Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[O:15][C:14](S)=[N:13][N:12]=3)[CH:9]=2)[CH:4]=[CH:3]1.[N:17]12[CH2:25][CH2:24][CH:21]([CH2:22][CH2:23]1)[NH:20][CH2:19][CH2:18]2.[OH-].[Na+].[C:28]([OH:35])(=[O:34])/[CH:29]=[CH:30]/[C:31]([OH:33])=[O:32]>CO.C(OCC)C.C(O)CC>[C:28]([OH:35])(=[O:34])/[CH:29]=[CH:30]/[C:31]([OH:33])=[O:32].[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[O:15][C:14]([N:20]4[CH:21]5[CH2:24][CH2:25][N:17]([CH2:23][CH2:22]5)[CH2:18][CH2:19]4)=[N:13][N:12]=3)[CH:9]=2)[CH:4]=[CH:3]1
Reactant: Cn1ccc2ccc(-c3nnc(S)o3)cc21
Reactant: C1CN2CCC(CC2)N1
Agent: O=C(O)/C=C/C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCCO
Solvent: CO
Solvent: CCOCC
Product: Cn1ccc2ccc(-c3nnc(N4CCN5CCC4CC5)o3)cc21
Temperature: 130 °C
Reaction time: 15 h
Yield: 29 %

Procedure:
A mixture of 5-(1-methyl-1H-indol-6-yl)[1,3,4]oxadiazole-2-thiol (1.25 g, 5.41 mmol), 1,4-Diazabicyclo[3.2.2]nonane (0.69 g, 5.41 mmol) and 1-propanol (5 ml) was stirred at 130° C. for 15 h. The reaction-mixture was allowed to cool to room-temperature. Aqueous sodium hydroxide (1 M) was added and the mixture was extracted twice with chloroform. The mixture was extracted twice with aqueous hydrochloric acid. The aqueous phase was washed with chloroform and was made alkaline by adding sodium hydroxide (4 M), followed by extraction three times with chloroform. The free base was isolated as a brown oil. Yield 500 mg (29%) The corresponding salt was obtained by addition of a diethyl ether and methanol mixture (9:1) saturated with fumaric acid. Yield 250 mg (36%). LC-ESI-HRMS of [M+H]+ shows 324.1823 Da. Calc. 324.182435 Da, dev. −0.4 ppm.
Reaction SMILES: [Na].[C:2]([O:10][CH2:11][CH3:12])(=[O:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:13]([O:17][C:18]([NH:20][CH2:21][CH2:22][CH2:23][CH2:24]Cl)=[O:19])([CH3:16])([CH3:15])[CH3:14].CCOC(C)=O.O>C(O)C>[CH2:11]([O:10][C:2](=[O:9])[CH:3]([N:20]([CH2:21][CH2:22][CH2:23][CH3:24])[C:18]([O:17][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:19])[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH3:12]
Reactant: CC(C)(C)OC(=O)NCCCCCl
Reactant: CCOC(=O)CC(=O)OCC
Agent: [Na]
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: CCCCN(C(=O)OC(C)(C)C)C(C(=O)OCC)C(=O)OCC
Temperature: 60 °C
Reaction time: 6 h

