Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[N:3]=1.[Br:18]Br.CCOCC>C(O)(=O)C>[Br:18][CH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[CH:9]=[CH:10][C:11]([C:14]([F:17])([F:15])[F:16])=[CH:12][CH:13]=2)[N:3]=1
Reactant: Cc1ccnc(-c2ccc(C(F)(F)F)cc2)n1
Reactant: BrBr
Solvent: CC(=O)O
Solvent: CCOCC
Product: FC(F)(F)c1ccc(-c2nccc(CBr)n2)cc1
Temperature: 80 °C
Yield: 82.6 %

Procedure:
A mixture of 4-methyl-2-(4-trifluoromethylphenyl)pyrimidine (3 g) and bromine (2.11 g) in 20 ml of acetic acid was warmed to 80° C. for 1 hour, and then allowed to cool to room temperature. Ether (10 ml) was added, and the precipitate filtered off and washed with ether, giving 3.3 g of 4-bromomethyl-2-(4-trifluoromethylphenyl)pyrimidine, m.p. 125° C.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH2:8][N:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([CH3:19])[N:17]=3)[C:12](=[O:20])[C:11]([C:21](O)=[O:22])=[CH:10]2)[CH:5]=[CH:4][CH:3]=1.[CH3:24][NH:25][O:26][CH3:27].C(N(C(C)C)CC)(C)C.O>ClCCl>[CH3:27][O:26][N:25]([CH3:24])[C:21]([C:11]1[C:12](=[O:20])[C:13]2[C:18](=[N:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[N:9]([CH2:8][C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([Br:1])[N:7]=2)[CH:10]=1)=[O:22]
Reactant: CNOC
Reactant: Cc1ccc2c(=O)c(C(=O)O)cn(Cc3cccc(Br)n3)c2n1
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)c1cn(Cc2cccc(Br)n2)c2nc(C)ccc2c1=O
Yield: 79.5 %

Procedure:
0.667 mL (3.75 mmol, 50% solution in ethyl acetate) of 1-propanephosphonic anhydride solution was added to 0.400 g (1.07 mmol) of 1-(6-Bromo-pyridin-2-ylmethyl)-7-methyl-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic acid, 0.208 g (2.13 mmol) of N,O-dimethylhydroxyl amine, and 0.653 mL (3.75 mmol) of diisopropylethylamine dissolved in 1 mL of dichloromethane. After the reaction was stirred at room temperature for 1 hour water was added and was extracted with dichloromethane (3×25 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product was purified on silica gel eluting with 100% ethyl acetate to yield 0.355 g of 1-(6-Bromo-pyridin-2-ylmethyl)-7-methyl-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic acid methoxy-methyl-amide as a white solid.
Reaction SMILES: C([C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:25])[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:13][C:12]=2[F:26])[CH:7]=[CH:6][N:5]=1)(=O)N.C[N:28](C=O)C>>[NH2:28][C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:25])[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:13][C:12]=2[F:26])[CH:7]=[CH:6][N:5]=1
Reactant: CN(C)C=O
Reactant: CCOC(=O)CC(=O)Nc1ccc(Oc2ccnc(C(N)=O)c2)c(F)c1
Product: CCOC(=O)CC(=O)Nc1ccc(Oc2ccnc(N)c2)c(F)c1
Yield: 86 %

