Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([NH2:12])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[N:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1>COCCOC.O>[N:19]1[CH:24]=[CH:23][C:22]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([NH2:12])=[CH:4][CH:3]=2)=[CH:21][CH:20]=1
Reactant: OB(O)c1ccncc1
Reactant: Nc1ccc(Br)c2ccccc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Nc1ccc(-c2ccncc2)c2ccccc12
Yield: 78.6 %

Procedure:
A stirred suspension of 4-bromonaphth-1-ylamine (10 g, 45 mnmole) in 1,2-dimethoxyethane (400 ml) and water (100 ml) containing sodium carbonate (14 g) was flushed with argon for 0.3h. Tetrakis (triphenylphosphine)palladium (0) (2.75 g, 2.4 mmole) was added followed by 4-pyridylboronic acid (5.7 g, 46 mmole) and the mixture heated at reflux for 5 h. The mixture was concentrated in vacuo to a brown slurry and partitioned between dichloromethane and water. The aqueous was further extracted with dichloromethane and the combined organics dried (Na2SO4) and concentrated in vacuo to a brown solid (13.2 g). Purification of the solid by flash chromatography eluting with ethyl acetate afforded the title compound as a yellow crystalline solid (7.8 g, 78%).
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:3]=1[CH2:4][C:5]1[C:6](=[O:18])[NH:7][C:8]2[C:13]([C:14]=1[CH3:15])=[C:12]([OH:16])[CH:11]=[CH:10][C:9]=2[F:17].[CH3:24][O:25][C:26](=[O:30])[CH:27](Br)[CH3:28]>>[CH3:24][O:25][C:26](=[O:30])[CH:27]([O:16][C:12]1[CH:11]=[CH:10][C:9]([F:17])=[C:8]2[C:13]=1[C:14]([CH3:15])=[C:5]([CH2:4][C:3]1[CH:19]=[CH:20][C:21]([Cl:23])=[CH:22][C:2]=1[Cl:1])[C:6](=[O:18])[NH:7]2)[CH3:28]
Reactant: COC(=O)C(C)Br
Reactant: Cc1c(Cc2ccc(Cl)cc2Cl)c(=O)[nH]c2c(F)ccc(O)c12
Product: COC(=O)C(C)Oc1ccc(F)c2[nH]c(=O)c(Cc3ccc(Cl)cc3Cl)c(C)c12

Procedure:
The title compound was prepared by the method of Preparation 34d using 3-(2,4-dichlorobenzyl)-8-fluoro-5-hydroxy-4-methyl-1H-quinolin-2-one and 2-bromopropionic acid methyl ester.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C@H:8]1[CH2:13][CH2:12][C@@H:11]([OH:14])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25].O>C(Cl)Cl>[C:1]([O:5][C:6]([NH:7][C@@H:8]1[CH2:9][CH2:10][C@H:11]([O:14][S:24]([CH3:23])(=[O:26])=[O:25])[CH2:12][CH2:13]1)=[O:15])([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](O)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](OS(C)(=O)=O)CC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 100.8 %

Procedure:
A solution of cis (4-hydroxy-cyclohexyl)-carbamic acid tert-butyl ester (1.00 g, 4.70 mmol) in DCM (10 mL) was treated with triethylamine (1.29 mL, 9.30 mmol) and the mixture was cooled to 0° C. Methanesulfonyl chloride (0.54 mL, 7.00 mmol) was added dropwise and the mixture was stirred at 0° C. for 15 minutes. Water was added and the phases were separated. The aqueous phase was extracted with DCM (×2) and the combined organic phase was washed with saturated sodium hydrogen carbonate solution, and brine, dried with sodium sulfate and concentrated under vacuum to give 1.39 g (quant) of Cis methanesulfonic acid 4 tert-butoxycarbonylamino-cyclohexyl ester as a peach coloured solid which was used without further purification. 1H NMR (400 MHz, CDCl3) δ: 4.89 (m, 1H), 4.46 (br s, 1H), 3.53 (br s, 1H), 3.01 (s, 3H), 2.05 (m, 2H), 1.84-(m, 2H), 1.73 (m, 2H), 1.58 (m, 2H), 1.45 (s, 9H).
Reaction SMILES: [ClH:1].[C:2]([O:5][CH:6]([C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[C:19]([O:24]CC3C=CC=CC=3)[CH:20]=2)[CH:15]=1)[CH2:7][O:8][CH2:9][CH2:10][N:11]([CH3:13])[CH3:12])(=[O:4])[CH3:3]>[C].[Pd].C(O)C>[ClH:1].[C:2]([O:5][CH:6]([C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[C:19]([OH:24])[CH:20]=2)[CH:15]=1)[CH2:7][O:8][CH2:9][CH2:10][N:11]([CH3:13])[CH3:12])(=[O:4])[CH3:3]
Reactant: CC(=O)OC(COCCN(C)C)c1ccc2cc(OCc3ccccc3)ccc2c1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CC(=O)OC(COCCN(C)C)c1ccc2cc(O)ccc2c1
Yield: 47.7 %

