Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C1C=C2C(=CC=1)[N:8](CC1C=CC=C(F)C=1)C(C(O)=O)=C2.[CH:25]1([N:31]=[C:32]=[N:33][CH:34]2[CH2:39][CH2:38]CC[CH2:35]2)[CH2:30][CH2:29][CH2:28]CC1.O.ON1C2C=CC=CC=2N=N1>CN(C=O)C>[CH3:35][C:34]1[N:33]=[C:32]2[CH:28]=[C:29]([NH2:8])[CH:30]=[CH:25][N:31]2[C:39]=1[CH3:38]
Reactant: O=C(O)c1cc2cc(C(F)(F)F)ccc2n1Cc1cccc(F)c1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc2cc(N)ccn2c1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 150.3 %

Procedure:
To a solution, stirred at 20° C. under an inert atmosphere, of 1 g (2.96 mmol) of 5-trifluoromethyl-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxylic acid (WO 2006/072736) in 70 mL of DMF are added 0.74 g (3.56 mmol) of dicyclohexylcarbodiimide (DCC) and 0.48 g (3.56 mmol) of 1-hydroxybenzotriazole hydrate (HOBT). The reaction mixture is stirred at room temperature for 30 minutes. 0.7 g (4.45 mmol) of 2,3-dimethylimidazo[1,2-a]pyrid-7-ylamine, obtained according to the protocol described in step 14.4, and 100 mg of dimethylaminopyridine (DMAP) are then added to the reaction mixture. After stirring for 12 hours at 50° C., the reaction mixture is concentrated to dryness. The residue obtained is taken up in a mixture of 50 mL of water and 50 mL of ethyl acetate. The phases are separated by settling and the aqueous phase is extracted with 200 mL of ethyl acetate. The combined organic phases are dried over sodium sulfate and then concentrated under reduced pressure. The product is isolated after successive purifications by chromatography on a column of silica, eluting with a mixture of dichloromethane and methanol. 50 mg of the expected product are thus obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]3[N:18]=[CH:19][C:20]([C:21](O)=[O:22])=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[S:24]([C:28]1[CH:29]=[C:30]([NH2:34])[CH:31]=[CH:32][CH:33]=1)(=[O:27])(=[O:26])[NH2:25]>>[S:24]([C:28]1[CH:29]=[C:30]([NH:34][C:21]([C:20]2[CH:19]=[N:18][N:11]3[C:12]([C:14]([F:17])([F:16])[F:15])=[CH:13][C:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)=[N:9][C:10]=23)=[O:22])[CH:31]=[CH:32][CH:33]=1)(=[O:26])(=[O:27])[NH2:25]
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(Cl)cc3)nc12
Reactant: Nc1cccc(S(N)(=O)=O)c1
Product: NS(=O)(=O)c1cccc(NC(=O)c2cnn3c(C(F)(F)F)cc(-c4ccc(Cl)cc4)nc23)c1

Procedure:
The title compound was prepared from 5-(4-chloro-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.4) and 3-sulfamoyl-phenylamine [commercially available] according to general procedure II. Yellow solid. MS (ISP) 494.0 [(M−H)−]; mp 260° C.
Reaction SMILES: [CH:1]1([C:6]2[N:7]=[C:8]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[C:9]3[CH2:15][CH2:14][NH:13][CH2:12][CH2:11][C:10]=3[N:16]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C=O.[BH-](OC(C)=O)(OC(C)=O)O[C:28](C)=O.[Na+]>CO.[OH-].[Na+]>[CH:1]1([C:6]2[N:7]=[C:8]([C:17]3[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=3)[C:9]3[CH2:15][CH2:14][N:13]([CH3:28])[CH2:12][CH2:11][C:10]=3[N:16]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Fc1ccc(-c2nc(C3CCCC3)nc3c2CCNCC3)cc1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CN1CCc2nc(C3CCCC3)nc(-c3ccc(F)cc3)c2CC1
Yield: 85.1 %