Procedure:
Prepared in a manner similar to that which is described in Step A of Example 91. Ethyl 3-(4-(2-carbamoylpyridin-4-yloxy)-3-fluorophenylamino)-3-oxopropanoate (900 mg, 2.5 mmol) in DMF (10.0 mL) was converted to ethyl 3-(4-(2-aminopyridin-4-yloxy)-3-fluorophenylamino)-3-oxopropanoate (710 mg, 86% yield). MS(ESI+) m/z 334.26 (M+H)+.
Reaction SMILES: [K+].[N:2]1([CH2:8][C:9]([O-:11])=O)[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.FC(F)(F)C(O)=O.[C:19]1([C:25]2[CH:30]=[C:29]([CH:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)[CH:28]=[CH:27][C:26]=2[NH:37][C:38]([C:40]2[NH:41][CH:42]=[C:43]([C:45]#[N:46])[N:44]=2)=[O:39])[CH2:24][CH2:23][CH2:22][CH2:21][CH:20]=1.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:19]1([C:25]2[CH:30]=[C:29]([CH:31]3[CH2:32][CH2:33][N:34]([C:9](=[O:11])[CH2:8][N:2]4[CH2:3][CH2:4][O:5][CH2:6][CH2:7]4)[CH2:35][CH2:36]3)[CH:28]=[CH:27][C:26]=2[NH:37][C:38]([C:40]2[NH:41][CH:42]=[C:43]([C:45]#[N:46])[N:44]=2)=[O:39])[CH2:24][CH2:23][CH2:22][CH2:21][CH:20]=1
Reactant: O=C([O-])CN1CCOCC1
Reactant: N#Cc1c[nH]c(C(=O)Nc2ccc(C3CCNCC3)cc2C2=CCCCC2)n1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: [K+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1c[nH]c(C(=O)Nc2ccc(C3CCN(C(=O)CN4CCOCC4)CC3)cc2C2=CCCCC2)n1
Reaction time: 8 h
Yield: 12.4 %

Procedure:
To a solution of morpholin-4-yl-acetic acid ethyl ester (117 mg, 0.67 mmol) in ethanol (4 mL) was added 6N KOH (110 μL, 0.67 mmol) via syringe and stirring was continued for 3 h. Concentration in vacuo afforded 122 mg (100%) of morpholin-4-yl-acetic acid potassium salt. To a mixture of morpholin-4-yl-acetic acid potassium salt (29 mg, 0.15 mmol), 4-cyano-1H-imidazole-2-carboxylic acid (2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl)-amide trifluoroacetic acid salt (65.1 mg, 0.13 mmol, as prepared in Example 14, step (b)) and PyBroP (93 mg, 0.19 mmol) in CH2Cl2 (4 mL) was added DIEA (51 μL, 0.29 mmol) and the reaction was allowed to stir overnight. The reaction was diluted with CH2Cl2 (50 mL), washed with H2O (2×25 mL), dried (Na2SO4) and concentrated in vacuo. Purification of the crude product by silica gel preparative TLC afforded 8.1 mg (12%) of the title compound as a white solid. 1H-NMR (CDCl3; 400 MHz): δ 1.68-2.04 (m, 5H), 2.20-2.29 (m, 4H), 2.53-2.78 (m, 5H), 3.09-3.23 (m, 6H), 3.35-3.40 (m, 1H), 3.72 (br s, 4H), 4.16-4.22 (m, 1H), 4.73-4.77 (m, 1H), 5.82 (s, 1H), 7.00 (s, 1H), 7.12 (dd, 1H, J=0.6, 8.0 Hz), 7.73 (s, 1 H), 8.27 (d, 1H, J=8.1 Hz), 9.48 (s, 1H); Mass spectrum (ESI, m/z): Calcd. for C28H34N6O3, 503.27 (M+H), found 503.1.
Reaction SMILES: [CH:1]([CH:3]1[O:8][CH2:7][CH2:6][N:5]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:4]1)=O.C1(P(C2C=CC=CC=2)(C2C=CC=CC=2)=[CH:26][C:27]([O:29][CH3:30])=[O:28])C=CC=CC=1>C(Cl)Cl>[CH3:30][O:29][C:27](=[O:28])[CH:26]=[CH:1][CH:3]1[O:8][CH2:7][CH2:6][N:5]([C:9]([O:11][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[O:10])[CH2:4]1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=CC1CN(C(=O)OCc2ccccc2)CCO1
Solvent: ClCCl
Product: COC(=O)C=CC1CN(C(=O)OCc2ccccc2)CCO1
Temperature: 25 °C
Reaction time: 12 h
Yield: 48 %