Procedure:
Metallic sodium (0.28 g, 0.012 mol) is dissolved in absolute ethyl alcohol (EtOH) (9 ml) under nitrogen atmosphere. The mixture is heated to 60° C. and diethyl malonate (3.8 g, 0.024 mol) is then dripped therein. N-tert-butoxycarbonyl-4-chloro-butylamine (2.5 g, 0.012 mol) is then gradually added, at room temperature, to the resulting solution. The reaction mixture is stirred at room temperature for 2 hours and at the reflux temperature for 6 hours, and then poured into a mixture AcOEt/water (100 ml 1/1 v/v). The organic phase which is separated is then washed repeatedly with water and dried over MgSO4.
Reaction SMILES: C(NC(C)C)(C)C.[Li].C[Li].C(OCC)C.C(NC(C)C)(C)C.[S:23]([NH:33][C@@H:34]1[CH2:39][O:38][C:36](=[O:37])[CH2:35]1)([C:26]1[CH:32]=[CH:31][C:29]([CH3:30])=[CH:28][CH:27]=1)(=[O:25])=[O:24].[CH2:40](Br)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>C1COCC1>[CH2:40]([C@H:35]1[C@H:34]([NH:33][S:23]([C:26]2[CH:27]=[CH:28][C:29]([CH3:30])=[CH:31][CH:32]=2)(=[O:25])=[O:24])[CH2:39][O:38][C:36]1=[O:37])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: BrCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)N[C@@H]2COC(=O)C2)cc1
Agent: [Li]
Agent: [Li]C
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1ccc(S(=O)(=O)N[C@@H]2COC(=O)[C@H]2Cc2ccccc2)cc1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
A solution of lithium diisopropylamine (LDA) in THF was generated by adding 1.5 M methyllithium in diethyl ether (30 mL, 45.0 mmol) to a solution of diisopropylamine (6.4 mL, 45.7 mmol) in 100 mL THF at 0° C. under nitrogen and stirring for 10 min. The solution was then cooled to -78° C., and a solution of (3S)-3-(tosylamino)butano-4-lactone (5.36 g, 21.1 mmol) in 30 mL THF was added dropwise. The resulting yellow solution was stirred for 1 hour at -78° C., and then benzyl bromide (10 mL, 84.1 mmol) was added rapidly. Stirring at -78° C. was continued for 2 hours, and the reaction was quenched with 20 mL sat. aq. NH4Cl solution and allowed to warm to room temperature. The mixture was acidified with 1 M HCl and extracted three times with methylene chloride. The combined organic extracts were dried over Na2SO4 and evaporated to give an orange semisolid that was purified by chromatography (silica gel, hexane/ethyl acetate 3:2) to yield 2.22 g (8.70 mmol, 41%) recovered starting material and 3.37 g (9.76 mmol; 46%) of 4. No diastereomeric addition product could be detected. For further purification 4 can be recrystallized from toluene to give colorless needles. mp. 108.5-109° C., 1H-NMR (300 MHz, CDCl3) δ 7.58 (d, J=8.5 Hz, 2 H), 7.31 (d, J=8.2 Hz, 2 H), 7.20 (m, 3 H), 6.92 (dd, J=7.7, 1.7 Hz, 2H), 4.97 (d, J=5.5 Hz, 1 H), 4.27 (dd, J=7.2, 9.8 Hz, 1 H), 3.98 (dd, J=7.2, 9.8 Hz, 1 H), 3.65 (m, 1 H), 3.00 (m, 1 H), 2.77 (m, 2 H), 2.46 (s, 3 H), 13C-NMR (75.5 MHz, CDCl3) δ 144.27 (C), 138.00 (C), 135.83 (C), 129.89 (CH), 128.97 (CH), 128.88 (CH), 127.10 (CH) 71.25 (CH2) 53.21 (CH), 46.54 (CH), 33.54 (CH2) 21.50 (CH3), EI MS m/e 345.1027 calc. for C18H19NO4S 345.1035. ##STR19##
Reaction SMILES: C([O:3][C:4](=[O:20])[C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]([OH:17])=O)=[CH:9][CH:8]=1)C.[CH3:21][CH:22]([NH2:26])[CH2:23][CH2:24][CH3:25].C(O[C@@H](CC1C=CC(O[C@@H](C(=O)NCCC2C=CC(OC3C=CC=CC=3)=CC=2)C)=CC=1)C(O)=O)C>>[CH3:19][O:18][C@@H:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][C:15](=[O:17])[NH:26][CH:22]([CH3:21])[CH2:23][CH2:24][CH3:25])=[CH:11][CH:12]=1)[C:4]([OH:3])=[O:20]
Reactant: CCCC(C)N
Reactant: CCOC(=O)[C@H](Cc1ccc(OCC(=O)O)cc1)OC
Agent: CCO[C@@H](Cc1ccc(O[C@H](C)C(=O)NCCc2ccc(Oc3ccccc3)cc2)cc1)C(=O)O
Product: CCCC(C)NC(=O)COc1ccc(C[C@H](OC)C(=O)O)cc1