Procedure:
To a solution of 2-cyclopentyl-4-(4-fluoro-phenyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine (0.035 g, 0.112 mmol) in MeOH (1 mL) was added formaldehyde (37% in water; 0.10 mL) and NaBH(OAc)3 (0.032 g, 0.151 mmol). After the reaction was judged complete, the mixture was diluted with 1 N NaOH and extracted with CH2Cl2 (3×). The combined organic layers were dried and concentrated. The resulting residue was purified via SiO2 chromatography (1-7% 2 M NH3 in MeOH/CH2Cl2) to give 0.031 g (87%) of the title compound. MS (ESI): exact mass calcd. for C20H24FN3, 325.20; m/z found, 326.4 [M+H]+. 1H NMR (CDCl3): 7.47 (dd, J=5.4, 8.8, 2H), 7.15 (t, J=8.7, 2H), 3.38-3.30 (m, 1H), 3.20 (dd, J=4.1, 6.3, 2H), 2.97 (dd, J=4.2, 5.9, 2H), 2.71-2.70 (m, 2H), 2.60 (m, 2H), 2.41 (s, 3H), 2.12-2.05 (m, 2H), 1.99-1.91 (m, 2H), 1.87-1.79 (m, 2H), 1.73-1.63 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:12]2[CH:22]=[CH:21][C:15]([C:16]([N:18]([CH3:20])[CH3:19])=[O:17])=[CH:14][CH:13]=2)=[N:6][C:7]=1[C:8]([NH:10][NH2:11])=[O:9].[N:23]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[C:24]=S.C(Cl)CCl>C1COCC1>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:12]2[CH:13]=[CH:14][C:15]([C:16]([N:18]([CH3:19])[CH3:20])=[O:17])=[CH:21][CH:22]=2)=[N:6][C:7]=1[C:8]1[O:9][C:24]([NH:23][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[N:11][N:10]=1
Reactant: CN(C)C(=O)c1ccc(-c2cnc(N)c(C(=O)NN)n2)cc1
Reactant: S=C=NCc1ccccc1
Solvent: C1CCOC1
Solvent: ClCCCl
Product: CN(C)C(=O)c1ccc(-c2cnc(N)c(-c3nnc(NCc4ccccc4)o3)n2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 73 %

Procedure:
A mixture of 4-(5-amino-6-(hydrazinecarbonyl)pyrazin-2-yl)-N,N-dimethylbenzamide (75 mg, 0.2497 mmol), isothiocyanatomethylbenzene (37.26 mg, 33.12 μL, 0.2497 mmol) and dry THF (1.500 mL) was stirred at RT for 4 hours. The reaction mixture was evaporated to dryness and treated with DCM followed by EDC (71.81 mg, 0.3746 mmol) and the resultant mixture allowed to stir at RT overnight. The reaction mixture was filtered and the resultant green precipitate dried under vacuum (78 mg, 73% Yield). 1H NMR (400.0 MHz, DMSO) d 2.96 (s, 3H), 3.00 (s, 3H), 4.50 (d, J=6.1 Hz, 2H), 7.29 (d, J=7.2 Hz, 1H), 7.35-7.42 (m, 4H), 7.51-7.53 (m, 2H), 7.65 (br s, 2H), 8.06 (dd, J=1.5, 6.9 Hz, 2H) and 8.81 (d, J=12.4 Hz, 2H) ppm; MS (ES+) 416.2
Reaction SMILES: [F:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[NH:10][C:11]1[C:16]([C:17]2[N:25]=[CH:24][N:23]=[C:22]3[C:18]=2[N:19]=[CH:20][N:21]3[CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)=[CH:15][CH:14]=[CH:13][N:12]=1.[O:32]1[C:36]2[C:37]([S:41](Cl)(=[O:43])=[O:42])=[CH:38][CH:39]=[CH:40][C:35]=2[CH2:34][CH2:33]1.N1C=CC=CC=1>ClCCl>[F:1][C:2]1[C:3]([NH:10][C:11]2[C:16]([C:17]3[N:25]=[CH:24][N:23]=[C:22]4[C:18]=3[N:19]=[CH:20][N:21]4[CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][O:27]3)=[CH:15][CH:14]=[CH:13][N:12]=2)=[C:4]([F:9])[CH:5]=[CH:6][C:7]=1[NH:8][S:41]([C:37]1[C:36]2[O:32][CH2:33][CH2:34][C:35]=2[CH:40]=[CH:39][CH:38]=1)(=[O:42])=[O:43]
Reactant: O=S(=O)(Cl)c1cccc2c1OCC2
Reactant: Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=S(=O)(Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F)c1cccc2c1OCC2
Temperature: 50 °C
Reaction time: 2 h