Procedure:
A mixture of benzyl 2-formylmorpholine-4-carboxylate (1.5 g, 6 mmol) and methyl 2-(triphenylphosphoranylidene)acetate (2.01 g, 6 mmol) in DCM (30 mL) was stirred at 25° C. for 12 hours under N2. The mixture was concentrated in vacuo, and the residue was purified by a silica gel column chromatography (PETROLEUM ETHER/EtOAc (V/V)=3/1) to give the title compound as colorless oil (0.88 g, 48%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [NH2:1][C:2]1[O:3][CH:4]=[CH:5][N:6]=1.[Li]CCCC.CS(O[CH2:17][C@@H:18]1[O:22][C:21](=[O:23])[N:20]([C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH2:31][CH2:32][O:33][CH2:34][CH:35]=3)=[C:26]([F:36])[CH:25]=2)[CH2:19]1)(=O)=O>C1COCC1>[O:3]1[CH:4]=[CH:5][N:6]=[C:2]1[NH:1][CH2:17][C@@H:18]1[O:22][C:21](=[O:23])[N:20]([C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH2:31][CH2:32][O:33][CH2:34][CH:35]=3)=[C:26]([F:36])[CH:25]=2)[CH2:19]1
Reactant: Nc1ncco1
Reactant: CS(=O)(=O)OC[C@H]1CN(c2ccc(C3=CCOCC3)c(F)c2)C(=O)O1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C1O[C@@H](CNc2ncco2)CN1c1ccc(C2=CCOCC2)c(F)c1
Yield: 3.5 %

Procedure:
To a stirred partial solution of 2-aminooxazole (169 mg, 2.0 mmol) in dry THF (10 ml), cooled to −78° C., under argon, was added slowly n-BuLi (1.33M, 1.5 ml, 2.0 mmol), followed after 1 h by 5(R)-methylsulfonyloxymethyl-3-(3-fluoro-4-(3,6-dihydro-(2H)-pyran-4-yl)phenyl)oxazolidin-2-one (see Example 41; 371 mg, 11.0 mol) suspended in dry THF (20 ml). The reaction was allowed to come to room temperature and then refluxed for 24 h. The reaction was quenched with ammonium chloride solution (10% w/v, 30 ml), extracting the mixture with chloroform (3×50 ml). The extracts were dried (magnesium sulfate), concentrated by rotary evaporation chromatographed by MPLC (Merck 9385 silica, 3–10% gradient methanol/dichloromethane eluent) and the pure fractions combined, concentrated and triturated with diethyl ether to give the title compound (25 mg, 4.6%).
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][O:8][C:9]1[C:20]([O:21][CH3:22])=[CH:19][C:12]2[CH2:13][C:14](=[O:18])[NH:15][CH:16]=[CH:17][C:11]=2[CH:10]=1.[CH2:23]([N:30]1[CH2:36][CH2:35][CH2:34][CH2:33][CH:32]([CH2:37]Br)[CH2:31]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CS(C)=O.C(OCC)(=O)C>[CH2:23]([N:30]1[CH2:36][CH2:35][CH2:34][CH2:33][CH:32]([CH2:37][N:15]2[C:14](=[O:18])[CH2:13][C:12]3[CH:19]=[C:20]([O:21][CH3:22])[C:9]([O:8][CH3:7])=[CH:10][C:11]=3[CH:17]=[CH:16]2)[CH2:31]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: BrCC1CCCCN(Cc2ccccc2)C1
Reactant: COc1cc2c(cc1OC)CC(=O)NC=C2
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COc1cc2c(cc1OC)CC(=O)N(CC1CCCCN(Cc3ccccc3)C1)C=C2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2.3 g (0.02 mol) of potassium tert.butoxide are added to a solution of 4.4 g (0.02 mol) of 7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one in 100ml of absolute dimethylsulphoxide. After stirring for 30 minutes at ambient temperature, 5.6 g (0.020 mol) of 1-benzyl-3-bromomethyl-hexahydro-azepine are added and the resulting mixture is stirred for 2 hours at ambient temperature. The reaction mixture is dissolved in ethyl acetate and extracted several times with water. The organic phase is dried over magnesium sulphate and evaporated down in vacuo. The residue is purified by column chromatography over aluminium oxide N (activity II, eluant: methylene chloride, methylene chloride+0.3% ethanol). Yield: 4.2 g (50% of theory), IR spectrum (methylene chloride): 1655 cm-1 (CO).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:31])[CH2:10][N:11]1C2C=CC=CC=2NC[C@H](NC(OC(C)(C)C)=O)[C:12]1=[O:30])[C:2]1C=CC=CC=1.[O:32]=[C:33]1[N:39](CC(N[C@H]2CC(=O)OC2OCC2C=CC=CC=2)=O)[C:38]2[CH:58]=[CH:59][CH:60]=[CH:61][C:37]=2[N:36]([C:62](=[O:65])[CH2:63][OH:64])[CH2:35][C@@H:34]1[NH:66][C:67](=[O:77])[C:68]1C=[C:72](C)[C:71](O)=[C:70](C)[CH:69]=1>>[O:32]=[C:33]1[N:39]([C:12]([NH:11][C@H:10]2[CH2:34][C:33](=[O:32])[O:31][CH:9]2[O:8][CH2:1][CH3:2])=[O:30])[C:38]2[CH:58]=[CH:59][CH:60]=[CH:61][C:37]=2[N:36]([C:62](=[O:65])[CH2:63][OH:64])[CH2:35][C@@H:34]1[NH:66][C:67]([C:68]1[C:69]2[C:58](=[CH:59][CH:72]=[CH:71][CH:70]=2)[CH:38]=[CH:37][N:36]=1)=[O:77]
Reactant: CC(C)(C)OC(=O)N[C@H]1CNc2ccccc2N(CC(=O)OCc2ccccc2)C1=O
Reactant: Cc1cc(C(=O)N[C@H]2CN(C(=O)CO)c3ccccc3N(CC(=O)N[C@H]3CC(=O)OC3OCc3ccccc3)C2=O)cc(C)c1O
Product: CCOC1OC(=O)C[C@@H]1NC(=O)N1C(=O)[C@@H](NC(=O)c2nccc3ccccc23)CN(C(=O)CO)c2ccccc21