Procedure:
The title compound was prepared from (2S)-3-(4-carboxymethoxy-phenyl)-2-methoxy-propionic acid ethyl ester (PREPARATION 3, step 2) and 1-methyl-butylamine via the same procedure used for the preparation of (2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionic acid (Example 1, step 3) to produce a colorless oil. MS (ES) for C17H25NO5 [M−H]−: 322.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[NH:11][CH2:12][C:13]1[CH:18]=[C:17]([N+:19]([O-])=O)[CH:16]=[CH:15][C:14]=1[OH:22].CO.[ClH:25]>[Pd]>[ClH:25].[ClH:25].[ClH:25].[OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[NH:11][CH2:12][C:13]1[CH:18]=[C:17]([NH2:19])[CH:16]=[CH:15][C:14]=1[OH:22]
Reactant: O=[N+]([O-])c1ccc(O)c(CNc2cc([N+](=O)[O-])ccc2O)c1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: Nc1ccc(O)c(CNc2cc(N)ccc2O)c1

Procedure:
16 g. of N-(2'-hydroxy-5'-nitrophenyl)-2-hydroxy-5-nitrobenzylamine was dissolved in 150 ml. of methanol. After addition of 2 g. of palladium/C as catalyst, the catalytic reduction was effected for about 3 hours. The precipitated crystals were dissolved in concentrated hydrochloric acid and filtered. The filtrate was concentrated, charged with 100 ml. of an alcohol and heated for 2 hours to obtain the end product in the form of white crystals. The melting point of the end product was 200°-240° C. (decomp.), and the yield was 12 g.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[CH2:13][CH:14]1C(=O)O[C:17](C)([CH3:21])[O:16][C:15]1=[O:23])([O-:3])=[O:2].C(O)C>N1C=CC=CC=1.[Cu]>[N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[CH2:13][CH2:14][C:15]([O:16][CH2:17][CH3:21])=[O:23])([O-:3])=[O:2]
Reactant: CC1(C)OC(=O)C(Cc2c[nH]c3ccc([N+](=O)[O-])cc23)C(=O)O1
Agent: [Cu]
Solvent: CCO
Solvent: c1ccncc1
Product: CCOC(=O)CCc1c[nH]c2ccc([N+](=O)[O-])cc12
Temperature: 25 °C
Reaction time: 66 h
Yield: 89.8 %

Procedure:
To a solution of 5-(5-nitroindol-3-ylmethyl)-2,2-dimethyl-1,3-dioxane-4,6-dione (10.0 g, 0.031 mol) in a mixture of pyridine (80 mL) and absolute ethanol (20 mL) was added 0.1 g of copper powder and the mixture was refluxed under Ar for 2h. After being stirred at room temperature for 66 h the mixture was refluxed for an additional 1 h. The cooled mixture was filtered and the filtrate was evaporated. The resulting residue was triturated with ether and a little CH2Cl2 to give the title compound (7.3 g, 89%) as a solid,
Reaction SMILES: [CH2:1]([C@@H:8]1[NH:13][CH2:12][CH2:11][N:10]([C:14]2[CH:22]=[C:21]3[C:17]([C:18]([CH2:28][CH3:29])=[N:19][N:20]3[CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)=[CH:16][CH:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:30]1[CH:34]=[C:33]([CH2:35][C:36](O)=[O:37])[N:32]=[CH:31]1>>[CH2:1]([C@H:8]1[CH2:9][N:10]([C:14]2[CH:22]=[C:21]3[C:17]([C:18]([CH2:28][CH3:29])=[N:19][N:20]3[CH:23]3[CH2:24][CH2:25][CH2:26][CH2:27]3)=[CH:16][CH:15]=2)[CH2:11][CH2:12][N:13]1[C:36](=[O:37])[CH2:35][C:33]1[N:32]=[CH:31][NH:30][CH:34]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1c[nH]cn1
Reactant: CCc1nn(C2CCCC2)c2cc(N3CCN[C@@H](Cc4ccccc4)C3)ccc12
Product: CCc1nn(C2CCCC2)c2cc(N3CCN(C(=O)Cc4c[nH]cn4)[C@@H](Cc4ccccc4)C3)ccc12
Yield: 50 %