Procedure:
The 2,6-difluoro-N1-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-yl)benzene-1,3-diamine (20 mg, 0.047 mmol) prepared at Step 9 was added and dissolved into dichloromethane solvent. 2,3-dihydrobenzofuran-7-sulfonyl chloride (15 mg, 0.07 mmol) and pyridine (8 uL, 0.094 mmol) were added into the reaction solution and stirred at 50° C. for 2 hours. After the reaction, the reactant was washed with 1N aqueous hydrochloric acid solution and salt water. After extraction with dichloromethane, the organic layer was dried with sulfuric anhydride magnesium and vacuum concentrated, and then refined by means of column chromatography, so that the target compound was obtained.
Reaction SMILES: C(OC([NH:8][C@H:9]([C:11]([O:13][CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:28]([C:29]#[N:30])=[C:27]([NH:31][CH3:32])[N:26]=[C:25]([S:33][CH2:34][C:35]3[N:36]=[C:37]([C:40]4[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][CH:41]=4)[S:38][CH:39]=3)[C:24]=2[C:47]#[N:48])=[CH:19][CH:18]=1)=[O:12])[CH3:10])=O)(C)(C)C.[F:49][C:50]([F:55])([F:54])[C:51]([OH:53])=[O:52]>ClCCl>[F:49][C:50]([F:55])([F:54])[C:51]([OH:53])=[O:52].[NH2:8][C@H:9]([C:11]([O:13][CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:28]([C:29]#[N:30])=[C:27]([NH:31][CH3:32])[N:26]=[C:25]([S:33][CH2:34][C:35]3[N:36]=[C:37]([C:40]4[CH:41]=[CH:42][C:43]([Cl:46])=[CH:44][CH:45]=4)[S:38][CH:39]=3)[C:24]=2[C:47]#[N:48])=[CH:19][CH:18]=1)=[O:12])[CH3:10]
Reactant: CNc1nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c(-c2ccc(OCCOC(=O)[C@H](C)NC(=O)OC(C)(C)C)cc2)c1C#N
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNc1nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c(-c2ccc(OCCOC(=O)[C@H](C)N)cc2)c1C#N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2.18 g (3.091 mmol) of 2-{4-(2-({(2-(4-chlorophenyl)-1,3-thiazol-4-yl)methyl}sulfanyl)-3,5-dicyano-6-(methylamino)pyridin-4-yl)phenoxy}ethyl N-(tert-butoxycarbonyl)-L-alaninate (Example 17A) were initially charged in 45 ml of dichloromethane. 4.76 ml (61.821 mmol) of trifluoroacetic acid were added, and the reaction solution was then stirred at RT overnight. The reaction solution was concentrated on a rotary evaporator and the residue was purified by preparative HPLC (acetonitrile/water+0.1% TFA). This gave 2.04 g (92% of theory) of the target compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:16])=[C:6]([C:8]2([CH3:15])[NH:12]C(=O)N[C:9]2=[O:14])[CH:7]=1.[OH-].[Na+].NC(C1C=C(Br)C=CC=1F)(C)[C:21](O)=[O:22].S(Cl)(Cl)=O>CO>[CH3:21][O:22][C:9](=[O:14])[C:8]([NH2:12])([C:6]1[CH:7]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=1[F:16])[CH3:15]
Reactant: CC(N)(C(=O)O)c1cc(Br)ccc1F
Reactant: CC1(c2cc(Br)ccc2F)NC(=O)NC1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=S(Cl)Cl
Solvent: CO
Product: COC(=O)C(C)(N)c1cc(Br)ccc1F