Procedure:
A mixture of 2.0 g of 1-acetoxy-1-(6-benzyloxy-2-naphthyl)-2-[2-(N,N-dimethylamino)ethoxy]ethane hydrochloride, 0.5 g of 5% palladium-carbon and 40 ml of ethanol was subjected to hydrogenation at room temperature under atomospheric pressure. After the completion of the reaction, the palladium-carbon was removed by filtration. The solvent was removed by distillation under reduced pressure. Acetone was added to the residue thus obtained. The resulting crystals were collected by filtration and dried to obtain 0.76 g of 1-acetoxy-1-(6-hydroxy-2-naphthyl)-2-[2-(N,N-dimethylamino)ethoxy]ethane hydrochloride (compound No. 287).
Reaction SMILES: C[O:2][C:3](=[O:22])[CH2:4][CH2:5][CH:6]1[CH:10]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[CH2:9][C:8](=[O:21])[NH:7]1.C[O:24][C:25](=[O:44])[CH2:26][CH:27]([C:34]1[CH:39]=[CH:38][C:37]([C:40]([F:43])([F:42])[F:41])=[CH:36][CH:35]=1)[CH:28]1[CH2:32][CH2:31][C:30](=[O:33])[NH:29]1.Cl>[OH-].[Na+]>[O:33]=[C:30]1[NH:29][CH:28]([CH:27]([C:34]2[CH:39]=[CH:38][C:37]([C:40]([F:43])([F:41])[F:42])=[CH:36][CH:35]=2)[CH2:26][C:25]([OH:44])=[O:24])[CH2:32][CH2:31]1.[O:21]=[C:8]1[NH:7][CH:6]([CH2:5][CH2:4][C:3]([OH:22])=[O:2])[CH:10]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:18])[F:19])=[CH:13][CH:12]=2)[CH2:9]1
Reactant: COC(=O)CCC1NC(=O)CC1c1ccc(C(F)(F)F)cc1
Reactant: COC(=O)CC(c1ccc(C(F)(F)F)cc1)C1CCC(=O)N1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CC(c1ccc(C(F)(F)F)cc1)C1CCC(=O)N1
Product: O=C(O)CCC1NC(=O)CC1c1ccc(C(F)(F)F)cc1

Procedure:
A solution of 93.4 g of 5-oxo-3-[4-(trifluoromethyl)phenyl]-2-pyrrolidinepropanoic acid methyl ester and 5-oxo-β-[4-(trifluoromethyl)phenyl]-2-pyrrolidinepropanoic acid methyl ester in 370 ml of 1 N aqueous sodium hydroxide solution is heated to 60° C. for four hours. Excess aqueous hydrochloric acid (1 N, 380 ml) is added and the solution concentrated under reduced pressure to give 5-oxo-β-[4-(trifluoromethyl)phenyl]-2-pyrrolidinepropanoic acid and 5-oxo-3-[4-(trifluoromethyl)phenyl]-2-pyrrolidinepropanoic acid. The acids are dissolved in 300 ml of acetic anhydride, and the solution is heated to 90° C. The solution is filtered hot and the filtrate concentrated in vacuo. The oil is chromatographed on silica gel (200-400 mesh) (elution with chloroform) to give cis-and trans-dihydro-1-(4-trifluoro-methylphenyl)-1H-pyrrolizine-3,5-(2H,6H)-diones as a white solid with a mp 173°-181° C.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[N:8]2[C:9]3[CH:10]=[CH:11][CH:12]=[C:13]([F:16])[C:14]=3[CH:15]=[C:7]2[C:6]2[N:17]=[C:18]([C:21]3[C:22]([N:41]([CH3:46])[S:42]([CH3:45])(=[O:44])=[O:43])=[CH:23][C:24]4[O:28][C:27]([C:29]5[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=5)=[C:26]([C:36]([NH:38][CH3:39])=[O:37])[C:25]=4[CH:40]=3)[CH:19]=[CH:20][C:5]=2[O:4]1.O=[CH:48][C:49]([O:51][CH2:52][CH3:53])=[O:50].C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[F:16][C:13]1[C:14]2[CH:15]=[C:7]3[C:6]4[N:17]=[C:18]([C:21]5[C:22]([N:41]([CH3:46])[S:42]([CH3:45])(=[O:43])=[O:44])=[CH:23][C:24]6[O:28][C:27]([C:29]7[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=7)=[C:26]([C:36](=[O:37])[NH:38][CH3:39])[C:25]=6[CH:40]=5)[CH:19]=[CH:20][C:5]=4[O:4][CH:3]([CH2:2][NH:1][CH2:48][C:49]([O:51][CH2:52][CH3:53])=[O:50])[N:8]3[C:9]=2[CH:10]=[CH:11][CH:12]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc4c(n3)-c3cc5c(F)cccc5n3C(CN)O4)cc12
Reactant: CCOC(=O)C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCOC(=O)CNCC1Oc2ccc(-c3cc4c(C(=O)NC)c(-c5ccc(F)cc5)oc4cc3N(C)S(C)(=O)=O)nc2-c2cc3c(F)cccc3n21
Temperature: 25 °C
Reaction time: 1 h
Yield: 19.9 %