Procedure:
Prepared using the same procedure described in Example 189 from (S)-6-(3-Benzyl-piperazin-1-yl)-1-cyclopentyl-3-ethyl-1H-indazole and (1H-imidazol-4-yl)-acetic acid to afford the title compound as colorless solid (66 mg, 50%). LC/MS (Method B) 2.68 min, [M+1]+ 497.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:9]3[CH:10]=[CH:11][CH:12]=[C:13]([Br:14])[C:8]=3[S:7][C:6]=2[CH:15]=1.[C:16]1([N:22]2[C:34]3[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][C:29]=3[C:28]3[C:23]2=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.C1(P([Pd-4](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)C=CC=CC=1>[Br:14][C:13]1[C:8]2[S:7][C:6]3[CH:15]=[C:2]([C:31]4[CH:32]=[CH:33][C:34]5[N:22]([C:16]6[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=6)[C:23]6[C:28]([C:29]=5[CH:30]=4)=[CH:27][CH:26]=[CH:25][CH:24]=6)[CH:3]=[CH:4][C:5]=3[C:9]=2[CH:10]=[CH:11][CH:12]=1
Reactant: Brc1ccc2c(c1)sc1c(Br)cccc12
Reactant: OB(O)c1ccc2c(c1)c1ccccc1n2-c1ccccc1
Agent: c1ccc([PH](c2ccccc2)(c2ccccc2)[Pd-4]([PH](c2ccccc2)(c2ccccc2)c2ccccc2)([PH](c2ccccc2)(c2ccccc2)c2ccccc2)[PH](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Brc1cccc2c1sc1cc(-c3ccc4c(c3)c3ccccc3n4-c3ccccc3)ccc12

Procedure:
2.47 g (8.1 mmol) of tetrakistriphenylphosphinopalladium(0) are added to a vigorously stirred suspension of 6.8 g (20 mmol) of 3,6-dibromodibenzothiophene, 15 g (40 mmol) of 9-phenyl-9H-carbazole-3-boronic acid and 63.9 g (127 mmol) of Na2CO3 in 500 ml of DMF, and the mixture is subsequently heated under reflux for 16 h. After cooling, the precipitated solid is filtered off with suction, washed three times with 50 ml of toluene, three times with 50 ml of ethanol:water (1:1, v:v) and three times with 100 ml of ethanol and recrystallised three times from DMF (about 15 ml/g). Yield 17.4 g (33 mmol), 86.0%, purity 99.9% (HPLC).
Reaction SMILES: C([Li])(C)(C)C.BrC1C(C)=CC(C)=CC=1C.[CH3:16][O:17][C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1.[Cl:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][C:29](=[O:34])[C:28]2=[O:35]>CCCCC.C1COCC1>[Cl:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][C:29](=[O:34])[C:28]2([OH:35])[C:19]1[C:18]([O:17][CH3:16])=[CH:23][CH:22]=[CH:21][N:20]=1
Reactant: COc1cccnc1
Reactant: O=C1Nc2ccc(Cl)cc2C1=O
Agent: Cc1cc(C)c(Br)c(C)c1
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: C1CCOC1
Product: COc1cccnc1C1(O)C(=O)Nc2ccc(Cl)cc21
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A 1.7 M solution of tert-butyllithium in pentane (57.8 mL) was added to THF (200 ml) at −78° C. 2-Bromomesitylene (3.6 mL) was added dropwise, keeping the temperature below −60° C., and the mixture stirred at −78° C. for 1 h. 3-Methoxypyridine (3.6 mL) was added dropwise at −78° C. and then the mixture was stirred between −30° C. and −20° C. The reaction mixture was re-cooled to −78° C. and a slurry of 5-chloroisatin (3.26 g) in THF (100 mL) was added portionwise, keeping the temperature below −60° C. The reaction mixture was stirred at −78° C. for 1 h. The cooling bath was removed and the reaction mixture was stirred for 30 min. The reaction mixture was quenched with 10% aqueous ammonium chloride solution and extracted several times with ethyl acetate. The combined organic layers were washed with water, dried over magnesium sulfate and evaporated to low volume. Upon standing, 1.05 g of a cream-colored solid separated which was filtered off, washed with ethyl acetate and dried in vacuo.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[C:9]1[CH:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][N:19]=[C:18]3[CH:22]=[N:23][N:24]([CH:25]4[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]4)[C:17]=23)[CH:12]=[CH:11][N:10]=1.C(N(CC)CC)C.[S:38](Cl)([CH3:41])(=[O:40])=[O:39]>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[C:9]1[CH:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][N:19]=[C:18]3[CH:22]=[N:23][N:24]([CH:25]4[CH2:26][CH2:27][N:28]([S:38]([CH3:41])(=[O:40])=[O:39])[CH2:29][CH2:30]4)[C:17]=23)[CH:12]=[CH:11][N:10]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ccc(F)c(-c2cc(Nc3ccnc4cnn(C5CCNCC5)c34)ccn2)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(F)c(-c2cc(Nc3ccnc4cnn(C5CCN(S(C)(=O)=O)CC5)c34)ccn2)c1
Temperature: 25 °C
Yield: 19.8 %