Procedure:
The hydrolysis of the (RS)-5-(5-bromo-2-fluoro-phenyl)-5-methyl-imidazolidine-2,4-dione with 6 N sodium hydroxide solution and esterification of the resulting (RS)-2-amino-2-(5-bromo-2-fluoro-phenyl)-propionic acid with methanol and thionylchloride yielded the (RS)-2-amino-2-(5-bromo-2-fluoro-phenyl)-propionic acid methylester as a light yellow oil. The purity of the product allowed using it in the next step without further purification. Mass (calculated) C10H11BrFNO2 [276.107]; (found) [M+H]+=276, 278.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][F:9])[N:3]=1.[CH2:10]([N:14]1[CH:22]=[C:21]2[C:16]([CH:17]=[C:18]([F:23])[CH:19]=[CH:20]2)=[N:15]1)[CH2:11][C:12]#[CH:13]>>[F:23][C:18]1[CH:19]=[CH:20][C:21]2[C:16]([CH:17]=1)=[N:15][N:14]([CH2:10][CH2:11][C:12]#[C:13][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][F:9])[N:3]=1)[CH:22]=2
Reactant: FCc1cccc(Br)n1
Reactant: C#CCCn1cc2ccc(F)cc2n1
Product: FCc1cccc(C#CCCn2cc3ccc(F)cc3n2)n1
Yield: 26.5 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromo-6-(fluoromethyl)pyridine (100 mg, 0.54 mmol) and 2-but-3-ynyl-6-fluoro-2H-indazole (93 mg, 0.49 mmol). Reaction time: 3 hours. The crude residue was purified by flash chromatography (cyclohexane/AcOEt 3:2) to yield 40 mg (0.13 mmol, 27%) of 6-fluoro-2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-2H-indazole as a brown solid.
Reaction SMILES: [CH3:1][N:2]1[C:6](OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:5][C:4]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:3]1.[C:24]([C:26]1[CH:30]=[CH:29][S:28][CH:27]=1)#[CH:25]>CCCCCCC.CCOC(C)=O>[CH3:1][N:2]1[C:6]([C:25]#[C:24][C:26]2[CH:30]=[CH:29][S:28][CH:27]=2)=[CH:5][C:4]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[N:3]1
Reactant: C#Cc1ccsc1
Reactant: Cc1ccc(S(=O)(=O)Oc2cc(-c3ccccc3)nn2C)cc1
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: Cn1nc(-c2ccccc2)cc1C#Cc1ccsc1

Procedure:
This product was prepared from toluene-4-sulfonic acid 2-methyl-5-phenyl-2H-pyrazol-3-yl ester and 3-ethynyl-thiophene following the general procedure for the Sonogashira cross-coupling reaction described above. Chromatography eluent: heptane/EtOAc 95:5; yield (60 mg, 45%); 1H NMR δ (CDCl3): 7.78 (d, J=8.10 Hz, 2H), 7.60 (m, 1H), 7.46-7.29 (m, 4H), 7.22 (m, 1H), 6.77 (s, 1H), 4.05 (s, 3H); LCMS m/z: 264.
Reaction SMILES: [CH:1]([C:4]1[C:8]2[CH:9]=[CH:10][C:11]([C:13]([F:16])([F:15])[F:14])=[CH:12][C:7]=2[S:6][C:5]=1[CH2:17][CH2:18][C:19]1[C:23]2[CH:24]=[C:25]([CH3:33])[C:26]([CH:28]=[CH:29][C:30]([OH:32])=[O:31])=[CH:27][C:22]=2[O:21][N:20]=1)([CH3:3])[CH3:2].O.NN>CO.Cl>[CH:1]([C:4]1[C:8]2[CH:9]=[CH:10][C:11]([C:13]([F:14])([F:15])[F:16])=[CH:12][C:7]=2[S:6][C:5]=1[CH2:17][CH2:18][C:19]1[C:23]2[CH:24]=[C:25]([CH3:33])[C:26]([CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[CH:27][C:22]=2[O:21][N:20]=1)([CH3:3])[CH3:2]
Reactant: Cc1cc2c(CCc3sc4cc(C(F)(F)F)ccc4c3C(C)C)noc2cc1C=CC(=O)O
Agent: Cl
Agent: NN
Solvent: O
Solvent: CO
Product: Cc1cc2c(CCc3sc4cc(C(F)(F)F)ccc4c3C(C)C)noc2cc1CCC(=O)O
Temperature: 25 °C
Yield: 79.9 %