Procedure:
(3S)-2-Oxo-3-(isoquinolin-1-oyl)amino-5-hydroxyacetyl-N-[(2RS,3S)-ethoxy-5-oxo-tetrahydrofuran-3-yl]-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-1-carboxamide (696b) was synthesized from 600b via methods used to prepare 690a from 600b to afford 696b. 1H NMR (CDCl3) δ 0.9(m, 3H), 1.15(q, 3H), 1.15(m, 1H), 1.65(m, 1H), 2.5(m, 1H), 2.8(m, 1H), 2.95-3.0(m, 2H), 3.6(m, 2H), 3.7-3.85(m, 4H), 4.0(m, 2H), 4.3(m, 1H), 4.55(m, 1H), 4.65(m, 1H), 4.85-4.95(m, 1H), 5.05(m, 1H), 5.35(s, 1H), 5.45(d, 1H), 6.85(d, 1H), 7.25(d, 1H), 7.35-7.85(6H), 8.85(dd, 2H), 9.05(m, 1H), 9.35(dd, 2H).
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[OH:12][C@@H:13]1[CH2:17][CH2:16][CH2:15][C@H:14]1[O:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=1>C(Cl)Cl.CCOCC>[F:26][C:25]([F:27])([F:28])[C:21]1[CH:20]=[C:19]([CH:24]=[CH:23][CH:22]=1)[O:18][CH:14]1[CH2:15][CH2:16][CH2:17][C:13]1=[O:12]
Reactant: O[C@@H]1CCC[C@H]1Oc1cccc(C(F)(F)F)c1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: O=C1CCCC1Oc1cccc(C(F)(F)F)c1
Reaction time: 0.25 h
Yield: 86.2 %

