Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=O.Cl.[NH:13]1[CH:17]=[C:16]([CH2:18][C:19]([NH2:21])=[S:20])[N:15]=[CH:14]1>CC(O)C>[NH:13]1[CH:17]=[C:16]([CH2:18][C:19]2[S:20][C:2]3[CH2:10][C:9]4[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=4[C:3]=3[N:21]=2)[N:15]=[CH:14]1
Reactant: NC(=S)Cc1c[nH]cn1
Reactant: O=C1c2ccccc2CC1Br
Agent: Cl
Solvent: CC(C)O
Product: c1ccc2c(c1)Cc1sc(Cc3c[nH]cn3)nc1-2
Yield: 32.4 %

Procedure:
0.34 g of 2-bromo-1-indanone and 0.26 g of 4-imidazolyl thioacetamide hydrochloride were dissolved in 7 ml of 2-propanol with heating, and the solution was heated for 30 minutes under reflux. After cooling the reaction solution, the precipitated crystals were collected by filtration and washed with ethyl acetate. The collected crystals were partitioned between chloroform and a saturated aqueous sodium bicarbonate solution, and the aqueous layer was extracted with chloroform several times. The combined chloroform layers were washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. By evaporation of the solvent, 0.12 g (32%) of 2-(4-imidazolylmethyl)-8H-indeno[1,2-d]thiazole was obtained. This free base was dissolved in methanol and mixed with 0.055 g of fumaric acid to effect crystallization. The resulting crude crystals were recrystallized from methanol-diethyl ether to obtain 0.10 g of fumarate.
Reaction SMILES: [CH3:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([CH3:9])[N:3]=1.[C:10](Cl)(Cl)=[S:11].C(N(C(C)C)C(C)C)C>C(Cl)Cl>[N:8]([C:7]1[C:2]([CH3:1])=[N:3][C:4]([CH3:9])=[CH:5][CH:6]=1)=[C:10]=[S:11]
Reactant: Cc1ccc(N)c(C)n1
Reactant: S=C(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc(N=C=S)c(C)n1
Yield: 66.4 %

Procedure:
The title compound was prepared following the procedure described for intermediate-2 using 2,6-dimethylpyridin-3-amine (1.0 g, 8.26 mmol), thiophosgene (0.949 g, 8.25 mmol) and N-ethyl di-isopropyl amine (3.20 g, 24.80 mmol) in DCM (20 mL) to afford 0.900 g of the desired product. 1HNMR (DMSO-d6): δ 2.44 (s, 6H), 7.18 (d, J=8.1 Hz, 1H), 7.70 (t, J=8.1 Hz, 1H); MS [M+H]+: 165.28.
Reaction SMILES: [CH3:1][C:2]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:3]=1[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12](=[O:17])[C:13]([NH:15][CH3:16])=[O:14].[BH4-].[Na+].Cl>CO>[CH3:1][C:2]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:3]=1[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH:12]([OH:17])[C:13]([NH:15][CH3:16])=[O:14]
Reactant: CNC(=O)C(=O)c1ccccc1COc1cc(C)ccc1C
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CNC(=O)C(O)c1ccccc1COc1cc(C)ccc1C
Reaction time: 0.5 h
Yield: 91.6 %

Procedure:
2-[2-(2,5-Dimethylphenoxymethyl)phenyl]-N-methyl-2-oxoacetamide (0.93 g, 3.1 mmol) was dissolved in methanol (10 ml). Sodium borohydride (0.06 g, 1.6 mmol) was added slowly under ice-cooling. After stirring for 30 minutes, the mixture was neutralized with 1N hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate, and the solvent was evaporated to give an oil. The oil was purified by column chromatography on silica gel (eluting with n-hexane-ethyl acetate) to give the desired compound 2-[2-(2,5-dimethylphenoxymethyl)phenyl]-2-hydroxy-N-methylacetamide (0.85 g, 91%) as white crystals.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:22])=[C:11]([CH2:13][C:14]([N:16]3[CH2:20][CH2:19][CH2:18][C@H:17]3[CH3:21])=O)[N:12]=2)=[CH:4][CH:3]=1.Br[CH2:24][C:25]1[S:29][C:28]([C:30]#[N:31])=[CH:27][CH:26]=1>>[CH3:22][C:10]1[O:9][C:8]([C:5]2[CH:6]=[CH:7][C:2]([O:1][CH2:24][C:25]3[S:29][C:28]([C:30]#[N:31])=[CH:27][CH:26]=3)=[CH:3][CH:4]=2)=[N:12][C:11]=1[CH2:13][CH2:14][N:16]1[CH2:20][CH2:19][CH2:18][C@H:17]1[CH3:21]
Reactant: Cc1oc(-c2ccc(O)cc2)nc1CC(=O)N1CCC[C@H]1C
Reactant: N#Cc1ccc(CBr)s1
Product: Cc1oc(-c2ccc(OCc3ccc(C#N)s3)cc2)nc1CCN1CCC[C@H]1C