Procedure:
To a solution of 5-(6-(aminomethyl)-11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indol-2-yl)-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (200 mg, 0.31 mmol) and ethyl 2-oxoacetate (64 mg, 0.62 mmol) in CH2Cl2 (4 mL) was added acetic acid (4 mg, 0.06 mmol). The mixture was stirred at room temperature for 1 hour, and then NaBH(AcO)3 (144 mg, 0.68 mmol) added to the mixture. After stirring overnight, the mixture diluted with CH2Cl2, washed with brine, dried over Na2SO4 and concentrated in vacuo. The resulting residue was purified using prep-HPLC give the product of ethyl 2-(((11-fluoro-2-(2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-(N-methylmethylsulfonamido)benzofuran-5-yl)-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indol-6-yl)methyl)amino)acetate (45 mg, yield: 20%). 1H-NMR (CDCl3, 400 MHz) δ 8.01 (s, 1H), 7.96 (dd, J=8.4, 5.2 Hz, 2H), 7.67 (s, 1H), 7.50 (s, 2H), 7.13˜7.25 (m, 5H), 6.84 (dd, J=9.2, 8.0 Hz, 1H), 6.50 (dd, J=7.6, 3.6 Hz, 1H), 5.99 (br s, 1H), 4.12 (q, J=7.2 Hz, 2H), 3.29˜3.44 (m, 5H), 3.20 (dd, J=12.8, 8.4 Hz, 1H), 3.00 (d, J=4.8 Hz, 3H), 2.86˜2.96 (m, 1H), 2.67 (s, 3H), 1.22 (t, J=7.2 Hz, 3H). MS (M+H)+: 730.
Reaction SMILES: [C:1]1([N:7]2[C:12](=[O:13])[NH:11][C:10](=[O:14])[C:9]([C:15]#[N:16])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C=O)C.[H-].[Na+].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>O>[C:1]1([N:7]2[C:12](=[O:13])[N:11]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:10](=[O:14])[C:9]([C:15]#[N:16])=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N#Cc1nn(-c2ccccc2)c(=O)[nH]c1=O
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1nn(-c2ccccc2)c(=O)n(Cc2ccccc2)c1=O
Reaction time: 0.5 h
Yield: 63.4 %

Procedure:
Intermediate c (9 g, 0.042 mol) was added to DMF (80 mL) under an ice bath. To the mixture was added NaH (1.3 g, 0.054 mmol) in batch under an ice bath. After stirring for 30 min, benzyl bromide (3.1 mL, 0.042 mol) was added dropwise. After the dropwise addition, the reaction was conducted at 50° C. for 4 h. After completion of the reaction, the reaction solution was poured into water (300 mL). A great deal of solid separated out and was filtered by suction. The filtered cake was washed with water and dried to produce Intermediate j (8.1 g) in a yield of 81%.
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][C@H:5]([C:8]([CH3:10])=[CH2:9])[CH2:4][CH:3]=1.C12(C)C(C)(C)C(CC1)CC2=O.C.[O-]S([O-])(=O)=O.[Mg+2]>O>[CH3:1][C:2]1[CH2:7][CH2:6][C@@H:5]([C:8]([CH3:10])=[CH2:9])[CH2:4][CH:3]=1
Reactant: C=C(C)[C@@H]1CC=C(C)CC1
Agent: CC12CCC(CC1=O)C2(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: O
Product: C=C(C)[C@H]1CC=C(C)CC1
Temperature: 220 °C

