed once with NaOH-solution, two times with water, dried over Na4SO4 and concentrated in vacuo. The residue was further purified by crystallisation.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C:11]([CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[OH:8].CN(C=O)C.CC#N.C([O-])([O-])=O.[K+].[K+].Br[CH2:33][CH:34]1[CH2:36][CH2:35]1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C:11]([CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[O:8][CH2:33][CH:34]1[CH2:36][CH2:35]1
Reactant: BrCC1CC1
Reactant: O=C(CCc1ccc(O)c(Cl)c1)C1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: O=C(CCc1ccc(OCC2CC2)c(Cl)c1)C1CCCC1
Temperature: 100 °C
Reaction time: 0.25 h
Yield: 96 %

Procedure:
A solution of 3-(3-chloro-4-hydroxyphenyl)-1-cyclopentylpropan-1-one ((25 g, 0.099 mol, from Step 2) in 1:1 DMF/CH3CN (200 mL) was treated with K2CO3 (15 g, 0.109 mol, 1.1 equiv), and the mixture stirred for 15 min. A solution of (bromomethyl)cyclopropane (17.4 g, 0.129 mol, 1.3 equiv) in DMF (50 mL) was added dropwise, and the reaction mixture heated to 100° C. for 1 h. The volatiles were removed in vacuo. The residue was dissolved in a minimal amount of ethyl acetate, and this solution washed with water, dried over Na2SO4, filtered, and evaporated. Chromatographic purification of the residue on silica gel using hexanes/ethyl acetate afforded 29.12 g (96%) of the title compound.
Reaction SMILES: I[C:2]1[CH:3]=[N:4][N:5]([CH2:7][C:8]([F:11])([F:10])[F:9])[CH:6]=1.[Br:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]#[CH:20])[CH:14]=1>C(N(CC)CC)C.C(#N)C.[Cu](I)I>[Br:12][C:13]1[CH:14]=[C:15]([C:19]#[C:20][C:2]2[CH:3]=[N:4][N:5]([CH2:7][C:8]([F:11])([F:10])[F:9])[CH:6]=2)[CH:16]=[CH:17][CH:18]=1
Reactant: C#Cc1cccc(Br)c1
Reactant: FC(F)(F)Cn1cc(I)cn1
Agent: I[Cu]I
Solvent: CCN(CC)CC
Solvent: CC#N
Product: FC(F)(F)Cn1cc(C#Cc2cccc(Br)c2)cn1
Temperature: 80 °C
Yield: 99.5 %

Procedure:
To a solution of 4-iodo-1-(2,2,2-trifluoroethyl)-1H-pyrazole (4.14 g, 15 mmol) in triethylamine (53 mL) is added tetrakis(triphenylphosphine)paddadium (1.20 g, 1.04 mmol), copper iodide (0.28 g, 1.46 mmol) and a solution of 1-bromo-3-ethynylbenzene (2.78 g, 15 mmol) in acetonitrile (15 mL) at room temperature. After heating for 1 hour at 80° C., the reaction mixture is cooled and concentrated. The crude material is purified by chromatography (silica gel, EtOAc/hexane: 5/95) to give the title compound as a solid (4.91 g, 99%). mp: 107-109° C. MS (+) EI: 328 M+.
Reaction SMILES: C[C:2]1[CH:8]=[C:7](C)[CH:6]=[C:5](C)[C:3]=1[NH2:4].[Li]CCCC.[Br:16][CH2:17][CH2:18][CH2:19]Br>O1CCOCC1.CCCCCC.CC(C)=O.CCCCCC>[Br:16][CH2:17][CH2:18][CH2:19][NH:4][C:3]1[CH:2]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: BrCCCBr
Reactant: Cc1cc(C)c(N)c(C)c1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1COCCO1
Solvent: CC(C)=O
Product: BrCCCNc1ccccc1
Temperature: 25 °C
Reaction time: 42 h
Yield: 22 %