Procedure:
The title compound is prepared in a manner substantially similar to Example 57 from 2-[2-(4-Hydroxy-phenyl)-5-methyl-oxazol-4-yl]-1-(2-(R)-methyl-pyrrolidin-1 -yl)-ethanone (See Example 56) and 5-bromomethyl-thiophene-2-carbonitrile [CAS 134135-41-4]. MS (m/e): 408.3 (M+1)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][CH2:11][N:12]2[CH:16]=[CH:15][N:14]=[CH:13]2)[CH:5]=[CH:6][C:7]=1[OH:8].Cl[CH2:18][C:19]1[N:20]=[C:21]([C:24]2[S:25][CH:26]=[CH:27][CH:28]=2)[O:22][CH:23]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][CH2:11][N:12]2[CH:16]=[CH:15][N:14]=[CH:13]2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:18][C:19]1[N:20]=[C:21]([C:24]2[S:25][CH:26]=[CH:27][CH:28]=2)[O:22][CH:23]=1
Reactant: ClCc1coc(-c2cccs2)n1
Reactant: Oc1ccc(CCCn2ccnc2)cc1Cl
Product: Clc1cc(CCCn2ccnc2)ccc1OCc1coc(-c2cccs2)n1
Yield: 77 %

Procedure:
In substantially the same manner as in Working Example 72, 1-[3-(3-chloro-4-hydroxyphenyl)propyl]imidazole was reacted with 4-chloromethyl-2-(2-thienyl)oxazole to obtain 4-[2-chloro-4-[3-(1-imidazolyl)propyl]phenoxymethyl]-2-(2-thienyl)oxazole. The yield was 77%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 93-94° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:11])[CH:10]=1)[C:5](O)=[O:6].[N:12]1C=CC=CC=1.CC(OC(OC(OC(C)(C)C)=O)=O)(C)C>CC#N>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:11])[CH:10]=1)[C:5]([NH2:12])=[O:6]
Reactant: O=C(O)c1cc(Cl)cc(Br)c1
Reactant: c1ccncc1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: CC#N
Product: NC(=O)c1cc(Cl)cc(Br)c1
Reaction time: 0.5 h