Procedure:
Product analysis and other analytical methods—An in situ bioassay was developed to evaluate functional expression of (−)-limonene hydroxylase activity. Expression cultures were incubated in the presence of ˜300 μM (−)-(4S)-limonene, which was added to the culture medium immediately following infection. At zero and various time intervals, 50-100 ml culture samples were removed and cells were harvested by centrifugation, washed, and resuspended in 3-6 ml of sodium phosphate buffer as described above. Resuspended cell suspensions were chilled on ice and extracted twice with 3 ml portions of ice cold ether after the addition of 25 nmol camphor as internal standard. The extract was decolorized with activated charcoal, backwashed with water, and the organic phase containing the products was passed through a short column of anhydrous MgSO4 and activated silica. The purified extracts were then concentrated to ˜500 μl under N2 and analyzed by capillary GLC (Hewlett-Packard 5890). GLC was performed on 0.25 mm i.d×30 m of fused silica capillary columns coated with superox FA or AT-1000 using “on column” injection and flame ionization detection with H2 as carrier gas at 13.5 psi (programmed from 45° C. (5 min) to 220° C. at 10° C. per min). The identities of the products, (−)-trans-carveol from C-6 hydroxylation and (−)-trans-isopiperitenol from C-3 hydroxlyation, were confirmed by coincidence of retention times with the corresponding authentic standard. Peak quantitation was by electronic integration based on the internal standard.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH:9]=[CH:10][C:11]([O:13][CH3:14])=[O:12])[CH:4]=1>CO.[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH:4]=1
Reactant: COC(=O)C=Cc1cc(OC)ccn1
Agent: [Pd]
Solvent: CO
Product: COC(=O)CCc1cc(OC)ccn1

Procedure:
43.1 g of methyl 3-(4-methoxypyridin-2-yl)acrylate (starting material A3) in 600 ml of methanol are hydrogenated over 3.0 g of 10% strength Pd/C until the starting material has disappeared (TLC). The catalyst is filtered off, and the mixture is then concentrated and dried under high vacuum. This gives 41.95 g of the title compound as a light-yellow oil. The mass spectrum shows the molecular peak MH+ at 196 Da.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6](=[O:24])[CH2:7][C:8]([NH:10][C:11]1[CH:16]=[C:15]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH:14]=[CH:13][C:12]=1[C:21](=O)[CH3:22])=[O:9])[CH3:4].CC(O)=O>CCO.O>[CH2:3]([O:5][C:6]([C:7]1[C:8]([OH:9])=[N:10][C:11]2[C:12]([C:21]=1[CH3:22])=[CH:13][CH:14]=[C:15]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH:16]=2)=[O:24])[CH3:4]
Reactant: CCOC(=O)CC(=O)Nc1cc(C(C)(C)C)ccc1C(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1c(O)nc2cc(C(C)(C)C)ccc2c1C
Temperature: 80 °C
Yield: 83.9 %

Procedure:
30 mg (0.68 mmol, 60% in mineral oil) sodium hydride were added to a solution of 190 mg (0.62 mmol) 3-(2-acetyl-5-tert-butyl-phenylamino)-3-oxopropanoic acid ethyl ester in EtOH (2 ml) and the mixture was heated for 2 h at 80° C. Then it was diluted with water and acidified with 5N AcOH. It was then extracted with EE. The organic phase was washed with water and brine, dried over Na2SO4, filtered and concentrated to small volume under vacuum. 150 mg (0.52 mmol, 84%) 7-tert-butyl-2-hydroxy-4-methyl-quinoline-3-carboxylic acid ethyl ester were obtained as the residue, which was reacted further with no additional purification.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH3:13][C@@H:14](O)[CH2:15][CH:16]=[CH2:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.CCOCC>[CH3:12][C:9]1[CH:10]=[CH:11][C:2]([O:1][C@H:16]([CH2:15][CH:14]=[CH2:13])[CH3:17])=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: C=CC[C@@H](C)O
Reactant: COC(=O)c1cc(C)ccc1O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=CC[C@H](C)Oc1ccc(C)cc1C(=O)OC
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 89.9 %