Procedure:
To a solution of the above-mentioned 3-[3-[2-[3-isopropyl-6-(trifluoromethyl)benzothiophen-2-yl]ethyl]-5-methylbenzisoxazol-6-yl]acrylic acid (75 mg, 0.15 mmol) in MeOH (0.8 mL) was added hydrazine monohydrate (0.15 mL, 3.1 mmol). The mixture was heated reflux for 4 hours, cooled to room temperature, diluted with ice-water and 1M HCl, and extracted with ethyl acetate. The organic layer was collected, washed with brine, dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give the titled compound as a brown oil (57 mg, yield 78%).
Reaction SMILES: C(=O)=[N:2][S:3](Cl)(=[O:5])=[O:4].[CH3:8][CH:9]([C:11]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[C:13]([CH:20]([CH3:22])[CH3:21])[C:12]=1[OH:23])[CH3:10]>C1(C)C=CC=CC=1>[S:3](=[O:4])(=[O:5])([O:23][C:12]1[C:13]([CH:20]([CH3:21])[CH3:22])=[CH:14][C:15]([N+:17]([O-:19])=[O:18])=[CH:16][C:11]=1[CH:9]([CH3:10])[CH3:8])[NH2:2]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CC(C)c1cc([N+](=O)[O-])cc(C(C)C)c1O
Solvent: Cc1ccccc1
Product: CC(C)c1cc([N+](=O)[O-])cc(C(C)C)c1OS(N)(=O)=O
Temperature: 25 °C
Yield: 59.6 %

Procedure:
N-Chlorosulfonyl isocyanate (7.2 mL, 82.6 mmol) was added slowly to a warm solution of 2,6-bis(1-methylethyl)-4-nitrophenol (17.57 g, 78.7 mmol) in 400 mL toluene. The resulting solution was heated to reflux for 6 hours and then cooled to room temperature and concentrated to give a brown oil. Quenched with 200 g ice and extracted with 4×500 mL dichloromethane. The organic solution was dried over MgSO4, filtered, and concentrated to give a tan solid. Recrystallization from dichloromethane gave 14.18 g (60%) of the title compound as an off-white solid; mp 163-167° C.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11](O)([C:14]#N)[CH2:10][CH2:9]1)C1C=CC=CC=1.[NH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>CO>[CH3:14][C:11]1([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: C1COCCN1
Reactant: N#CC1(O)CCN(Cc2ccccc2)CC1
Solvent: CO
Product: CC1(N2CCOCC2)CCNCC1