Procedure:
To a solution of 3-bromo-5-chlorobenzoic acid (2.88 g; 12.2 mmol; Note 1) and pyridine (1.04 mL; 12.8 mmol) in MeCN (100 mL) at room temperature was added (Boc)2O (3.47 g; 15.9 mmol) in one portion. The mixture was aged 30 min, (NH4)2CO3 was added in one portion.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([CH3:13])=[C:11]([CH:14]2[CH2:18][C:17](=O)[CH2:16][S:15]2)[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)C.Cl.[OH:24][NH2:25].C([O-])(=O)C.[Na+]>O>[CH2:1]([N:8]1[C:12]([CH3:13])=[C:11]([CH:14]2[CH2:18][C:17](=[N:25][OH:24])[CH2:16][S:15]2)[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NO
Reactant: Cc1c(C2CC(=O)CS2)ncn1Cc1ccccc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1c(C2CC(=NO)CS2)ncn1Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-(1-Benzyl-5-methyl-4-imidazolyl)-4-oxotetrahydrothiophene (0.14 g., 0.5 mole) is dissolved in 1 ml. of ethanol and 1 ml. of water is added. Then hydroxyamine hydrochloride (38 mg., 0.55 mole) and sodium acetate (45 mg., 0.55 mole) are added. The mixture is stirred at room temperature overnight. The reaction mixture is concentrated in vacuo. The residue is triturated with chloroform and the mixture is filtered. The chloroform extract is dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude oxime, 2-(1-benzyl-5-methyl-4-imidazolyl)-4-oxotetrahydrothiophene oxime, is a brown viscous oil (0.15 g.).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([CH:7]=[N:8][OH:9])=[CH:5][CH:4]=1.[Cl:12]N1C(=O)CCC1=O.Cl.O>CN(C=O)C.O1CCOCC1>[CH:11]1[C:3]([CH2:2][Cl:1])=[CH:4][CH:5]=[C:6](/[C:7](/[Cl:12])=[N:8]\[OH:9])[CH:10]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: ON=Cc1ccc(CCl)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1COCCO1
Solvent: O
Product: O/N=C(/Cl)c1ccc(CCl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
4-Chloromethylbenzaldehyde oxime (12.69 g, 74.82 mmol) was dissolved in DMF (250 ml), N-chlorosuccinimide (12.00 g, 89.87 mmol), and then 4N hydrogen chloride in 1,4-dioxane (120 ml) were added, and the mixture was stirred at room temperature for 30 min. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (15.27 g, 100%).
Reaction SMILES: [C:1]([C:9]1[N:10]=[C:11]([CH2:16][CH2:17][CH2:18][CH3:19])[NH:12][C:13]=1[C:14]#[N:15])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[C:29]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])=[CH:30][CH:31]=[CH:32][CH:33]=2)=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C(=O)C>[C:1]([C:9]1[N:10]=[C:11]([CH2:16][CH2:17][CH2:18][CH3:19])[N:12]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])=[CH:24][CH:23]=2)[C:13]=1[C:14]#[N:15])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCc1nc(C(=O)c2ccccc2)c(C#N)[nH]1
Reactant: CC(C)(C)OC(=O)c1ccccc1-c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CCCCc1nc(C(=O)c2ccccc2)c(C#N)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Yield: 80.7 %

Procedure:
Following a procedure similar to that described in Example 11(a), but using 1.27 g of 4-benzoyl-2-butyl-5-cyanoimidazole (prepared as described in Preparation 6), 1.74 g of t-butyl 4'-bromomethylbiphenyl-2-carboxylate, 0.69 of potassium carbonate and 20 ml of N,N-dimethylacetamide, and then purifying the product by column chromatography through silica gel, using a 2:1 by volume mixture of hexane and ethyl acetate as the eluent, 2.1 g of the title compound were obtained.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([Cl:11])[CH:10]=1)[CH:7]([NH2:12])[CH2:6][CH2:5]2.ClC1C=CC=C2C=1C(=O)CC2>>[Cl:11][C:9]1[CH:10]=[CH:2][CH:3]=[C:4]2[C:8]=1[CH:7]([NH2:12])[CH2:6][CH2:5]2
Reactant: NC1CCc2cc(Cl)cc(Cl)c21
Agent: O=C1CCc2cccc(Cl)c21
Product: NC1CCc2cccc(Cl)c21

Procedure:
This compound was prepared using a method analogous to that of 5,7-dichloro-2,3-dihydro-1H-inden-1-amine (A.2.13), 7-chloro-1-indanone replacing 5,7-dichloro-1-indanone.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]1[N:6]([CH2:25][CH2:26][CH2:27][N:28]2[CH2:32][CH2:31][CH2:30][C:29]2=[O:33])[C:7]2[C:16]3[CH:15]=[C:14]([CH:17]=[CH:18][C:19]([N:21]([CH3:23])[CH3:22])=[O:20])[CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:24]=1>[Pd].CO>[CH3:1][O:2][CH2:3][CH2:4][C:5]1[N:6]([CH2:25][CH2:26][CH2:27][N:28]2[CH2:32][CH2:31][CH2:30][C:29]2=[O:33])[C:7]2[C:16]3[CH:15]=[C:14]([CH2:17][CH2:18][C:19]([N:21]([CH3:23])[CH3:22])=[O:20])[CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:24]=1
Reactant: COCCc1nc2cnc3ccc(C=CC(=O)N(C)C)cc3c2n1CCCN1CCCC1=O
Agent: [Pd]
Solvent: CO
Product: COCCc1nc2cnc3ccc(CCC(=O)N(C)C)cc3c2n1CCCN1CCCC1=O
Temperature: 50 °C
Reaction time: 72 h
Yield: 108.5 %