Procedure:
To a stirred ice-cold solution of 2,4,6-trimethylaniline (13.5 g, 100 mmol) in dioxane (50 mL) under argon was added 1.2 equivalents of 1.6 M n-BuLi in hexane drop-wise. The brown mixture was allowed to warm up to room temperature during 1 h. At the end 50 mL (approx. 5 equiv.) of 1,3-dibromopropane was added in one lot and stirred for 42 h. Precipitated LiBr was filtered and the volatiles were removed in vacuo. The residue was partitioned between ethyl acetate (300 mL) and water (3×100 mL). The organic layer was dried (Na2SO4) and evaporated to give the crude product whose purity by LC-MS analysis was 61%. Silica gel chromatography of the crude product with acetone/hexane (1:9) as eluent gave pure bromopropyl aniline (3.3 g) and an impure fraction which upon crystallization from ethyl acetate hexane gave an additional 2.4 g. (22% yield). LC/MS: tR=1.2 min; [M+H]=256, 258 (bromine pattern), 1H NMR (CD3OD) δ 7.07 (2 H, s), 3.59 (2 H, t, Jvic=6.4 Hz), 3.51 (2 H, t, Jvic=8.1 Hz), 2.46 (6 H, s), 2.45-2.38 (2 H, m), 2.30 (3 H, s).
Reaction SMILES: C([O:3][C:4](=[O:41])[CH2:5][CH2:6][NH:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=1[C:15](=[O:40])[N:16]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]([CH3:39])([CH3:38])[CH3:37])=[CH:32][CH:31]=1)[CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=1)C.[OH-].[Na+]>CCO>[C:36]([C:33]1[CH:34]=[CH:35][C:30]([CH2:29][N:16]([CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:27])([F:28])[F:26])[CH:20]=2)[C:15]([C:9]2[CH:10]=[C:11]([Cl:14])[CH:12]=[CH:13][C:8]=2[NH:7][CH2:6][CH2:5][C:4]([OH:41])=[O:3])=[O:40])=[CH:31][CH:32]=1)([CH3:39])([CH3:37])[CH3:38]
Reactant: CCOC(=O)CCNc1ccc(Cl)cc1C(=O)N(CCc1cccc(C(F)(F)F)c1)Cc1ccc(C(C)(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)c1ccc(CN(CCc2cccc(C(F)(F)F)c2)C(=O)c2cc(Cl)ccc2NCCC(=O)O)cc1
Yield: 99.3 %

Procedure:
A solution of 150 mg (0.31 mmol) of 2-amino-N-(4-tert-butyl-benzyl)-5-chloro-N-[2-(3-trifluoromethyl-phenyl)-ethyl]-benzamide and 76 mg (0.46 mmol) of formylpropionic acid ethylester (prepared by stirring 3,3-diethoxypropionic acid ethylester at RT with 1N—HCl followed by extraction with diethylether and concentration in vacuo) in 3 ml EtOH was refluxed for two hours. The reaction mixture was cooled down to RT and reacted with 17 mg (0.46 mmol) of sodium borohydride. After 5 min at RT and 30 min under reflux additional 9 mg (0.29 mmol) of sodium borohydride were added followed by 5 min at RT and 30 min under reflux. The reaction mixture was then concentrated, treated with diethylether and 2 drops 1N—HCl, and extracted twice with ethylacetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (silica gel; heptane/EtOAc 90:10 to 50:50) to give 53 mg (28%) of 3-(2-{(4-tert-butyl-benzyl)-[2-(3-trifluoromethyl-phenyl)-ethyl]-carbamoyl}-4-chloro-phenylamino)-propionic acid ethyl ester as a light yellow viscous oil [MS (ISP) 489.4 (M+H)+] and 12 mg (7%) of N-(4-tert-butyl-benzyl)-5-chloro-2-(3-hydroxy-propylamino)-N-[2-(3-trifluoromethyl-phenyl)-ethyl]-benzamide as light yellow amorphous solid [MS (ISP) 547.4 (M+H)+]. A solution of 42 mg (0.07 mmol) of 3-(2-{(4-tert-butyl-benzyl)-[2-(3-trifluoromethyl-phenyl)-ethyl]-carbamoyl}-4-chloro-phenylamino)-propionic acid ethyl ester in 1 ml EtOH and 0.14 ml 1N-NaOH was stirred at 50° C. for 17 hours. The reaction mixture was concentrated in vacuo, treated with water and the pH was adjusted to 3 with 1N—HCl. The mixture was extracted twice with diethylether, washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo to give 39 mg (93%) of 3-(2-{(4-tert-butyl-benzyl)-[2-(3-trifluoromethyl-phenyl)-ethyl]-carbamoyl}-4-chloro-phenylamino)-propionic acid as an off-white foam. MS (ISP) 561.5 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[OH:12].[Cl:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][N:22]=1)[C:17](O)=[O:18].CCN=C=NCCCN(C)C>N1C=CC=CC=1>[Cl:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][N:22]=1)[C:17]([NH:1][C:2]1[CH:7]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:5]=[CH:4][C:3]=1[OH:12])=[O:18]
Reactant: Nc1cc(C(F)(F)F)ccc1O
Reactant: O=C(O)c1ccnc(Cl)c1
Agent: CCN=C=NCCCN(C)C
Solvent: c1ccncc1
Product: O=C(Nc1cc(C(F)(F)F)ccc1O)c1ccnc(Cl)c1
Temperature: 60 °C
Yield: 60.8 %

