Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[CH2:7]([N:14]([CH2:35][CH2:36][O:37][C:38]1[CH:43]=[CH:42][C:41]([O:44][CH2:45][C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)=[C:40]([C:52](=[O:54])[NH2:53])[CH:39]=1)[CH2:15][CH:16]([OH:34])[CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[NH:26][CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[N:29]=2)=[CH:21][CH:20]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.CI>CN(C)C=O>[CH2:7]([N:14]([CH2:35][CH2:36][O:37][C:38]1[CH:43]=[CH:42][C:41]([O:44][CH2:45][C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)=[C:40]([C:52](=[O:54])[NH2:53])[CH:39]=1)[CH2:15][CH:16]([OH:34])[CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[N:26]([CH3:1])[CH:27]=[C:28]([C:30]([F:31])([F:32])[F:33])[N:29]=2)=[CH:21][CH:20]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: NC(=O)c1cc(OCCN(Cc2ccccc2)CC(O)COc2ccc(-c3nc(C(F)(F)F)c[nH]3)cc2)ccc1OCc1ccccc1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1cc(C(F)(F)F)nc1-c1ccc(OCC(O)CN(CCOc2ccc(OCc3ccccc3)c(C(N)=O)c2)Cc2ccccc2)cc1
Reaction time: 0.33 h

Procedure:
At 0°, 0.18 g of potassium tert.-butoxide is added to a solution of 1.0 g of 1-[N-benzyl-2-(3-carbamoyl-4-benzyloxyphenoxy)-ethylamino]-3-[4-[4-(trifluoromethyl)-1H-imidazol-2-yl]-phenoxy]-2-propanol in 5 ml of dimethylformamide and the mixture is stirred for 20 minutes in an ice bath. At 0°-5°, a solution of 0.12 ml of methyl iodide in 3 ml of dimethylformamide is added and the mixture is then stirred for 4 hours at room temperature. The reaction solution is concentrated by evaporation, the residue is dissolved in water and the solution is extracted with ethyl acetate. After drying the organic phase over sodium sulphate, this is concentrated to dryness by evaporation, yielding the crude 1-[N-benzyl-2-(3-carbamoyl-4-benzyloxyphenoxy)-ethylamino]-3-[4-[1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl]-phenoxy]-2-propanol which is further processed in that form.
Reaction SMILES: [CH2:1]([C:8]1([CH3:22])[CH2:16][C:15]2[C:10](=[C:11]([Cl:20])[C:12]([Cl:19])=[C:13]([O:17]C)[CH:14]=2)[C:9]1=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.N1C=CC=CC=1>O>[CH2:1]([C:8]1([CH3:22])[CH2:16][C:15]2[C:10](=[C:11]([Cl:20])[C:12]([Cl:19])=[C:13]([OH:17])[CH:14]=2)[C:9]1=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc2c(c(Cl)c1Cl)C(=O)C(C)(Cc1ccccc1)C2
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CC1(Cc2ccccc2)Cc2cc(O)c(Cl)c(Cl)c2C1=O
Temperature: 180 °C
Yield: 34.8 %