Procedure:
A glass Parr vessel was charged with 10% palladium on carbon (0.07 g), methanol (50 mL) and 3-{2-(2-methoxyethyl)-1-[3-(2-oxopyrrolidin-1-yl)propyl]-1H-imidazo[4,5-c]quinolin-8-yl}-N,N-dimethylprop-2-enamide (0.66 g, 1.47 mmol). The vessel was evacuated and charged with hydrogen gas (40 psi, 2.8×105 Pa). The mixture was shaken at 50° C. for approximately 72 hours. The reaction mixture was cooled to ambient temperature and filtered. The filtrate was concentrated under reduced pressure to provide 720 mg of crude 3-{2-(2-methoxyethyl)-1-[3-(2-oxopyrrolidin-1-yl)propyl]-1H-imidazo[4,5-c]quinolin-8-yl}-N,N-dimethylpropanamide as a white semi-solid. MS (ESI) m/z 452 (M+H)+.
Reaction SMILES: [N:1]([C@H:4]1[C:8]([CH3:10])([CH3:9])[CH2:7][O:6][C:5]1=[O:11])=[N+]=[N-].[O:12](C(OC(C)(C)C)=O)[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=O>CO.C(Cl)Cl.CCOC(C)=O.[Pd]>[CH3:9][C:8]1([CH3:10])[CH2:7][O:6][C:5](=[O:11])[C@H:4]1[NH:1][C:13](=[O:12])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: CC1(C)COC(=O)[C@H]1N=[N+]=[N-]
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H]1C(=O)OCC1(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of (S)-3-azido-4,4-dimethyldihydrofuran-2(3H)-one (5.52 g) in MeOH 910 mL) was added 10% Pd/C (0.379 g, 0.356 mmol) under N2. The reaction mixture was stirred under H2 at rt for 16 hrs. The reaction was filtered through diatomaceous earth (Celite®), washed with EtOAc and the filtrate was concentrated to yield a clear oil. To the above oil in DCM (10 mL) was added BOC2O (9.09 mL) and TEA (13.88 mL). The reaction mixture was stirred at rt for 16 hrs. The reaction mixture was diluted with EtOAc, washed with sat. NaHCO3, citric acid, water, sat. NaCl, dried over anhydrous Na2SO4, filtered and concentrated to yield an oil. The crude product was purified by silica gel chromatography (0-100% EtOAc in hexane) to yield (S)-tert-butyl 4,4-dimethyl-2-oxotetrahydrofuran-3-ylcarbamate (3.8 g) as a white solid. LC/MS (Cond. N-1): [M+Na]+ 252.06, RT=2.75 min. 1H NMR (400 MHz, CHLOROFORM-d) ppm 4.81-4.95 (1H, m), 4.38 (1H, d, J=7.78 Hz), 3.97-4.07 (2H, m), 1.47 (9H, s), 1.25 (3H, s), 1.01 (3H, s).
Reaction SMILES: [C:1]([C:3]1[C:8]([OH:9])=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])#[N:2].S(C1C=CC([N+]([O-])=O)=CC=1)(O[CH2:22][C@@H:23]1[O:25][CH2:24]1)(=O)=O>>[CH2:22]([O:9][C:8]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:3]=1[C:1]#[N:2])[C@@H:23]1[O:25][CH2:24]1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)OC[C@H]2CO2)cc1
Reactant: CCOC(=O)CCCc1cccc(O)c1C#N
Product: CCOC(=O)CCCc1cccc(OC[C@H]2CO2)c1C#N
Yield: 80.2 %

Procedure:
Using the method of example 1(a), supra, ethyl 4-(2-cyano3-hydroxyphenyl)butanoate (1.9 g, 7.33 mmol) and (R)-glycidyl nosylate (1.78 g, 7.6 mmol) were used to prepare 1.70 g (80%) of the title compound as a white solid.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([C:14]3[CH:15]=[C:16]([S:20](Cl)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=3)[CH:9]=2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:3]=1.[NH:34]1[CH2:39][CH2:38][S:37][CH2:36][CH2:35]1>C1COCC1.CCOC(C)=O>[CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([N:34]4[CH2:39][CH2:38][S:37][CH2:36][CH2:35]4)(=[O:22])=[O:21])[CH:15]=3)[CH:9]=2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:3]=1
Reactant: C1CSCCN1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2ccnc(-c3cccc(S(=O)(=O)Cl)c3)c2)n1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2ccnc(-c3cccc(S(=O)(=O)N4CCSCC4)c3)c2)n1
Temperature: 25 °C
Yield: 66 %