Procedure:
N-(2-(2-Fluoro-5-methylphenyl)pyridin-4-yl)-1-(piperidin-4-yl)-1H-pyrazolo[4,3-b]pyridin-7-amine (17 mg, 0.042 mmol) and triethylamine (0.018 ml, 0.127 mmol) were combined in dichloromethane (3 mL) and cool in an ice bath. Mesyl chloride (3.61 μl, 0.046 mmol) was added and the reaction was briefly warmed to room temperature. The reaction mixture was concentrated and purified by silica column chromatography eluting with 0-5% methanol in dichloromethane to give to afford N-(2-(2-fluoro-5-methylphenyl)pyridin-4-yl)-1-(1-(methylsulfonyl)piperidin-4-yl)-1H-pyrazolo[4,3-b]pyridin-7-amine (4 mg, 20%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.93 (d, J=10.61 Hz, 2H) 2.24-2.43 (m, 5H) 2.55-2.69 (m, 2H) 2.76 (s, 3H) 3.84 (d, J=12.63 Hz, 2H) 4.57 (t, J=10.74 Hz, 1H) 6.29 (br. s., 1H) 6.60 (dd, J=5.56, 2.02 Hz, 1H) 6.88-7.09 (m, 1H) 7.09-7.25 (m, 3H) 7.75 (dd, J=7.45, 2.15 Hz, 1H) 8.33 (s, 1H) 8.50 (d, J=5.56 Hz, 1H) 8.56 (d, J=4.55 Hz, 1H). MS [M+H] found 481.4.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]([F:12])([F:11])[F:10])=[CH:4][C:3]=1[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=O.[F:21][C:22]([F:30])([F:29])[C:23](=[O:28])[CH2:24][C:25](=O)[CH3:26]>CCCCCCC.C(OCC)(=O)C>[F:21][C:22]([F:30])([F:29])[C:23]([C:24]1[C:25]([CH3:26])=[N:1][C:2]2[C:3]([C:13]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:4][C:5]([O:8][C:9]([F:12])([F:11])[F:10])=[CH:6][CH:7]=2)=[O:28]
Reactant: Nc1ccc(OC(F)(F)F)cc1C(=O)c1ccccc1
Reactant: CC(=O)CC(=O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: Cc1nc2ccc(OC(F)(F)F)cc2c(-c2ccccc2)c1C(=O)C(F)(F)F
Reaction time: 44 h
Yield: 63 %