Procedure:
To a mixture of 0.71 g of 2-amino-4-(trifluoromethyl)phenol, 0.63 g of 2-chloroisonicotinic acid and 7 ml of pyridine, 1.05 g of WSC was added and stirred while heating at 60° C. for four hours. The reaction mixture was cooled to room temperature, and then concentrated under reduced pressure. Water was added to the residue, followed by extraction with ethyl acetate twice. The combined organic layers were washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.77 g of 2-chloro-N-[2-hydroxy-5-(trifluoromethyl)phenyl]isonicotinamide.
Reaction SMILES: [I-:1].[Na+].Cl[CH2:4][S:5][C:6]1[N:11]=[CH:10][C:9]([Cl:12])=[CH:8][N:7]=1>CC(C)=O>[I:1][CH2:4][S:5][C:6]1[N:11]=[CH:10][C:9]([Cl:12])=[CH:8][N:7]=1
Reactant: [I-]
Reactant: ClCSc1ncc(Cl)cn1
Agent: [Na+]
Solvent: CC(C)=O
Product: Clc1cnc(SCI)nc1
Yield: 86 %

Procedure:
Sodium iodide (30 mmol) was added to a solution of 2-chloromethylthio-5-chloropyrimidine (6.7 mmol) in acetone (30 ml) and the mixture heated under reflux for 4 h. The precipitated sodium chloride was removed by filtration, the filtrate evaporated to dryness, the residue triturated with water and recrystallized from ethanol; yield 86%, m.p. 67° C. 1H NMR (CDCl3): δ4.82 (SCH2), 8.67 (H-4, H-6).
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([Cl:11])[N:5]=[C:4]([S:12][CH3:13])[N:3]=1.O.O.Cl[Sn]Cl>CCO>[Cl:1][C:2]1[C:7]([NH2:8])=[C:6]([Cl:11])[N:5]=[C:4]([S:12][CH3:13])[N:3]=1
Reactant: CSc1nc(Cl)c([N+](=O)[O-])c(Cl)n1
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: CSc1nc(Cl)c(N)c(Cl)n1
Temperature: 90 °C
Reaction time: 2 h
Yield: 81.9 %

Procedure:
To a solution of 4,6-dichloro-2-methylsulfanyl-5-nitro-pyrimidine (1.0 g, 4.2 mmol) in EtOH (20 mL) was added SnCl2.2H2O (3.8 g, 17 mmol). The mixture was heated to 90° C. After 2 h, the reaction mixture was cooled and the solution was concentrated. The residue was treated with saturated (satd.) aqueous (aq.) NaHCO3 until pH 8. The resulting mixture was then extracted with EtOAc (3×100 mL). The combined organic extracts were dried, filtered, and concentrated. The residue was purified by FCC to afford a colorless solid (723 mg, 87%). MS (ESI): mass calcd. for C5H5Cl2N3S, 208.9; m/z found, 210.3 [M+H]+. 1H NMR ((CD3)2SO): 5.89 (s, 2H), 2.45 (s, 3H).
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[C:7]([C:9]#[N:10])[CH:6]=[CH:5][N:4]=1)[NH2:2].[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18](=O)[CH2:19][C:20](OCC)=[O:21]>>[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]1[CH:19]=[C:20]([OH:21])[N:1]([C:3]2[CH:8]=[C:7]([C:9]#[N:10])[CH:6]=[CH:5][N:4]=2)[N:2]=1
Reactant: N#Cc1ccnc(NN)c1
Reactant: CCOC(=O)CC(=O)c1ccccc1Cl
Product: N#Cc1ccnc(-n2nc(-c3ccccc3Cl)cc2O)c1
Yield: 75 %