Procedure:
The title compound was prepared from the solution of 3-[6-methyl-4-(4-trifluoromethyl-phenyl)-[2,4′]bipyridinyl-2′-yl]-benzenesulfonyl chloride (example 346 step 2) (ca. 0.2 g, 0.41 mmol) by treatment with excess thiomorpholine in THF (5 mL) at 50° C. for 16 h. Cooled to rt, diluted with EtOAc, washed with 1 N HCl, dried organic layer over Na2SO4. Removal of the solvent in vacuum left a crude product, which was purified by silica gel column chromatography with n-heptane/EtOAc followed by trituration with n-heptane/diethyl ether to give the title compound (0.150 g, 66%) as a white solid. MS (ISP) 555.8 [(M+H)+]; mp 156° C. (dec.).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.[F:12][C:13]([F:24])([F:23])[C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Na+].[Na+]>O.C(O)C.C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:12][C:13]([F:24])([F:23])[C:14]1[CH:19]=[CH:18][C:17]([C:2]2[CH:10]=[C:9]3[C:5]([CH:6]=[CH:7][N:8]3[CH3:11])=[CH:4][CH:3]=2)=[CH:16][CH:15]=1
Reactant: Cn1ccc2ccc(Br)cc21
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: Cn1ccc2ccc(-c3ccc(C(F)(F)F)cc3)cc21
Temperature: 25 °C
Yield: 50.8 %

Procedure:
The mixture of 6-bromo-1-methyl-1H-indole (0.216 g, 1.03 mmol), 4-trifluoromethylbenzeneboronic acid (0.216 g, 1.14 mmol), tetrakis(triphenylphosphine)palladium (0.0541 g, 0.0468 mmol) and sodium carbonate (0.438 g, 4.13 mmol) in water (2.5 mL), ethanol (1 mL) and toluene (5 mL) was refluxed for 1.6 hours. The mixture was cooled to room temperature then evaporated to dryness. The residue was partitioned in methylene chloride and water. The organic phase was washed with water, brine, dried over anhydrous magnesium sulfate and evaporated to dryness. The residue was purified by flash chromatography using 0-0.2% ethyl acetate in hexane as an eluant to give the title compound (0.144 g, 51%) as a white solid, mp: ˜100° C.; 1HNMR (200 MHz, DMSO-d6): δ 8.0 (d, 2H, J=6.6 Hz), 7.8 (d, 3H, J=8.7 Hz), 7.65 (d, 1H, J=8.7 Hz), 7.35-7.5 (m, 2H), 6.45 (d, 1H, J=2.6 Hz), and 3.8-3.95 ppm (m, 3H).
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:10]([O:12]CC3C=CC=CC=3)=[O:11])=[N:8][CH:9]=2)[CH2:3][CH2:2]1>CO.[OH-].[OH-].[Pd+2]>[CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:10]([OH:12])=[O:11])=[N:8][CH:9]=2)[CH2:2][CH2:3]1
Reactant: O=C(OCc1ccccc1)c1ccc(C2CC2)cn1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(C2CC2)cn1

Procedure:
To a solution of benzyl 5-cyclopropylpicolinate in MeOH (15 mL) was added 20% Pd(OH)2/C (100 mg). The hydrogenolysis with H2 was carried out at room temperature under a H2 balloon. The desired product 5-cyclopropylpicolinic acid (305 mg) was obtained after filtration and concentration.
Reaction SMILES: [CH2:1]([C@H:7]1[C@H:10]([CH2:11][C@H:12]([OH:17])[CH2:13][CH2:14][CH:15]=[CH2:16])[O:9][C:8]1=[O:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH:19]([NH:21][C@H:22]([C:27](O)=[O:28])[CH2:23][CH:24]([CH3:26])[CH3:25])=[O:20]>>[CH2:1]([C@@H:7]1[C:8](=[O:18])[O:9][C@H:10]1[CH2:11][CH:12]([O:17][C:27](=[O:28])[C@H:22]([CH2:23][CH:24]([CH3:26])[CH3:25])[NH:21][CH:19]=[O:20])[CH2:13][CH2:14][CH:15]=[CH2:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CC(C)C[C@H](NC=O)C(=O)O
Reactant: C=CCC[C@@H](O)C[C@@H]1OC(=O)[C@H]1CCCCCC
Product: C=CCCC(C[C@@H]1OC(=O)[C@H]1CCCCCC)OC(=O)[C@H](CC(C)C)NC=O