Procedure:
To a suspension of 327.43 g of pyridinium chlorochromate in one liter of methylene chloride is added 220 g of trans-1-hydroxy-2-(3-trifluoromethylphenoxy)cyclopentane in 500 ml of methylene chloride. The mixture is stirred for 2 hours 15 minutes. Another 50 g of the oxidizing agent is added and the mixture is stirred for 41/2 hours. The mixture is diluted with ether and decanted from a black residue which is washed with more ether. The combined solutions are filtered through silica gel. The solvent is removed. The residue is dissolved in ether and again filtered through silica-gel. The solvent is removed and the residue is distilled (bp 113°-116° C., 1.5 mm) to give 188 g of 2-(3-trifluoromethylphenoxy)cyclopentanone.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[C:7]([N+:9]([O-])=O)[CH:6]=[C:5]([C:12]([F:15])([F:14])[F:13])[C:4]=1[NH2:16]>O1CCCC1.[Zn]>[Br:2][C:3]1[CH:8]=[C:7]([NH2:9])[CH:6]=[C:5]([C:12]([F:15])([F:14])[F:13])[C:4]=1[NH2:16]
Reactant: Nc1c(Br)cc([N+](=O)[O-])cc1C(F)(F)F
Agent: Cl
Agent: [Zn]
Solvent: C1CCOC1
Product: Nc1cc(Br)c(N)c(C(F)(F)F)c1
Yield: 99.2 %

Procedure:
Aqueous hydrochloric acid (2 M, 45 mL) was added slowly to a mixture of zinc dust (8.6 g) and 2-bromo-4-nitro-6-trifluoromethyl-phenylamine (2.5 g) in tetrahydrofuran (50 mL). The reaction mixture was stirred for 1-hour, filtered and neutralized with saturated aqueous sodium bicarbonate (100 mL). Water (100 mL) was added and the mixture was extracted with ethyl acetate (2×100 mL). The combined organic phases were washed with water (2×200 mL) and brine (200 mL), dried over sodium sulfate and concentrated in vacuo to furnish 2.22 g (98% yield) of the title compound as a red solid. 1H NMR (500 MHz, DMSO-d6): 4.55 (s, 2H), 4.91 (s, 2H), 6.76 (d, 1H), 7.01 (d, 1H).
Reaction SMILES: [OH:1][C@@H:2]([CH2:6][CH:7]([CH3:9])[CH3:8])[C:3]([OH:5])=[O:4].[H-].[Na+].I[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].O>CN(C=O)C>[CH3:8][CH:7]([CH3:9])[CH2:6][C@H:2]([O:1][CH2:3][CH2:2][CH2:6][CH2:7][CH3:8])[C:3]([O:5][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[O:4]
Reactant: CCCCCI
Reactant: CC(C)C[C@H](O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCOC(=O)[C@H](CC(C)C)OCCCCC
Reaction time: 0.33 h