Procedure:
2-Benzyl-2-methyl-5-methoxy-6,7-dichloro-1-indanone (6 g.) is mixed with pyridine hydrochloride (60 g.) and the mixture is heated at 180°C. for three hours. The dark liquid is poured into water (1 l.) and the dark powdery product is collected and crystallized from acetic acid to obtain 2-benzyl-2-methyl-5-hydroxy-6,7-dichloro-1-indanone (2 g.), m.p. 219°-221°C. The product is identified by its nuclear magnetic resonance spectrum.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][OH:11])=[CH:5][CH:4]=1)#[N:2].N1C=CN=C1.[Si:17](Cl)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18].CN(C1C=CC=CN=1)C>CN(C)C=O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][O:11][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(CCO)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccccn1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCc1ccc(C#N)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
5 g of 2-(4-cyanophenyl)ethanol are introduced into 50 ml of dimethylformamide 2.54 g of imidazole, 5,63 g of tert-butyldimethylsilyl chloride and a spatula tip-ful of dimethylaminopyridine are added. The reaction medium is left for 2 hours at room temperature and is then added to an ice-water mixture. The mixture is extracted with ethyl acetate and the extracts dried over anhydrous sodium sulphate. The product is purified by chromatography on a column of silica gel, using a mixture of cyclohexane and ethyl acetate (10:1 v/v) as eluent, to give 1-cyano-4-(tert-butyldimethylsilyloxyethyl)benzene.
Reaction SMILES: [CH3:1][C:2]1[S:24][C:5]2[C:6]3[C:22]([CH3:23])=[N:21][O:20][C:7]=3[C@H:8]([CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[NH:9][C:10](=[O:11])[C:4]=2[C:3]=1[CH3:25].S1C=[CH:29][CH:28]=[CH:27]1.IC(C)C>C1(C)C=CC=CC=1.[Ag]=O>[CH:28]([O:11][C:10]1[C:4]2[C:3]([CH3:25])=[C:2]([CH3:1])[S:24][C:5]=2[C:6]2[C:22]([CH3:23])=[N:21][O:20][C:7]=2[C@H:8]([CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[N:9]=1)([CH3:29])[CH3:27]
Reactant: Cc1noc2c1-c1sc(C)c(C)c1C(=O)N[C@H]2CC(=O)OC(C)(C)C
Reactant: c1ccsc1
Agent: O=[Ag]
Solvent: Cc1ccccc1
Solvent: CC(C)I
Product: Cc1noc2c1-c1sc(C)c(C)c1C(OC(C)C)=N[C@H]2CC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 72 %

Procedure:
A mixture of tert-butyl 2-((6S)-2,3,9-trimethyl-4-oxo-5,6-dihydro-4H-isoxazolo[5,4-c]thieno[2,3-e]azepin-6-yl)acetate (17 wherein ring A is thiophene; 100 mg, 0.276 mmol), silver oxide (70 mg, 0.304 mmol) and 2-iodopropane (61 mg, 0.359 mmol) in toluene (5 mL) was heated to 90° C., and stirred overnight. After cooling to room temperature, the reaction mixture was evaporated to dryness and the residue was purified by flash chromatography eluting with petroleum ether/ethyl acetate=5:1 to give tert-butyl 2-((6S)-4-isopropoxy-2,3,9-trimethyl-6H-isoxazolo[5,4-c]thieno[2,3-e]azepin-6-yl)acetate as a yellow solid (80 mg, 72% yield). LC/MS m/z 404 [M+1-1]+; 1H NMR (300 MHz, CDCl3) δ 5.30-5.03 (m, 1H), 4.51 (t, J=6 Hz, 1H), 3.11-3.08 (m, 2H), 2.43 (s, 3H), 2.39 (s, 3H), 2.26 (s, 3H), 1.46 (s, 9H), 1.30 (d, J=6 Hz, 3H), 1.20 (d, J=6 Hz, 3H).
Reaction SMILES: C(O[C:4](=[O:22])[CH2:5][N:6]1[CH2:10][C@H:9]([O:11][CH3:12])[C@@H:8]([NH:13][C:14]([C:16]2[S:17][C:18]([Cl:21])=[CH:19][CH:20]=2)=[O:15])[CH2:7]1)C.[NH2:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][C:31]2=[O:36])=[CH:26][CH:25]=1>>[CH3:12][O:11][C@H:9]1[CH2:10][N:6]([CH2:5][C:4](=[O:22])[NH:23][C:24]2[CH:25]=[CH:26][C:27]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][C:31]3=[O:36])=[CH:28][CH:29]=2)[CH2:7][C@@H:8]1[NH:13][C:14]([C:16]1[S:17][C:18]([Cl:21])=[CH:19][CH:20]=1)=[O:15]
Reactant: CCOC(=O)CN1C[C@H](NC(=O)c2ccc(Cl)s2)[C@@H](OC)C1
Reactant: Nc1ccc(N2CCOCC2=O)cc1
Product: CO[C@H]1CN(CC(=O)Nc2ccc(N3CCOCC3=O)cc2)C[C@@H]1NC(=O)c1ccc(Cl)s1