Procedure:
by esterifying (S)-3-hexyl-(S)-4-[(R)-2-hydroxy-5-hexenyl)-2-oxetanone with N-formyl-L-leucine there was obtained
Reaction SMILES: C(OC([N:8]1[C@@H:12]([C:13]([O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22](=[O:24])[CH3:23])=[CH:18][CH:17]=2)=[O:14])[CH2:11][O:10]C1(C)C)=O)(C)(C)C.[F:27][C:28]([F:33])([F:32])[C:29]([OH:31])=[O:30]>ClCCl>[F:27][C:28]([F:33])([F:32])[C:29]([OH:31])=[O:30].[NH2:8][C@H:12]([CH2:11][OH:10])[C:13]([O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22](=[O:24])[CH3:23])=[CH:18][CH:17]=1)=[O:14]
Reactant: CC(=O)c1ccc(OC(=O)[C@H]2COC(C)(C)N2C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)c1ccc(OC(=O)[C@H](N)CO)cc1
Reaction time: 1 h

Procedure:
Under nitrogen, 4-acetylphenyl 3-tert-butoxycarbonyl-2,2-dimethyloxazolidine-4-(R)-carboxylate (440 mg) is dissolved in dichloromethane (15 ml), and trifluoroacetic acid (TFA; 8 ml) is added. After being subjected to agitation for 1 hour, the reaction mixture is concentrated and ether is added. The formed precipitate is filtered, then vacuum dried to obtain the desired product as a white powder (280 mg). Melting point: 115-118° C.
Reaction SMILES: CS(C)=O.[CH:5]1([N:10]2[C:19]3[C:14](=[CH:15][C:16]([F:21])=[C:17](F)[CH:18]=3)[C:13](=[O:22])[C:12]([N+:23]([O-:25])=[O:24])=[CH:11]2)[CH2:9][CH2:8][CH2:7][CH2:6]1.[CH:26]1([NH2:32])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>O>[CH:26]1([NH:32][C:17]2[CH:18]=[C:19]3[C:14]([C:13](=[O:22])[C:12]([N+:23]([O-:25])=[O:24])=[CH:11][N:10]3[CH:5]3[CH2:9][CH2:8][CH2:7][CH2:6]3)=[CH:15][C:16]=2[F:21])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: O=c1c([N+](=O)[O-])cn(C2CCCC2)c2cc(F)c(F)cc12
Reactant: NC1CCCCC1
Solvent: O
Solvent: CS(C)=O
Product: O=c1c([N+](=O)[O-])cn(C2CCCC2)c2cc(NC3CCCCC3)c(F)cc12
Temperature: 90 °C
Reaction time: 8 h

Procedure:
To a 40 ml DMSO solution of 2.0 g of 1-cyclopentyl-6,7-difluoro-3-nitroquinolin-4(1H)-one was added 2.3 ml of cyclohexylamine, followed by overnight stirring at 90° C. The reaction mixture was cooled to room temperature and poured into ice-cooled water, and then the insoluble materials were collected by filtration. By recrystallizing the resulting solid from ethanol, 2.5 g of 7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-3-nitroquinolin-4(1H)-one was obtained.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([OH:12])[CH:3]=1.[Br:13][C:14]1[CH:19]=[C:18]([N+]([O-])=O)[CH:17]=[C:16]([Br:23])[N:15]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[CH3:9][O:8][C:6](=[O:7])[C:5]1[CH:10]=[CH:11][C:2]([F:1])=[CH:3][C:4]=1[O:12][C:18]1[CH:17]=[C:16]([Br:23])[N:15]=[C:14]([Br:13])[CH:19]=1
Reactant: COC(=O)c1ccc(F)cc1O
Reactant: O=[N+]([O-])c1cc(Br)nc(Br)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(F)cc1Oc1cc(Br)nc(Br)c1