Procedure:
A solution of 5.25 g (23.8 mmol) 1-benzyl-4-hydroxy-piperidine-4-carbonitrile and 2.2 mL (25.2 mmol) morpholine in 30 mL MeOH was refluxed for 6 h. The mixture was evaporated to dryness i. vac., while the product was obtained in the form of crystals.
Reaction SMILES: [C@H:1]1([OH:7])[CH:5]=[CH:4][C@@H:3]([OH:6])[CH2:2]1.[H-].[Na+].[C:10]([O:14][C:15](=[O:18])[CH2:16]Br)([CH3:13])([CH3:12])[CH3:11]>CN(C=O)C.C1COCC1>[C:10]([O:14][C:15](=[O:18])[CH2:16][O:6][CH:3]1[CH2:2][CH:1]([OH:7])[CH:5]=[CH:4]1)([CH3:13])([CH3:12])[CH3:11]
Reactant: O[C@@H]1C=C[C@H](O)C1
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)COC1C=CC(O)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Dissolve 2.0 g (20 mmol) of cis-4-cyclopentene-1,3-diol in 1.5 ml of DMF and 15 ml of THF and, at 0° C., add 799 mg (60% strength, approx. 20 mmol) of sodium hydride in portions. After the end of the addition, warm the mixture to RT and stir at RT for a further 1 h, before adding 2.7 ml (18.2 mmol) of bromoacetic acid tert-butyl ester. Then stir the mixture at RT overnight. Then add water, extract with dichloromethane, wash the organic phase with satd. sodium chloride solution, concentrate under reduced pressure and dry the residue under high vacuum. Isolate the product by chromatography on silica gel (eluent: cyclohexane/ethyl acetate 5:1→2:1). 1.10 g (25.6% of theory) of the target compound are obtained.
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]([F:28])([F:27])[O:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[O:21][C:20](=[O:23])[C:19]([C:24]([OH:26])=O)=[CH:18]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:53]([O:55][C:56]1[CH:61]=[CH:60][C:59]([C:62]2[CH:67]=[CH:66][CH:65]=[C:64]([NH2:68])[CH:63]=2)=[CH:58][C:57]=1[CH3:69])[CH3:54]>CN(C=O)C>[CH2:53]([O:55][C:56]1[CH:61]=[CH:60][C:59]([C:62]2[CH:67]=[CH:66][CH:65]=[C:64]([NH:68][C:24]([C:19]3[C:20](=[O:23])[O:21][C:22]4[C:17]([CH:18]=3)=[CH:16][CH:15]=[CH:14][C:13]=4[O:12][C:11]([F:10])([F:28])[F:27])=[O:26])[CH:63]=2)=[CH:58][C:57]=1[CH3:69])[CH3:54]
Reactant: O=C(O)c1cc2cccc(OC(F)(F)F)c2oc1=O
Reactant: CCOc1ccc(-c2cccc(N)c2)cc1C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOc1ccc(-c2cccc(NC(=O)c3cc4cccc(OC(F)(F)F)c4oc3=O)c2)cc1C
Temperature: 25 °C
Yield: 52.5 %

Procedure:
DIEA (0.013 mL, 0.072 mmol) was added to 8-trifluoromethoxy-3-carboxy-coumarin (0.020 g, 0.067 mmol) and HATU (0.028 g, 0.072 mmol) in 0.37 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 4′-ethoxy-3′-methyl-biphenyl-3-ylamine (0.015 g, 0.067 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.017 g of product in 53% yield: LCMS (ESI) m/z 484 (MH+).
Reaction SMILES: [NH:1]1[CH2:4][CH2:3][CH2:2]1.[CH3:5][O:6][CH:7]1[CH2:11][CH2:10][N:9]([C:12]2[N:32]=[C:15]3[CH:16]=[CH:17][C:18]([NH:20][C:21]([C:23]4[N:27]([CH3:28])[N:26]=[CH:25][C:24]=4[C:29](O)=[O:30])=[O:22])=[CH:19][N:14]3[N:13]=2)[CH2:8]1>>[CH3:5][O:6][CH:7]1[CH2:11][CH2:10][N:9]([C:12]2[N:32]=[C:15]3[CH:16]=[CH:17][C:18]([NH:20][C:21]([C:23]4[N:27]([CH3:28])[N:26]=[CH:25][C:24]=4[C:29]([N:1]4[CH2:4][CH2:3][CH2:2]4)=[O:30])=[O:22])=[CH:19][N:14]3[N:13]=2)[CH2:8]1
Reactant: C1CNC1
Reactant: COC1CCN(c2nc3ccc(NC(=O)c4c(C(=O)O)cnn4C)cn3n2)C1
Product: COC1CCN(c2nc3ccc(NC(=O)c4c(C(=O)N5CCC5)cnn4C)cn3n2)C1