Procedure:
Using general procedure F {(3S,4S)-3-[(5-chloro-thiophene-2-carbonyl)-amino]-4-methoxy-pyrrolidin-1-yl}-acetic acid ethyl ester (example 25.2) was reacted with 4-(4-aminophenyl)-morpholin-3-one (CAS 438056-69-0) to give 5-chloro-thiophene-2-carboxylic acid ((3S,4S)-4-methoxy-1-{[4-(3-oxo-morpholin-4-yl)-phenylcarbamoyl]-methyl}-pyrrolidin-3-yl)-amide. Yellow solid. MS 493.0 ([M+H]+)
Reaction SMILES: [C:1]([C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:15])[CH3:14])=[CH:8][CH:7]=1)(=[O:5])[CH2:2][CH2:3][CH3:4].[Li+].[CH3:17][CH:18]([N-]C(C)C)C.C1COCC1.ICC>C1COCC1>[CH2:3]([CH:2]([CH2:17][CH3:18])[C:1]([C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:15])[CH3:14])=[CH:8][CH:7]=1)=[O:5])[CH3:4]
Reactant: CCCC(=O)c1ccc(NC(C)=O)cc1
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCI
Solvent: C1CCOC1
Product: CCC(CC)C(=O)c1ccc(NC(C)=O)cc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of N-(4-butyrylphenyl)acetamide (3 g, 14.6 mmol) in THF (300 mL) was added 2.0 M LDA THF (18.3 mL) at −78° C. and then the reaction mixture was stirred for 1 h at −78° C. Iodoethane was added and stirred overnight at RT. The reaction mixture was quenched with sat. aq. NH4Cl and then extracted with ethyl acetate. The combined organic layers were dried over MgSO4, filtered and then concentrated. The crude product was purified by preparative TLC using 50% ethyl acetate in hexane as eluent to afford N-(4-(2-ethylbutanoyl)phenyl)acetamide as white solid. MS (ES+): m/z 234.28 (MH+).
Reaction SMILES: [NH2:1][C:2]([NH:4][C:5]1[CH:9]=[C:8](Br)[S:7][C:6]=1[C:11]([NH2:13])=[O:12])=[O:3].[S:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[CH:16]=[C:15]1B(O)O>>[NH2:1][C:2]([NH:4][C:5]1[CH:9]=[C:8]([C:15]2[S:14][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[CH:16]=2)[S:7][C:6]=1[C:11]([NH2:13])=[O:12])=[O:3]
Reactant: OB(O)c1cc2ccccc2s1
Reactant: NC(=O)Nc1cc(Br)sc1C(N)=O
Product: NC(=O)Nc1cc(-c2cc3ccccc3s2)sc1C(N)=O

Procedure:
The title compound was prepared from 3-[(aminocarbonyl)amino-5-bromothiophene-2-carboxamide and 1-benzothien-2-ylboronic acid in a similar manner to Example 11 (g).
Reaction SMILES: [CH3:1][O:2][CH:3]1[NH:7][C:6](=[O:8])[CH2:5][CH2:4]1.[Li+].CCC[CH2-].[CH:14]([S:22](Cl)(=[O:24])=[O:23])=[CH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O1CCCC1.CCCCCC>[CH:14]([S:22]([N:7]1[CH:3]([O:2][CH3:1])[CH2:4][CH2:5][C:6]1=[O:8])(=[O:24])=[O:23])=[CH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COC1CCC(=O)N1
Reactant: O=S(=O)(Cl)C=Cc1ccccc1
Agent: [CH2-]CCC
Agent: [Li+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COC1CCC(=O)N1S(=O)(=O)C=Cc1ccccc1
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 37.3 %

Procedure:
3.29 g of 5-methoxy-2-oxo pyrrolidine (SYNTHESIS 4, 315-17 (1980)) is dissolved in 100 cm3 of anhydrous tetrahydrofuran. After cooling to -20° C. 17.86 cm3 of a 1.6M solution of N-butyllithium in hexane is a while keeping the temperature at about -30° C. The mixture is agitated for 30 minutes at -35° to -30° C., then a solution of 5.80 g of styrenesulphonyl chloride (CA 47, 3262c, 1953) in 14 cm3 of anhydrous tetrahydrofuran is added slowly. After allowing this to return to ambient temperature, the solvent is evaporated under reduced pressure, and the residue is chromatographed on silica gel, eluting with a mixture of ethyl acetate and n-hexane (1--). The product obtained is crystallized from isopropanol, and 3 g of the expected product is obtained. m.p. 98°-99° C.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].CC(C)=O.C1(O)C=CC=CC=1.[CH2:18]([O:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][C:28]=1[OH:29])[CH:24]=[O:25])[CH3:19].Br[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[CH2:37][C:38]([O:40][CH3:41])=[O:39]>>[CH2:18]([O:20][C:21]1[CH:22]=[C:23]([CH:24]=[O:25])[CH:26]=[CH:27][C:28]=1[O:29][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[CH2:37][C:38]([O:40][CH3:41])=[O:39])[CH3:19]
Reactant: CCOc1cc(C=O)ccc1O
Reactant: COC(=O)Cc1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: Oc1ccccc1
Product: CCOc1cc(C=O)ccc1Oc1ccccc1CC(=O)OC
Yield: 92 %