Procedure:
To a solution of (2S)-2-hydroxy-4-methylpentanoic acid 8 (1 g, 7.6 mmol) in 50 mL DMF at 0° C. was added NaH (0.6 g, 15.2 mmol) and stirred for 20 min, followed by the addition of iodopentane (1.5 g, 7.6 mmol). The reaction mixture was stirred at rt for additional 16 h. The solution was poured into water and the layers separated. The aqueous layer was extracted with methylene chloride and the combined extracts were washed with sat'd NaHCO3, dried over magnesium sulfate, and concentrated to a crude product. Upon further purification, compound 9 was obtained as an oil (80 mg, 4%). MS [M+H]+ 273. Step 2: Preparation of (2S)-4-methyl-2-pentyloxypentanoic acid 10. To a solution of (2S)-pentyl 4-methyl-2-pentyloxypentanoate 9 (80 mg, 0.3 mmol) in 20 mL of THF cooled to 0° C. was added dropwise a solution of lithium hydroxide monohydrate (25 mg, 0.6 mmol) in 5 mL of water. The reaction mixture was stirred at rt for 16 h. THF was removed under reduced pressure to give an yellow oil which was diluted with 10 mL of 1 N HCl. The aqueous phase was extracted with CH2Cl2 (8×15 mL), and the extracts were combined, dried over Na2SO4, and concentrated to afford compound 10 (45 mg, 74%). MS [M+H]+ 203. Step 3: Preparation of (7S)-[(2S)-1-oxo-2-pentyloxy-(4-methylpentyl)]amino-5-methyl-5H,7H-dibenzo[b,d]azepin-6-one, 12. To a solution of (2S)-4-methyl-2-pentyloxypentanoic acid 10 (45 mg, 0.22 mmol) in CH2Cl2/DMF (5:1, 15 mL) at 0° C. was added HOBT (40 mg, 0.26 mmol) and EDC (50 mg, 0.26 mmol). The mixture was stirred for 10 min then the amine 11 (52 mg, 0.22 mmol) was added and stirring was continued for 1 h. The solution was poured into water and the layers separated. The aqueous layer was extracted with methylene chloride and the combined extracts were washed with water, 1 N HCl, sat'd NaHCO3, dried over magnesium sulfate, and concentrated to a glassy solid compound 12 (80 mg, 86%). MS [M+H]+ 423.
Reaction SMILES: Br[C:2]1=[CH:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]1[O:10][CH2:11][CH2:12][CH:13]=[CH2:14].C1CCN2C(=NCCC2)CC1.CCOC(C)=O.Cl>CS(C)=O>[CH2:11]([O:10][CH:9]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]#[C:2]1)[CH2:12][CH:13]=[CH2:14]
Reactant: C=CCCOC1CCCCCC=C1Br
Agent: C=CCCOC1CCCCC/C=C\1Br
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: C1CCC2=NCCCN2CC1
Product: C=CCCOC1C#CCCCCC1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 87.2 %

Procedure:
The compound 2 (2.04 g, 7.8 mmol) is dissolved in anhydrous DMSO (10 ml) and heated to 60° C. DBU (2.3 ml, 2 eq.) is added and the solution is stirred for 15 min. before adding further DBU (4.6 ml, 4 eq.) and again stirring for 15 min. Finally, DBU (4.6 ml, 4 eq.) is added a final time and the solution is stirred at 60° C. overnight and subsequently left to return to ambient temperature. 150 ml of AcOEt are added to this solution and extraction is carried out with HCl (1M). When the pH becomes basic, the organic phase is washed with water to neutrality. The extracted phase is dried over MgSO4, filtered and purified by flash chromatography (cyclohexane/AcOEt 99:1) in order to produce the compound 3 (1.22 g, 6.8 mmol, 87%), a colorless liquid.
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[CH:12]([O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[CH:18][N:17]=1)([CH3:14])[CH3:13].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH:12]([O:15][C:16]1[N:17]=[CH:18][C:19]([C:22]2[S:4][C:3]3[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=3[C:1](=[O:10])[N:23]=2)=[CH:20][CH:21]=1)([CH3:14])[CH3:13]
Reactant: CC(C)Oc1ccc(C#N)cn1
Reactant: COC(=O)c1ccccc1S
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)Oc1ccc(-c2nc(=O)c3ccccc3s2)cn1
Yield: 29.8 %

Procedure:
A mixture of methyl thiosalicylate (1.85 g, 11.0 mmol), 2-isopropoxy-5-cyanopyridine (1.62 g, 10.0 mmol), triethylamine (1.80 ml, 12.9 mmol) and toluene (10 ml) was refluxed under nitrogen atmosphere for 30 hrs. The reaction mixture was concentrated. The residue was subjected to a silica gel column chromatography, eluted with ethyl acetate-hexane (2:1, v/v) and recrystallized from ethyl acetate-isopropylether to give the titled compound (0.89 g, 30%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5].[OH-].[Na+].[C:9]([C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18](=[N:21][C:22]#[N:23])SC)=[CH:13][CH:12]=1)#[N:10]>O.C(O)C.C(=O)([O-])[O-].[Na+].[Na+]>[C:22]([N:21]=[C:18]([NH:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]#[N:10])=[CH:12][CH:13]=1)[NH:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5])#[N:23]
Reactant: CSC(=NC#N)Nc1ccc(C#N)cc1
Reactant: NCCC(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: N#CN=C(NCCC(=O)O)Nc1ccc(C#N)cc1
Yield: 63.4 %