Procedure:
The title compound was prepared from (2-Amino-5-trifluoromethoxy-phenyl)-phenyl-methanone [example A6] and 1,1,1-trifluoro-2,4-pentanedione according to the procedure of example 1, except that the reaction time was of 44 h and heptane/ethyl acetate (10:1) was used. Yield: 63%; MS: m/z=399 (M).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:25])[C:5]([CH3:24])=[C:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][C:21](O)=[O:22])=[CH:15][CH:14]=2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10].[CH2:26]([CH2:28][NH2:29])[OH:27]>>[CH3:1][O:2][C:3]1[C:4](=[O:25])[C:5]([CH3:24])=[C:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][C:21]([NH:29][CH2:28][CH2:26][OH:27])=[O:22])=[CH:15][CH:14]=2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(CCC(=O)O)cc2)=C(C)C1=O
Reactant: NCCO
Product: COC1=C(OC)C(=O)C(Cc2ccc(CCC(=O)NCCO)cc2)=C(C)C1=O
Yield: 31 %

Procedure:
3-[4-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)phenyl]propionic acid (200 mg, 0.58 mmol) obtained in Example 1 and ethanolamine (47 mg, 0.75 mmol) were used, and a method similar to that described in Example 3 was employed to obtain the title compound (65 mg, 0.18 mmol, yield 29%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1.[F:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=1[F:28])[C:22](Cl)=[O:23]>N1C=CC=CC=1>[F:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=1[F:28])[C:22]([NH:15][C:14]1[CH:16]=[CH:17][C:11]([C:9]2[N:10]=[C:5]3[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][N:6]3[CH:8]=2)=[CH:12][CH:13]=1)=[O:23]
Reactant: O=C(Cl)c1ccc(F)c(F)c1
Reactant: Cc1ccc2nc(-c3ccc(N)cc3)cn2c1
Solvent: c1ccncc1
Product: Cc1ccc2nc(-c3ccc(NC(=O)c4ccc(F)c(F)c4)cc3)cn2c1
Yield: 68.3 %

Procedure:
Prepared as described in the Amide Coupling section using 4-(6-methylimidazo[1,2-a]pyridin-2-yl)aniline (0.50 g, 2.24 mmol) and 3,4-difluorobenzoyl chloride (0.395 g, 2.24 mmol) in dry pyridine (20 ml) to give the title compound (0.556 g, 68%) as a colourless solid after work-up and recrystallisation from AcOH.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C:19]([CH3:56])([C:21]([NH:23][C@H:24]([C:28]([N:30]([C@@H:32]([C@@H:52]([CH3:55])[CH2:53][CH3:54])[C@H:33]([O:50][CH3:51])[CH2:34][C:35]([N:37]3[CH2:41][CH2:40][CH2:39][C@H:38]3[C@H:42]([O:48][CH3:49])[C@H:43]([C:45](O)=[O:46])[CH3:44])=[O:36])[CH3:31])=[O:29])[CH:25]([CH3:27])[CH3:26])=[O:22])[CH3:20])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:57][C@H:58]1[NH:62][C:61](=[O:63])[NH:60][C@H:59]1[CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][C:69]([NH:71][CH2:72][CH2:73][NH:74][C:75](=[O:85])[C@H:76]([CH2:78][C:79]1[CH:84]=[CH:83][CH:82]=[CH:81][CH:80]=1)[NH2:77])=[O:70].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH:10]1[C:11]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C:19]([CH3:20])([C:21]([NH:23][C@H:24]([C:28]([N:30]([C@@H:32]([C@@H:52]([CH3:55])[CH2:53][CH3:54])[C@H:33]([O:50][CH3:51])[CH2:34][C:35]([N:37]3[CH2:41][CH2:40][CH2:39][C@H:38]3[C@@H:42]([C@@H:43]([CH3:44])[C:45](=[O:46])[NH:77][C@@H:76]([CH2:78][C:79]3[CH:80]=[CH:81][CH:82]=[CH:83][CH:84]=3)[C:75](=[O:85])[NH:74][CH2:73][CH2:72][NH:71][C:69](=[O:70])[CH2:68][CH2:67][CH2:66][CH2:65][CH2:64][C@H:59]3[C@@H:58]([CH3:57])[NH:62][C:61](=[O:63])[NH:60]3)[O:48][CH3:49])=[O:36])[CH3:31])=[O:29])[CH:25]([CH3:27])[CH3:26])=[O:22])[CH3:56])=[O:17])[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)O)OC)N(C)C(=O)[C@@H](NC(=O)C(C)(C)NC(=O)OCC1c2ccccc2-c2ccccc21)C(C)C
Reactant: C[C@H]1NC(=O)N[C@H]1CCCCCC(=O)NCCNC(=O)[C@@H](N)Cc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)C(=O)NCCNC(=O)CCCCC[C@@H]1NC(=O)N[C@@H]1C)OC)N(C)C(=O)[C@@H](NC(=O)C(C)(C)NC(=O)OCC1c2ccccc2-c2ccccc21)C(C)C
Yield: 27.4 %