Procedure:
Using the K2CO3 /acetone conditions for phenol alkylation described in Step A of Example 30, 1.00 g (6.02 mmol) of 3-ethoxy-4-hydroxybenzaldehyde was alkylated with 1.52 g (6.62 mmol) of methyl 2-bromophenylacetate to afford 1.74 g (92%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:37]=[CH:36][C:17]([O:18][CH2:19][C:20]([C:28]4[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=4[Cl:35])([OH:27])[CH2:21][N:22]4[CH:26]=[N:25][CH:24]=[N:23]4)=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.N1C=CC=CC=1.[Cl:44][CH2:45][CH2:46][CH2:47][S:48](Cl)(=[O:50])=[O:49]>C(Cl)Cl>[Cl:44][CH2:45][CH2:46][CH2:47][S:48]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:37]=[CH:36][C:17]([O:18][CH2:19][C:20]([C:28]4[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=4[Cl:35])([OH:27])[CH2:21][N:22]4[CH:26]=[N:25][CH:24]=[N:23]4)=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1)(=[O:50])=[O:49]
Reactant: Nc1ccc(N2CCN(c3ccc(OCC(O)(Cn4cncn4)c4ccc(Cl)cc4Cl)cc3)CC2)cc1
Reactant: O=S(=O)(Cl)CCCCl
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=S(=O)(CCCCl)Nc1ccc(N2CCN(c3ccc(OCC(O)(Cn4cncn4)c4ccc(Cl)cc4Cl)cc3)CC2)cc1
Reaction time: 2 h

Procedure:
To a solution of 3-(4-[4-(4-aminophenyl)piperazin-1-yl]phenoxy)-2-(2,4-dichlorophenyl)-1-(1H-1,2,4-triazol-1-yl)propan-2-ol (see Preparation 1) (0.2 g, 0.37 mmole) and pyridine (0.1 g, 1.2 mmole) in methylene chloride (15 ml) at 0° was added, dropwise, a solution of 3-chloropropanesulphonyl chloride (0.072 g, 0.4 mmole) in methylene chloride (1 ml). The resulting mixture was stirred at 0° for 2 hours, an additional portion of 3-chloropropanesulphonyl chloride (0.036 g, 0.2 mmole) was added and stirring was continued overnight at room temperature, the reaction mixture was quenched by the addition of aqueous citric acid, the organic phase separated and washed with water. After drying over magnesium sulphate, the organic phase was concentrated under reduced pressure and the resulting gum purified by flash chromatography on silica gel eluting with ethyl acetate to yield, after collection and evaporation of appropriate fractions, the desired product as a foam, m.p. 80°- 81° (0.24 g, 96%).
Reaction SMILES: O.ON1C2C=CC=CC=2N=N1.[CH2:12]([NH2:15])[CH:13]=[CH2:14].[F:16][C:17]([F:29])([F:28])[O:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=1.Cl.C(N=C=NCCCN(C)C)C>CN(C=O)C>[CH2:12]([NH:15][C:23](=[O:24])[C:22]1[CH:26]=[CH:27][C:19]([O:18][C:17]([F:16])([F:28])[F:29])=[CH:20][CH:21]=1)[CH:13]=[CH2:14]
Reactant: C=CCN
Reactant: O=C(O)c1ccc(OC(F)(F)F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: C=CCNC(=O)c1ccc(OC(F)(F)F)cc1
Reaction time: 2.5 h
Yield: 96 %