Procedure:
A mixture of 12.3 g (0.138 mol) of β-alanine and of 5.52 g (0.138 mol) of sodium hydroxide in 100 cm3 of water is added to a solution of 20 g (0.092 mol) of N-(4-cyanophenyl)-N'-cyano-S-methylisothiourea in 300 cm3 of 95% ethanol. The mixture is heated to reflux for 4 hours. After cooling, the solution is filtered then concentrated to dryness in vacuo. The residue obtained is dissolved in 200 cm3 of a 2% sodium carbonate solution. The resulting solution is washed by dichloromethane (3×50 cm3) then acidified by a 3N HCl solution until a pH close to 2 is obtained. The white solid formed is filtered, then washed with water (2×10 cm3) and dried in vacuo. After recrystallization in water, 15 g (yield 63%) of N-[cyanoimino(4-cyanophenylamino)methyl]-3-aminopropanoic acid, which is a solid having a melting point of 158°-162° C., are obtained.
Reaction SMILES: C(OC(=O)[C:5]([O:15][C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[C:18]([CH3:23])[CH:17]=1)([CH3:14])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)C.[CH3:25][C:26]1[O:30][C:29]([C:31]2[CH:36]=[CH:35][C:34]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[CH:33][CH:32]=2)=[N:28][C:27]=1[CH2:43][CH2:44]OS(C1C=CC(C)=CC=1)(=O)=O.[C:56]([O-:59])([O-])=[O:57].[K+].[K+].[OH-].[Na+]>C(O)C>[C:34]1([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:35]=[CH:36][C:31]([C:29]2[O:30][C:26]([CH3:25])=[C:27]([CH2:43][CH2:44][O:13][C:10]3[CH:9]=[CH:8][C:7]([CH2:6][C:5]([O:15][C:16]4[CH:21]=[CH:20][C:19]([CH3:22])=[C:18]([CH3:23])[CH:17]=4)([CH3:14])[C:56]([OH:59])=[O:57])=[CH:12][CH:11]=3)[N:28]=2)=[CH:32][CH:33]=1
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3ccc(-c4ccccc4)cc3)oc2C)cc1
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccc(C)c(C)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccc(OC(C)(Cc2ccc(OCCc3nc(-c4ccc(-c5ccccc5)cc4)oc3C)cc2)C(=O)O)cc1C