Procedure:
The title compound was prepared in 75% yield from 2-hydrazinylpyridine-4-carbonitrile (PREPARATION 2) and ethyl 3-(2-chlorophenyl)-3-oxopropanoate according to the procedure for the preparation of Example 3, part A. [M+H] Calc'd for C15H9ClN4O 297; Found, 297.
Reaction SMILES: CC1(C)[O:7][CH2:6][C:5]([NH:26]C(=O)OC(C)(C)C)([CH2:8][N:9]2[C:17]3[C:12](=[CH:13][C:14]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:15][CH:16]=3)[CH2:11][CH2:10]2)[CH2:4][O:3]1.CC1(C)OCC(NC(=O)OC(C)(C)C)(CNC2C=CC(CCCCCCCC)=CC=2)CO1>>[NH2:26][C:5]([CH2:8][N:9]1[C:17]2[C:12](=[CH:13][C:14]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:15][CH:16]=2)[CH2:11][CH2:10]1)([CH2:6][OH:7])[CH2:4][OH:3]
Reactant: CCCCCCCCc1ccc2c(c1)CCN2CC1(NC(=O)OC(C)(C)C)COC(C)(C)OC1
Agent: CCCCCCCCc1ccc(NCC2(NC(=O)OC(C)(C)C)COC(C)(C)OC2)cc1
Product: CCCCCCCCc1ccc2c(c1)CCN2CC(N)(CO)CO
Yield: 71 %

Procedure:
When the product of Step D was substituted for tert-butyl 2,2-dimethyl-5-((4-octylphenylamino)methyl)-1,3-dioxan-5-ylcarbamate in Example 1, Step B, the identical process afforded the title compound in 71% yield., as colourless solid. 1H-NMR (CDCl3) 0.86 (tr, 3H, J=6.84 Hz); 1.26 (m, 10H); 1.52 (m, 2H); 2.17 (broad s, 4H); 2.47 (tr, 2H, J=7.92 Hz); 2.94 (tr, 2H, J=8.1 Hz); 3.04 (s, 2H); 3.42 (tr, 2H, J=8.1 Hz); 3.58 (s, 4H); 6.53 (d, 1H, J=7.92 Hz); 6.87 (d, 1H, J=7.92 Hz); 6.91 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C@@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C@@H:13]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[CH3:14])[CH:7]=1.[CH2:23]([O:25][C:26]([C:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[NH:30][CH:29]=1)=[O:27])[CH3:24].[O-]P([O-])([O-])=O.[K+].[K+].[K+].CN[C@H]1CCCC[C@@H]1NC>C1(C)C=CC=CC=1.[Cu](I)I>[CH2:23]([O:25][C:26]([C:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[N:30]([C:2]2[CH:3]=[N:4][CH:5]=[C:6]([C@@H:8]3[CH2:12][CH2:11][CH2:10][N:9]3[C@@H:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[CH3:14])[CH:7]=2)[CH:29]=1)=[O:27])[CH3:24]
Reactant: CCOC(=O)c1c[nH]c2ccccc12
Reactant: COc1ccc([C@@H](C)N2CCC[C@H]2c2cncc(Br)c2)cc1
Agent: I[Cu]I
Agent: CN[C@H]1CCCC[C@@H]1NC
Agent: O=P([O-])([O-])[O-]
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cn(-c2cncc([C@@H]3CCCN3[C@H](C)c3ccc(OC)cc3)c2)c2ccccc12
Temperature: 110 °C
Yield: 77.4 %

Procedure:
To a suspension of 3-bromo-5-{(S)-1-[(R)-1-(4-methoxy-phenyl)-ethyl]-pyrrolidin-2-yl}-pyridine (2.0 g, 5.5 mmol), 1H-Indole-3-carboxylic acid ethyl ester (1.3 g, 6.6 mmol), copper iodide (0.11 g, 0.55 mmol), K3PO4 (2.5 g, 11.6 mmol) in toluene (5 mL) was added (1S,2S)—N1,N2-dimethylcyclohexane-1,2-diamine (0.16 g, 1.1 mmol). After being flushed with N2, the resulting mixture was heated at 110° C. overnight, cooled to room temperature, filtered through celite and concentrated under reduced pressure to give an oil. This oil was purified by silica gel column chromatography using 30-50% EtOAc/heptane to give the titled compound as a light yellow foam (2.0 g, 77%).
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[Br:9]Br.O>ClCCCC>[Br:9][CH2:5][C:3](=[O:4])[CH2:2][C:1]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)CC(C)=O
Reactant: BrBr
Solvent: CCCCCl
Solvent: O
Product: COC(=O)CC(=O)CBr
Temperature: 0 °C
Reaction time: 8 h
Yield: 110.2 %