Procedure:
To a solution of 1-hydroxybenzotriazole hydrate (5.4 g, 40 mmol), allyl amine (60 mmol), and 4-(trifluoromethoxy)benzoic acid (8.3 g, 40 mmol) in DMF (110 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide-HCl (11.5 g, 60 mmol) at R.T. After the reaction mixture was stirred for 2.5 hrs, the solution was partitioned between 10% citric acid and ether. The organic layer was washed with sat. aqueous sodium bicarbonate, dried (sodium sulfate), filtered, and concentrated. The residue was purified by silica gel chromatography (20% ether/hexanes) to yield the title compound (colorless solid 96%). 1H NMR (400 MHz, CDCl3) δ7.85 (d, J=7.1 Hz, 2 H, Ar), 7.28 (d, J=5.9 Hz, 2 H, Ar), 6.31 (s, 1 H, NH), 5.94 (m, 1 H, CH2CHCH2), 5.25 (dd,J=8.6, 7.1 Hz, 2 H, NHCH2CH), 4.10 (m, 2 H, CHCH2);
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].N1CCCC1>C(O)C>[C:11]([O:15][C:16]([N:18]1[CH2:19][CH:20]=[C:21]([C:6]2[C:5]3[C:9](=[CH:10][C:2]([Br:1])=[CH:3][CH:4]=3)[NH:8][CH:7]=2)[CH2:22][CH2:23]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: Brc1ccc2cc[nH]c2c1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Solvent: CCO
Solvent: C1CCNC1
Product: CC(C)(C)OC(=O)N1CC=C(c2c[nH]c3cc(Br)ccc23)CC1
Yield: 46.9 %

Procedure:
A stirred solution of 6-bromoindole (390 mg, 2.0 mmol), t-butyl-4-oxo-1-piperidinecarboxylate (438 mg, 2.2 mmol), and pyrrolidine (0.42 mL, 5.0 mmol) in ethanol (10 mL) was heated at reflux for 16 hours. Solvent was evaporated and the residue subjected to chromatography on silica gel with 20% ethyl acetate/hexanes to afford a yellow solid (354 mg, 47%).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:4]([CH2:13][CH3:14])[N:3]=1.[Br:15]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:4]([CH:13]([Br:15])[CH3:14])[N:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1ccc(Cl)nc1CC
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1ccc(Cl)nc1C(C)Br

Procedure:
A solution of ethyl 6-chloro-2-ethylnicotinate (1.0 g, 4.7 mmol), N-bromosuccinimide (0.85 g, 4.8 mmol) and benzoyl peroxide (10 mg) in 10 ml of carbon tetrachloride is heated to reflux while irradiated with a floodlamp for 3 hours. The reaction mixture is cooled and the solid succinimide is removed by filtration. The solid is washed several times with carbon tetrachloride and the filtrate is stripped by rotoevaporation to give ethyl 6-chloro-2-(1-bromoethyl)nicotinate.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[CH2:8][C:9]1[CH:43]=[CH:42][C:12]([C:13]([NH:15][C:16]2[C:17]3[CH:30]=[C:29]([C:31]([NH:33][N:34]([CH3:41])[C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)=[O:32])[S:28][C:18]=3[N:19](C(OC(C)(C)C)=O)[N:20]=2)=[O:14])=[CH:11][CH:10]=1.ClCC1C=CC(C(NC2C3C=C(C(NN(C4C=CC(Cl)=CC=4)C)=O)SC=3N(C(OC(C)(C)C)=O)N=2)=O)=CC=1>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O>[CH3:41][N:34]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[NH:33][C:31]([C:29]1[S:28][C:18]2[NH:19][N:20]=[C:16]([NH:15][C:13](=[O:14])[C:12]3[CH:42]=[CH:43][C:9]([CH2:8][N:1]4[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]4)=[CH:10][CH:11]=3)[C:17]=2[CH:30]=1)=[O:32]
Reactant: CN(NC(=O)c1cc2c(NC(=O)c3ccc(CCl)cc3)nn(C(=O)OC(C)(C)C)c2s1)c1ccccc1
Reactant: C1CNCCN1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CN(NC(=O)c1cc2c(NC(=O)c3ccc(CCl)cc3)nn(C(=O)OC(C)(C)C)c2s1)c1ccc(Cl)cc1
Agent: [I-]
Solvent: CN(C)C=O
Product: CN(NC(=O)c1cc2c(NC(=O)c3ccc(CN4CCNCC4)cc3)n[nH]c2s1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
27 mg (74 μmol) of tetrabutylammonium iodide, followed by 96 mg (1.11 mmol) of piperazine, are added to a solution of 200 mg (0.37 mmol) of an approximately 70:30 mixture of tert-butyl 3-(4-chloromethylbenzoylamino)-5-(N′-methyl-N′-phenylhydrazinocarbonyl)thieno[2,3-c]pyrazole-1-carboxylate and tert-butyl 3-(4-chloromethylbenzoylamino)-5-(N′-(4-chlorophenyl)-N′-methylhydrazinocarbonyl)-thieno[2,3-c]pyrazole-1-carboxylate in 6 mL of dimethylformamide under argon. The reaction mixture is stirred at a temperature in the region of 25° C. for 16 hours, and then treated with ice. It is then extracted with ethyl acetate and then twice with dichloromethane. The organic extracts are combined and then concentrated to dryness under vacuum (2 kPa) at a temperature in the region of 40° C. The residue is dissolved in 3 mL of methanol and the solution is introduced into a microwave oven tube. The tube is stoppered and the reaction mixture is irradiated at a temperature in the region of 100° C. for twice 30 minutes. The reaction mixture is then concentrated to dryness under vacuum (2 kPa) at a temperature in the region of 40° C. The residue is purified by preparative LC/MS (conditions B). 83 mg of N-[5-(N′-methyl-N′-phenylhydrazinocarbonyl)-1H-thieno[2,3-c]pyrazol-3-yl]-4-piperazin-1-ylmethylbenzamide are thus obtained in the form of a yellow powder melting at 176° C. LC-MS-DAD-ELSD: 490(+)=M(+H)(+).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:4][CH2:3]1.C[Si](C)(C)[C:20]([F:23])([F:22])[F:21].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>[CH2:11]([O:10][C:8]([N:5]1[CH2:4][CH2:3][C:2]([OH:1])([C:20]([F:23])([F:22])[F:21])[CH2:7][CH2:6]1)=[O:9])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1CCC(O)(C(F)(F)F)CC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 62.9 %