Procedure:
Following general procedure D using #105 (36.6 mg, 0.047 mmol, 1.0 eq.), #255 (19 mg, 0.047 mmol, 1.0 eq.), HATU (22.4 mg, 0.056 mmol, 1.2 eq.) and Hunig's base (0.025 mL, 0.141 mmol) in 1.5 mL of DMF following by purification (Method J) yielded #256 (15 mg, 27%) as a white solid. LC-MS (Protocol Q1): m/z 1164.8 [M+H+], retention time=0.99 minutes.
Reaction SMILES: BrCCCCC(C)(C1C=CC(C)=CC=1)CO.[Br:17][CH2:18][CH2:19][CH2:20][C:21]([CH3:28])([CH3:27])[C:22](OCC)=[O:23].[Li+].[BH4-].CO>C(Cl)Cl>[Br:17][CH2:18][CH2:19][CH2:20][C:21]([CH3:28])([CH3:27])[CH2:22][OH:23]
Reactant: CCOC(=O)C(C)(C)CCCBr
Agent: Cc1ccc(C(C)(CO)CCCCBr)cc1
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: ClCCl
Product: CC(C)(CO)CCCBr
Yield: 108.1 %

Procedure:
According to the procedure given for the synthesis of 206e, 205a (94.0 g, 0.37 mol) was reduced with LiBH4 (12.97 g, 0.60 mol) and methanol (19.04 g, 0.60 mol) in CH2Cl2 (400 mL) to give 206a (78.0 g, 100%) as an oil. 1H NMR (DMSO-d6): δ 4.42 (s, 1H), 3.45 (t, 2H, J=6.6), 3.08 (s, 2H), 1.84-1.69 (m, 2H), 1.27 (t, 2H, J=8.3), 0.78 (s, 6H). 13C NMR (DMSO-d6): δ 69.7, 36.9, 35.7, 34.5, 27.4, 24.0.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][C:3]=1[C:11]1[C:16]([F:17])=[CH:15][CH:14]=[CH:13][N:12]=1.Br[C:19]1[N:23]2[CH:24]=[CH:25][C:26]([C:28]([F:31])([F:30])[F:29])=[N:27][C:22]2=[N:21][CH:20]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:19]2[N:23]3[CH:24]=[CH:25][C:26]([C:28]([F:29])([F:30])[F:31])=[N:27][C:22]3=[N:21][CH:20]=2)=[CH:4][C:3]=1[C:11]1[C:16]([F:17])=[CH:15][CH:14]=[CH:13][N:12]=1
Reactant: FC(F)(F)c1ccn2c(Br)cnc2n1
Reactant: OB(O)c1ccc(F)c(-c2ncccc2F)c1
Product: Fc1ccc(-c2cnc3nc(C(F)(F)F)ccn23)cc1-c1ncccc1F