Procedure:
A solution of methyl 4-fluoro-2-hydroxybenzoate (2.00 g), 2,6-dibromo-4-nitropyridine (3.65 g), and cesium carbonate (4.21 g) in N,N-dimethylformamide (100 mL) was heated to 55° C. for 16 hours, cooled, added to water, and extracted with 50% ethyl acetate in hexanes. The organic extract was washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated and purified by flash column chromatography on silica gel using 30-50% ethyl acetate in hexanes.
Reaction SMILES: Cl[C:2](=[CH2:5])[C:3]#[N:4].[CH2:6]([O:13][N:14]1[C:20](=[O:21])[N:19]2[CH2:22][C@H:15]1[CH2:16][CH2:17][C@H:18]2[C:23](Cl)=[N:24][OH:25])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(Cl)Cl>[CH2:6]([O:13][N:14]1[C:20](=[O:21])[N:19]2[CH2:22][C@H:15]1[CH2:16][CH2:17][C@H:18]2[C:23]1[CH:5]=[C:2]([C:3]#[N:4])[O:25][N:24]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C1N2C[C@@H](CC[C@H]2C(Cl)=NO)N1OCc1ccccc1
Reactant: C=C(Cl)C#N
Solvent: ClCCl
Product: N#Cc1cc([C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)no1
Temperature: -5 °C
Reaction time: 2 h
Yield: 16.2 %

Procedure:
2-Chloroacrylonitrile (1.08 g, 12.4 mmol) was added to a solution of (2S,5R)-6-(benzyloxy)-N-hydroxy-7-oxo-1,6-diaza-bicyclo[3.2.1]octane-2-carbimidoyl chloride (1.9 g, 6.2 mmol) in DCM (19 mL) at −5° C., followed by dropwise addition of TEA (1.25 g, 1.24 mmol). The mixture was stirred at −5° C. for 2 hrs and was then quenched with 10% critic acid (20 mL). The organic phase was separated, washed with 10% critic acid, H2O, and saturated sodium chloride, then concentrated. The residue was purified by silica gel column chromatography (gradient elution 15:1 to 4:1 petroleum ether/EtOAc) to afford 3-((2S,5R)-6-(benzyloxy)-7-oxo-1,6-diaza-bicyclo[3.2.1]octan-2-yl)isoxazole-5-carbonitrile (325 mg, 16%) as a white solid. 1H-NMR (500 MHz, CDCl3): δ 7.45-7.35 (m, 5H), 7.04 (s, 1H), 5.09 (d, J=11.3 Hz, 1H), 4.94 (d, J=11.3 Hz, 1H), 4.64 (d, J=7.0 Hz, 1H), 3.34 (s, 1H), 2.90 (br d, J=12.0 Hz, 1H), 2.54 (d, J=12.0 Hz, 1H), 2.40-2.35 (m, 1H), 2.31-2.25 (m, 1H), 2.14-2.11 (m, 1H), 1.80-1.74 (m, 1H).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([OH:11])=[N:3][CH:2]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][C:25]1[C:26](=[O:33])[CH:27]=[C:28]([CH2:31][OH:32])[O:29][CH:30]=1.O>CN(C=O)C>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([O:11][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][C:25]2[C:26](=[O:33])[CH:27]=[C:28]([CH2:31][OH:32])[O:29][CH:30]=2)=[N:3][CH:2]=1
Reactant: Oc1ncnc2ccccc12
Reactant: O=c1cc(CO)occ1OCCCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1cc(CO)occ1OCCCCCOc1ncnc2ccccc12
Reaction time: 0.17 h
Yield: 26 %

Procedure:
Quinazolin-4-ol (1.0 g, 6.84 mmol) was dissolved in DMF (7 mL). Cs2CO3 (2.23 g, 6.84 mmol) was added at RT and the mixture was stirred for 10 min. A solution of 5-(5-bromo-pentyloxy)-2-hydroxymethyl-pyran-4-one 10 (1.90 g, 6.52 mmol) in DMF (7 mL) was added via syringe. This mixture was stirred at 50° C. for 2 h. Water (150 mL) was added and the mixture extracted with EtOAc (2×100 mL), washed with water (3×100 mL), brine (3×100 mL), dried over MgSO4, filtered and evaporated. The crude product was purified by column chromatography on silica using as eluent CH2Cl2:MeOH=95:5. 5-(5-(Quinazolin-4-yloxy)pentyloxy)-2-(hydroxymethyl)-4H-pyran-4-one 15 was obtained (0.61 g, 26% yield) as a pale yellow solid.