Procedure:
22.7 kg of methyl acetoacetate was dissolved in 113.3 kg of 1-chlorobutane and cooled to 0° C. To this mixture was added dropwise 31.4 kg of bromine at 5° C. over 2 hours, and the mixture was thereafter kept at that temperature for 8 hours. The reaction mixture was cooled to −10° C. and added dropwise to 22.7 kg of water at a temperature 10° C. or less in 2 hours, then washed and separated to give an organic layer. The obtained organic layers were concentrated under reduced pressure at a temperature of 40° C. or less to give 42.0 kg of crude methyl 4-bromoacetoacetate. The gas chromatography analysis indicated that the content of methyl 4-bromoacetoacetate in the crude product was 65.3% (27.4 kg, 72% yield), wherein the content of 1-chlorobutane was 19.7%.
Reaction SMILES: [CH:1]1[C:18]2[C:17]3[C:16]4[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=4[CH:10]=[CH:9][C:8]=3[CH:7]=[C:6](B(O)O)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Br:22][C:23]1[CH:24]=[C:25](I)[CH:26]=[CH:27][CH:28]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.C1(C)C=CC=CC=1>[Br:22][C:23]1[CH:24]=[C:25]([C:3]2[CH:2]=[CH:1][C:18]3[C:17]4[C:16]5[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=5[CH:10]=[CH:9][C:8]=4[CH:7]=[CH:6][C:5]=3[CH:4]=2)[CH:26]=[CH:27][CH:28]=1
Reactant: Brc1cccc(I)c1
Reactant: OB(O)c1cc2ccc3ccccc3c2c2ccccc12
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: [Na+]
Solvent: Cc1ccccc1
Product: Brc1cccc(-c2ccc3c(ccc4ccc5ccccc5c43)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.9 %

Procedure:
Under an argon atmosphere, 3.26 g of the benzo[c]phenanthrene-5-boronic acid obtained, 2.83 g of 3-bromoiodobenzene, 0.231 g of tetrakis(triphenylphosphine)palladium(0), 40 mL of toluene and 20 mL of a 2M aqueous solution of sodium carbonate were placed in a flask. The resultant was refluxed with stirring for 8 hours. After cooling to room temperature, the reaction solution was extracted with toluene. An aqueous phase was removed and an organic phase which had been separated was washed with water and saturated brine sequentially, and then dried with magnesium sulfate. After the magnesium sulfate was filtered out, the organic phase was concentrated. The resulting residue was purified by means of silica gel column chromatography, whereby 3.64 g (yield: 95%) of 10-(3-bromophenyl)benzo[c]phenanthrene was obtained.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:8][O:9][C:10]=2[C:11]([F:14])([F:13])[F:12])[N:3]=[CH:2]1.F[C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=1>>[N+:28]([C:25]1[CH:26]=[CH:27][C:22]([N:1]2[CH:5]=[C:4]([C:6]3[C:7]([C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=4)=[N:8][O:9][C:10]=3[C:11]([F:14])([F:12])[F:13])[N:3]=[CH:2]2)=[CH:23][CH:24]=1)([O-:30])=[O:29]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: FC(F)(F)c1onc(-c2ccccc2)c1-c1c[nH]cn1
Product: O=[N+]([O-])c1ccc(-n2cnc(-c3c(-c4ccccc4)noc3C(F)(F)F)c2)cc1
Yield: 12 %

Procedure:
As described for Example 3, 4-(1H-imidazol-4-yl)-3-phenyl-5-trifluoromethyl-isoxazole (70 mg, 0.25 mmol) was converted, using 4-fluoronitrobenzene instead of 4-fluoroacetophenone, to the title compound (12 mg, 12%) which was obtained as a yellow solid. MS: m/e=401.0 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](Cl)=[O:5])[CH3:2].[NH2:7][CH:8]([C:13]([NH2:15])=[O:14])[CH2:9][CH2:10][S:11][CH3:12].[OH-].[Na+]>O>[CH2:1]([O:3][C:4]([NH:7][CH:8]([C:13]([NH2:15])=[O:14])[CH2:9][CH2:10][S:11][CH3:12])=[O:5])[CH3:2]
Reactant: CCOC(=O)Cl
Reactant: CSCCC(N)C(N)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCOC(=O)NC(CCSC)C(N)=O
Temperature: 2.5 °C
Yield: 57.4 %