Procedure:
Using azetidine and 5-[2-(3-Methoxy-pyrrolidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-6-ylcarbamoyl]-1-methyl-1H-pyrazole-4-carboxylic acid, the title compound was prepared in the same manner as described for example 2. Off white solid (57 mg, 43%). MS: m/z=425 (M+H+).
Reaction SMILES: [OH:1][C@H:2]1[C@H:7](OC2CCC(=O)C=2)[C:6]2[CH:15]=[C:16]([C:19]#[N:20])[CH:17]=[CH:18][C:5]=2[O:4][C:3]1([CH3:22])[CH3:21].[NH2:23][C:24]1[CH2:28][O:27][C:26](=[O:29])[CH:25]=1.[H-].[Na+]>CS(C)=O>[OH:1][C@H:2]1[C@H:7]([NH:23][C:24]2[CH2:28][O:27][C:26](=[O:29])[CH:25]=2)[C:6]2[CH:15]=[C:16]([C:19]#[N:20])[CH:17]=[CH:18][C:5]=2[O:4][C:3]1([CH3:21])[CH3:22]
Reactant: NC1=CC(=O)OC1
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@@H](OC2=CC(=O)CC2)[C@@H]1O
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC1(C)Oc2ccc(C#N)cc2[C@@H](NC2=CC(=O)OC2)[C@@H]1O

Procedure:
34,5 mg of the epoxide of example 1 and 17 mg of 4-Amino-2-(5H)-furanone (CAS 92089-08-2) are reacted analogously to example 5 with sodium hydride in dimethylsulfoxide. The usual working up yields yellowish crystalls of the title compound having a m.p. of 182° C. (from ethanol/dichloromethane, decomposition).
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]([C:7]1[C:8]([CH3:16])=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10](O)=[O:11])#[N:6]>>[C:5]([C:7]1[C:8]([CH3:16])=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([Cl:3])=[O:11])#[N:6]
Reactant: Cc1c(C#N)cccc1C(=O)O
Reactant: O=S(Cl)Cl
Product: Cc1c(C#N)cccc1C(=O)Cl

Procedure:
75 cc of thionyl chloride and 30 g of 3-cyano-2-methyl-benzoic acid [prepared by process in C. R. Acad. Sci., Vol. 235(1952), p. 1660] were refluxed for 11/2 hours and after cooling, excess thionyl chloride was removed under reduced pressure. The last traces of thionyl chloride were removed by addition of benzene and distillation under reduced pressure. The residue was purified by rectification under reduced pressure to obtain 27.4 g of 3-cyano-2-methyl-benzoyl chloride in the form of colorless crystals melting at 62° C.
Reaction SMILES: [C:1]([C:3]1[C:4]([CH3:16])=[CH:5][C:6]([C:11]([O:13]CC)=[O:12])=[N:7][C:8]=1[O:9][CH3:10])#[N:2].[OH-].[Na+]>CO.C1COCC1>[C:1]([C:3]1[C:4]([CH3:16])=[CH:5][C:6]([C:11]([OH:13])=[O:12])=[N:7][C:8]=1[O:9][CH3:10])#[N:2]
Reactant: CCOC(=O)c1cc(C)c(C#N)c(OC)n1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1nc(C(=O)O)cc(C)c1C#N
Temperature: 60 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
To a stirred solution of ethyl 5-cyano-6-methoxy-4-methylpicolinate (1.0 g, 4.54 mmol) in MeOH (30 mL) and THF (10 mL) was added 6N NaOH (2 mL, 12.00 mmol). The suspension was heated to 60° C. and stirred for 2 hr. (The reaction cleared up right away.) LCMS indicated that the reaction was complete. The reaction was cooled to RT and concentrated to near dryness. The slurry was neutralized with 6N HCl (2 mL) diluted with water, filtered, washed with water and dried under vacuum to give the product 5-cyano-6-methoxy-4-methylpicolinic acid (0.76 g, 3.95 mmol, 87% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ13.65 (br. s., 1H), 7.73 (s, 1H), 4.03 (s, 3H), 2.54 (s, 3H). MS(ES)+ m/e 192.9 [M+H]+.
Reaction SMILES: [O:1]=[C:2]([CH2:6][CH3:7])[C:3]([OH:5])=[O:4].S(=O)(=O)(O)O.[CH3:13][CH2:14]O>>[O:1]=[C:2]([CH2:6][CH3:7])[C:3]([O:5][CH2:13][CH3:14])=[O:4]
Reactant: CCC(=O)C(=O)O
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)C(=O)CC
Reaction time: 4 h
Yield: 98 %