Procedure:
A mixture of 2-(3,4-dimethylphenoxy)-3-(4-hydroxyphenyl)-2-methyl-propionic acid ethyl ester (0.030 mmol) (see Ex. 32, Part C), toluene-4-sulfonic acid 2-(5-methyl-2-biphenyl-4-yl-oxazol-4-yl)ethyl ester (0.030 mmol) (see Ex. 1, Part I) and 325 mesh K2CO3 (0.084 g, 0.60 mmol) in ethanol (2 mL) was heated to reflux for 24 h under N2. Aqueous 5N NaOH (0.5 mL) and additional ethanol (1 mL) was added to the reaction mixture and it was heated at reflux for an additional 2 h. The reaction was cooled and the solvent removed in vacuo. The residue was acidified with aqueous 1 N HCl (5 mL), extracted with water and CH2Cl2 and the organic layer dried by passing it through a Varian Chem Elut 1003 cartridge. The solvent was removed in vacuo to give 3-{4-[2-(2-biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-(3,4-dimethyl-phenoxy)-2-methyl-propionic acid. 1H NMR (400 MHz, CDCl3) δ 8.10 (d, 2H, J=8.4 Hz), 7.71 (d, 2H, J=8.4 Hz), 7.65–7.62 (m, 2H), 7.49–7.45 (m, 2H), 7.42–7.30 (m, 1H), 7.19 (d, 2H, J=8.4 Hz), 7.00 (d, 1H, J=8.4 Hz), 6.83 (d, 2H, J=8.4 Hz), 6.70 (d, 1H, J=2.4 Hz), 6.64 (dd, 1H, J=8.4, 2.4 Hz), 4.26 (t, 2H, J=6.0 Hz), 3.22 and 3.11 (d of Abq, 2H, J=14.0 Hz), 3.09 (t, 2H, J=6.0 Hz), 2.44 (s, 3H), 2.19 (s, 3H), 2.18 (s, 3H), 1.39 (s, 3H). IR (KBr) 3480, 2950, 1718, 1611, 1512, 1248, 1177 cm−1. HRMS (ES+) m/z exact mass calcd for C36H36NO5 562.2593, found 562.2595.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][CH3:9])=[CH:6][N:5]=[C:4]2[N:10]([CH2:13][CH3:14])[N:11]=[CH:12][C:3]=12.CCN(C(C)C)C(C)C.[F:24][C:25]([F:43])([F:42])[C:26]1[CH:27]=[C:28]([C:36]([CH3:41])([CH3:40])[C:37](Cl)=[O:38])[CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1>C(Cl)Cl>[F:43][C:25]([F:24])([F:42])[C:26]1[CH:27]=[C:28]([C:36]([CH3:41])([CH3:40])[C:37]([N:8]([C:7]2[C:2]([Cl:1])=[C:3]3[CH:12]=[N:11][N:10]([CH2:13][CH3:14])[C:4]3=[N:5][CH:6]=2)[CH3:9])=[O:38])[CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1
Reactant: CC(C)(C(=O)Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CCn1ncc2c(Cl)c(NC)cnc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCn1ncc2c(Cl)c(N(C)C(=O)C(C)(C)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)cnc21
Temperature: 40 °C
Yield: 94.7 %

Procedure:
To a solution of (4-chloro-1-ethyl-1H-pyrazolo[3,4-b]pyridin-5-yl)-methyl-amine (2.24 g, 10.63 mmol) in CH2Cl2 (50 mL) was added iPr2NEt (3.69 mL, 21.20 mmol) and 2-(3,5-Bis-trifluoromethyl-phenyl)-2-methyl-propionyl chloride (described in J. Org. Chem, 2006, 71, 2000-2008, 4.38 g, 13.70 mmol). The reaction mixture was heated at 40° C. for 2 hours, diluted with CH2Cl2 (100 mL), and washed with H2O. The organic phase was dried over Na2SO4, concentrated under vacuo, and column chromatography (SiO2, EtOAc/Heptane 1/4) afforded 4.96 g (95%) of the title compound as a light yellow solid. ES-MS m/e: 493.2 (M+H+).
Reaction SMILES: [NH2:1][C:2]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[NH:4][C:3]1=[O:12].[N+:20]([C:23]1[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1)([O-:22])=[O:21]>>[NH2:1][C:2]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[N:4]([S:29]([C:26]2[CH:25]=[CH:24][C:23]([N+:20]([O-:22])=[O:21])=[CH:28][CH:27]=2)(=[O:30])=[O:31])[C:3]1=[O:12]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: NC1(c2ccccc2Cl)C(=O)Nc2ccc(Cl)cc21
Product: NC1(c2ccccc2Cl)C(=O)N(S(=O)(=O)c2ccc([N+](=O)[O-])cc2)c2ccc(Cl)cc21

Procedure:
This compound is prepared according to the procedure described in EXAMPLE 1 from 10 g of 3-amino-5-chloro-3-(2-chlorophenyl)-1,3-dihydroindol-2-one and 7.55 g of 4-nitrobenzenesulfonyl chloride. The expected product is obtained after crystallization from a DCM/iso ether mixture. m=14 g. M.p.=202° C.