Procedure:
106 ml (1.10 moles) ethylchloroformate were dripped into a solution of 150 g (1.02 moles) DL-methionine amide in 200 ml water at 5-10° C., during which the pH was maintained at 7-9 by adding sodium hydroxide solution. A thick, finely crystalline precipitate rapidly formed. A suspension which was just able to still be agitated was obtained by the addition of 800 ml water, which suspension was agitated 3 hours further at room temperature. Then the colorless crystals were filtered off, washed with water and recrystallized out of 900 ml water. After cooling to 0-5° C., filtering off, washing with water and drying, 129 g (57%) Nαethoxycarbonyl-DL-methionine amide with a melting point of 110-112° C. was obtained.
Reaction SMILES: [CH:1]1([CH2:6][C:7]([OH:9])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH3:11][O:12][C:13](=[O:17])[C@H:14]([CH3:16])[NH2:15]>>[CH3:11][O:12][C:13](=[O:17])[C@H:14]([CH3:16])[NH:15][C:7](=[O:9])[CH2:6][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)CC1CCCC1
Reactant: COC(=O)[C@H](C)N
Agent: Cl
Product: COC(=O)[C@H](C)NC(=O)CC1CCCC1

Procedure:
Following General Procedure BD above, and using cyclopentylacetic acid (Aldrich) with L-alanine methyl ester hydrochloride (Sigma) the title compound was prepared.
Reaction SMILES: [C:1]([C:4]1[C:12](=[O:13])[N:11]2[C:7]([S:8][C:9]3[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:10]=32)=[N:6][CH:5]=1)([OH:3])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:33][C:34]1[NH:38][N:37]=[N:36][N:35]=1>CC(N(C)C)=O>[NH:35]1[C:34]([NH:33][C:1]([C:4]2[C:12](=[O:13])[N:11]3[C:7]([S:8][C:9]4[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:10]=43)=[N:6][CH:5]=2)=[O:3])=[N:38][N:37]=[N:36]1
Reactant: Nc1nnn[nH]1
Reactant: O=C(O)c1cnc2sc3ccc([N+](=O)[O-])cc3n2c1=O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CC(=O)N(C)C
Product: O=C(Nc1nnn[nH]1)c1cnc2sc3ccc([N+](=O)[O-])cc3n2c1=O

Procedure:
3-Carboxy-7-nitro-4-oxo-4H-pyrimido[2,1-b]benzothiazole (1.34 g.) and 827 mg. of 1,1'-carbonyldiimidazole are added to 60 ml. of dimethylacetamide, and the suspension heated on a steam bath for 15 min. To the resulting solution is added 434 mg. of 5-aminotetrazole and the heating continued for 20 min. The suspension is cooled and filtered. The desired product can be further purified by recrystallization from dimethylformamide.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([C:9]1[C:10]([NH2:26])=[N:11][C:12]([C:21]2[O:22][CH:23]=[CH:24][CH:25]=2)=[C:13]([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)[N:14]=1)#[CH:8]>CN1CCCC1=O>[O:22]1[CH:23]=[CH:24][CH:25]=[C:21]1[C:12]1[N:11]=[C:10]2[NH:26][CH:8]=[CH:7][C:9]2=[N:14][C:13]=1[C:15]1[CH:16]=[CH:17][N:18]=[CH:19][CH:20]=1
Reactant: C#Cc1nc(-c2ccncc2)c(-c2ccco2)nc1N
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: c1coc(-c2nc3[nH]ccc3nc2-c2ccncc2)c1
Yield: 40.1 %

Procedure:
A mixture of potassium t-butoxide (45 mg, 0.40 mmol) in N-methylpyrrolidone (1 mL) was stirred under nitrogen and a solution of 3-ethynyl-6-(2-furyl)-5-pyridin-4-ylpyrazin-2-amine (Example 65, 50 mg, 0.19 mmol) in N-methylpyrrolidone (1 mL) was added. The mixture was stirred at room temperature overnight, partitioned between water and ethyl acetate, the aqueous phase was extracted twice with ethyl acetate, the organic extracts washed with water and brine, dried (MgSO4) and concentrated under vacuum. Silica gel flash column chromatography (dichloromethane/methanol 95:5) gave the title compound as a yellow solid (20 mg, 40%).