Procedure:
4-Fluoro-3-(3-fluoropyridin-2-yl)phenylboronic acid was coupled with 3-bromo-7-trifluoromethylimidazo[1,2-α]pyrimidine by the method of Example 78. Purification by chromatography on silica gel eluting with dichloromethane containing 3.5% methanol and crystallisation from methanol gave 3-[4-fluoro-3-(3-fluoropyridin-2-yl)phenyl]-7-trifluoromethylimidazo[1,2-α]pyrimidine: δH (400 MHz, DMSO) 9.28 (1H, d, J 7), 8.61 (1H, m), 8.31 (1H, s), 7.90-7.99 (3H, m), 7.62 (2H, m), 7.52 (1H, d, J 7); m/z (ES+) 377 (MH+).
Reaction SMILES: [CH:1]1(Br)[CH2:3][CH2:2]1.[Mg].[F:6][C:7]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:8]=1[C:17](=[O:19])[CH3:18]>BrC(Br)C.C(OCC)C>[CH:1]1([C:17]([C:8]2[CH:9]=[CH:10][C:11]([C:13]([F:14])([F:15])[F:16])=[CH:12][C:7]=2[F:6])([OH:19])[CH3:18])[CH2:3][CH2:2]1
Reactant: CC(=O)c1ccc(C(F)(F)F)cc1F
Reactant: BrC1CC1
Agent: CC(Br)Br
Agent: [Mg]
Solvent: CCOCC
Product: CC(O)(c1ccc(C(F)(F)F)cc1F)C1CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A few drops of dibromoethane and then 6.30 g (52.1 mmol) of cyclopropyl bromide, dissolved in 20 ml of diethyl ether, were added under argon to 1.33 g (54.7 mmol) of magnesium in 90 ml of dry diethyl ether. The mixture was heated under reflux for 2 h. After cooling, 21 ml (9.94 mmol) of the supernatant reaction solution were added dropwise under argon to a solution of 850 mg (4.12 mmol) of 1-[2-fluoro-4-(trifluoromethyl)phenyl]ethanone in 17 ml of diethyl ether, and the mixture was stirred at RT overnight. The reaction mixture was added to ice-water, the phases were separated, the aqueous phase was extracted with dichloromethane, and the combined organic phases were dried over magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography on silica gel (mobile phase: toluene/ethyl acetate gradient with addition of 0.1% triethylamine) to result in 157 mg (15% of theory) of a mixture of the diastereomers of the title compound.
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]3[C:15]([C:16]([OH:18])=O)=[CH:14][CH:13]=[CH:12][C:10]=3[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:19][CH:20]1[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]1>>[CH3:26][N:23]1[CH2:24][CH2:25][CH:20]([NH:19][C:16]([C:15]2[C:9]3[O:8][C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[N:11][C:10]=3[CH:12]=[CH:13][CH:14]=2)=[O:18])[CH2:21][CH2:22]1
Reactant: O=C(O)c1cccc2nc(-c3ccccc3)oc12
Reactant: CN1CCC(N)CC1
Product: CN1CCC(NC(=O)c2cccc3nc(-c4ccccc4)oc23)CC1
Yield: 58 %

Procedure:
N-(1-Methylpiperidin-4-yl)-2-phenylbenzoxazole-7-carboxamide was prepared from 2-phenylbenzoxazole-7-carboxylic acid and 4-amino-1-methylpiperidine using the method outlined in Step C of Example 7. This compound was obtained in 58% yield and obtained as a white solid: mp 209-210° C.; 1H NMR (300 MHz, CDCl3) δ 8.22 (m, 1H), 8.21 (dd, J=5.7, 1.8 Hz, 1H), 8.10 (dd, J=8.1, 0.9 Hz, 1H), 7.91 (dd, J=9.9, 1.2 Hz, 1H), 7.64-7.54 (m, 3H), 7.48 (t, J=7.8, 1H), 4.26-4.17 (m, 1H), 2.93 (d, J=11.4 Hz, 2H), 2.46 (s, 3H), 2.30 (t, J=11.1 Hz, 2H), 2.22-2.17 (m, 2H), 1.85-1.73 (m, 2H); MS (ESI) m/z 336 [M+H]+