Procedure:
In a 3-neck round-bottomed flask, benzyl 4-oxopiperidine-1-carboxylate (1.0 g, 4.3 mmol) was dissolved in THF (10 mL). The reaction mixture was cooled to 0° C. and trimethyl(trifluoromethyl)silane (0.78 mL, 5.3 mmol) was added. Then added TBAF (1.0M solution in THF, 0.05 mL, 0.05 mmol) which caused the internal temperature to rise to 30° C. The reaction mixture was stirred at room temperature overnight. Additional TBAF (1.0M solution in THF, 4.3 mL, 4.3 mmol) was added and the reaction mixture was stirred at room temperature for 4.25 h. The reaction mixture was quenched with water and extracted with CH2Cl2 (2×). The organic layers were combined, dried over sodium sulfate, filtered and concentrated. The residue was triturated with toluene to afford 0.82 g (63%) of 4-hydroxy-4-trifluoromethyl-piperidine-1-carboxylic acid benzyl ester as a light yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH:11]([OH:13])[CH:10]([N:14]3[CH2:19][CH2:18][N:17]([C:20]([C:22]4[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=4)=[O:21])[CH2:16][CH2:15]3)[CH2:9]2)=[C:4]([N+:29]([O-:31])=[O:30])[CH:3]=1.CCN(CC)CC.[C:39](Cl)(=[O:41])[CH3:40]>C(Cl)Cl>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([C:20]([N:17]2[CH2:16][CH2:15][N:14]([CH:10]3[CH2:9][N:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=4[N+:29]([O-:31])=[O:30])[CH2:12][CH:11]3[O:13][C:39](=[O:41])[CH3:40])[CH2:19][CH2:18]2)=[O:21])=[CH:23][CH:24]=1
Reactant: CC(=O)Cl
Reactant: O=C(c1ccc(Cl)cc1)N1CCN(C2CN(c3ccc(Cl)cc3[N+](=O)[O-])CC2O)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OC1CN(c2ccc(Cl)cc2[N+](=O)[O-])CC1N1CCN(C(=O)c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.3 %