Procedure:
To a solution of 2-oxobutanoic acid (6.0 g, 58.8 mmol) in EtOH (100 mL) was added sulfuric acid (1 mL) at room temperature. The resulting mixture was stirred for 4 h under reflux. The solvent was removed, and the residue was diluted with water (50 mL) and the pH was adjusted to 7 with a solution of NaOH (1 N). The mixture was extracted with EtOAc (100 mL×3). The combined organic layer was dried over sodium sulfate and concentrated to give ethyl 2-oxobutanoate (7.5 g, 98% yield). ESI MS: m/z 131 [M+H]+.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([NH:12][NH2:13])=[O:11])=[CH:9][C:4]=2[CH2:3][CH2:2]1.[F:14][C:15]1[CH:16]=[C:17]([CH:22]=[CH:23][CH:24]=1)[CH2:18][N:19]=[C:20]=[O:21]>N1C=CC=CC=1.C(OCC)(=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([NH:12][NH:13][C:20]([NH:19][CH2:18][C:17]3[CH:22]=[CH:23][CH:24]=[C:15]([F:14])[CH:16]=3)=[O:21])=[O:11])=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: NNC(=O)c1ccc2c(c1)CCO2
Reactant: O=C=NCc1cccc(F)c1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: O=C(NCc1cccc(F)c1)NNC(=O)c1ccc2c(c1)CCO2
Yield: 64.8 %

Procedure:
A solution of 2,3-dihydro-1-benzofuran-5-carbohydrazide (0.50 g, 2.81 mmol) and 3-fluorobenzyl isocyanate (0.85 g, 5.61 mmol) in pyridine (5 mL) was stirred at room temperature for 3 days. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was washed with ethyl acetate to give the title compound (0.60 g, yield 65%) as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[O:13][C:14]([F:17])([F:16])[F:15])[C:3]=1[C:18]([OH:20])=O.Cl.C(N=C=NCCCN(C)C)C.OC1C2N=NNC=2C=CC=1.[N:43]1([C:49]2[CH:54]=[CH:53][C:52]([OH:55])=[CH:51][CH:50]=2)[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1>>[NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[O:13][C:14]([F:15])([F:16])[F:17])[C:3]=1[C:18]([N:46]1[CH2:45][CH2:44][N:43]([C:49]2[CH:50]=[CH:51][C:52]([OH:55])=[CH:53][CH:54]=2)[CH2:48][CH2:47]1)=[O:20]
Reactant: Oc1ccc(N2CCNCC2)cc1
Reactant: Nc1onc(-c2ccccc2OC(F)(F)F)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Product: Nc1onc(-c2ccccc2OC(F)(F)F)c1C(=O)N1CCN(c2ccc(O)cc2)CC1
Yield: 73.9 %

Procedure:
In a similar manner as described in Example 1, by using dimethylformimide (15 mL), 5-amino-3-(2-(trifluoromethoxy)phenyl)isoxazol-4-carboxylic acid (530 mg, 1.84 mmol), 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (388 mg, 2.02 mmol), hydroxybenzotriazole (299 mg, 2.21 mmol) and 4-(piperazine-1-yl)phenol (328 mg, 1.84 mmol), a white solid required compound (608 mg, 1.36 mmol, 73%) was obtained.