Procedure:
To a solution of {4-[1-(4-chloro-2-nitro-phenyl)-4-hydroxy-pyrrolidin-3-yl]-piperazin-1-yl}-(4-chloro-phenyl)-methanone (300 mg, 0.64 mmol) in CH2Cl2 (5 mL) at 0° C., was added Et3N (0.2 mL, 1.42 mmol) and acetyl chloride (112 mg, 1.42 mmol). The mixture was stirred at RT for overnight. The organic phase was washed with Saturated NaHCO3, dried over Na2SO4, and concentrated. The residue was purified by column chromatography (Ethyl acetate) to give the desired product (160 mg, 50% yield) as a yellow oil. MS: (ESI), M/Z, 507(M+1). Retention time: 2.59 min (FA-polar).
Reaction SMILES: [O:1]1[CH:3]([CH2:4][O:5][C:6]2[S:7][C:8]([C:11]([NH:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]#[CH:19])=[O:12])=[CH:9][N:10]=2)[CH2:2]1.[C:20]([NH2:24])([CH3:23])([CH3:22])[CH3:21]>C(O)C>[C:20]([NH:24][CH2:2][CH:3]([OH:1])[CH2:4][O:5][C:6]1[S:7][C:8]([C:11]([NH:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]#[CH:19])=[O:12])=[CH:9][N:10]=1)([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)N
Reactant: C#CCCCCNC(=O)c1cnc(OCC2CO2)s1
Solvent: CCO
Product: C#CCCCCNC(=O)c1cnc(OCC(O)CNC(C)(C)C)s1
Temperature: -20 °C
Reaction time: 12 h

Procedure:
This examole illustrates methods for preparing the compounds of the present invention. In this examole a mixture containing 12 g. (0.037 mole) of 1,2-epoxy-3-[5-(hex-5-ynylaminocarbonyl)thiazol-2-yloxy]propane, 12 g. (0.164 mole) of t-butylamine and 20 ml. of ethanol is allowed to stand at room temperature for 12 hours. The mixture is then evaporated under vacuum to remove the ethanol solvent and the resulting residue dissolved in 50 ml. of ethyl acetate and cooled to -20° C, and maintained at this temperature for two hours. The mixture is then filtered and the resulting filter cake washed with cold (about 0° C) ethyl ether and then recrystallized from ethyl acetate affording 1-t-butylamino-3-[5-(hex-5-ynylaminocarbonyl)thiazol-2-yloxy]propan-2-ol, m.p. 140°-148° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[O:16][CH2:17][CH3:18])=[CH:13][C:12]([CH:19]=O)=[CH:11][CH:10]=2)=[O:5])[CH3:2].[C:21]1([C@@H:27]2[CH2:29][C@H:28]2[NH:30][C:31]2[S:32][CH2:33][C:34](=[O:36])[N:35]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[O:16][CH2:17][CH3:18])=[CH:13][C:12](/[CH:19]=[C:33]1/[C:34](=[O:36])[N:35]=[C:31]([NH:30][C@@H:28]3[CH2:29][C@H:27]3[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[S:32]/1)=[CH:11][CH:10]=2)=[O:5])[CH3:2]
Reactant: O=C1CSC(N[C@@H]2C[C@H]2c2ccccc2)=N1
Reactant: CCOC(=O)c1cnc2ccc(C=O)cc2c1OCC
Product: CCOC(=O)c1cnc2ccc(/C=C3\SC(N[C@@H]4C[C@H]4c4ccccc4)=NC3=O)cc2c1OCC

Procedure:
Similar procedure as described in example 1g was used, starting from 6-formyl-4-ethoxy-quinoline-3-carboxylic acid ethyl ester (example 9b) and 2-((1R,2S)-2-phenyl-cyclopropylamino)-thiazol-4-one (example 1f) to give 4-ethoxy-6-[4-oxo-2-((1R,2S)-2-phenyl-cyclopropylamino)-4H-thiazol-(5Z)-ylidenemethyl]-quinoline-3-carboxylic acid ethyl ester. LC-MS m/e 488 (MH+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH:10]=[CH:11][N:12]=2)=[CH:4][CH:3]=1.[C:13]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14]>>[C:16]([O:15][C:13]([N:20]1[CH2:25][CH2:24][N:23]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[O:9][CH:10]=[CH:11][N:12]=3)=[CH:4][CH:3]=2)[CH2:22][CH2:21]1)=[O:14])([CH3:19])([CH3:17])[CH3:18]
Reactant: Brc1ccc(-c2ncco2)cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3ncco3)cc2)CC1

Procedure:
Prepared in analogy to example 4.4 (a) from 2-(4-Bromo-phenyl)-oxazole and N-BOC -piperazine. MS (m/e): 330.3 (MH+, 100%)