Procedure:
To a solution of methyl 2-hydroxy-5-methylbenzoate (1.0 g, 6.02 mmol) in THF (14 ml) were added (R)-(−)-pent-4-en-2-ol (1.037 g, 12.04 mmol) and triphenylphosphine (2.052 g, 7.82 mmol). DIAD (1.521 ml, 7.82 mmol) was added dropwise (exotherm) and the mixture was stirred at rt. After 4.5 h, the mixture was diluted with Et2O and washed with 1N NaOH followed by water (3×'s) then brine, dried (Na2SO4), filtered and concentrated. The yellow oil was purified by flash chromatography (Biotage; 0%-100% EtOAc/hexane; 20 CV) to give (S)-methyl 5-methyl-2-(pent-4-en-2-yloxy)benzoate (1.2664 g, 5.41 mmol, 90% yield) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.58 (d, J=2.2 Hz, 1H), 7.23 (dd, J=8.3, 2.0 Hz, 1H), 6.90 (d, J=8.6 Hz, 1H), 6.03-5.77 (m, 1H), 5.21-4.99 (m, 2H), 4.61-4.35 (m, 1H), 3.89 (s, 3H), 2.60-2.46 (m, 1H), 2.46-2.34 (m, 1H), 2.34-2.25 (m, 3H), 1.34 (d, J=6.1 Hz, 3H).
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([CH:23]5[CH2:28][CH2:27][N:26]([C:29]([CH3:33])([CH3:32])[C:30]#[N:31])[CH2:25][CH2:24]5)[CH:20]=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].S(=O)(=O)(O)[OH:35].C(=O)([O-])[O-].[Na+].[Na+]>>[CH:1]([N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([CH:23]5[CH2:28][CH2:27][N:26]([C:29]([CH3:33])([CH3:32])[C:30]([NH2:31])=[O:35])[CH2:25][CH2:24]5)[CH:20]=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CCN(C(C)(C)C#N)CC3)ccc1-2
Reactant: O=S(=O)(O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CCN(C(C)(C)C(N)=O)CC3)ccc1-2
Reaction time: 5.5 h
Yield: 19 %

Procedure:
2-{4-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-piperidin-1-yl}-2-methyl-propionitrile (346 mg, ˜50% pure, ˜0.40 mmol) was treated with concentrated sulphuric acid (5 mL) and the mixture was stirred for 5.5 hours then diluted with ice chips (˜50 mL) and made basic with solid sodium carbonate. The mixture was extracted with 10% MeOH in DCM (×4) and the combined organic extracts were dried (Na2SO4) and concentrated in vacuo. The resultant residue was purified by flash chromatography (SiO2, 0-5% MeOH in DCM first time then 0-100% EtOAc in DCM) to give 483 as a white solid (36 mg, 19%). LCMS: RT=3.28 min, [M+H]+=481. 1H NMR δ (ppm) (DMSO-d6): 9.54 (1H, s), 8.27 (1H, d, J=8.13 Hz), 8.05 (1H, s), 7.98 (1H, s), 7.86 (1H, s), 7.05 (1H, d, J=8.29 Hz), 6.90 (1H, s), 5.81-5.73 (1H, m), 4.32 (2H, s), 3.41-3.30 (4H, m), 3.12 (1H, m), 2.83 (1H, m), 2.13 (2H, d, J=13.80 Hz), 1.99 (1H, d, J=13.56 Hz), 1.72 (1H, s), 1.50 (12H, d, J=6.50 Hz). 1 Proton obscured by water peak
Reaction SMILES: Br[C:2]1[O:6][C:5]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)[CH:11]=2)=[O:8])=[CH:4][CH:3]=1.[N:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Na+].[Na+]>O.COCCOC.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>[CH3:17][O:16][C:13]1[CH:14]=[CH:15][C:10]([NH:9][C:7]([C:5]2[O:6][C:2]([C:28]3[CH:29]=[CH:30][N:25]=[CH:26][CH:27]=3)=[CH:3][CH:4]=2)=[O:8])=[CH:11][C:12]=1[N:18]1[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]1
Reactant: OB(O)c1ccncc1
Reactant: COc1ccc(NC(=O)c2ccc(Br)o2)cc1N1CCN(C)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: COCCOC
Product: COc1ccc(NC(=O)c2ccc(-c3ccncc3)o2)cc1N1CCN(C)CC1

Procedure:
5-bromo-N-[4-methoxy-3-(4-methyl-1-piperazinyl)phenyl]furan-2-carboxamide (0.3 g;0.76 mmol) was stirred with 4-pyridylboronic acid (0.094 g;0.76 mmol), tetrakis(triphenylphosphine)palladium(0) (0.045 g;5 mol %) and anhydrous sodium carbonate (0.089 g;0.84 mmol) in water (14 ml) and DME (14 ml) and the whole heated at reflux under Ar (18 hours). The reaction mixture was poured into 10% Na2CO3 (aq) (30 ml) and extracted into CHCl3. The organic extracts were combined, dried over Na2 SO4, filtered and the filtrate evaporated in vacuo to a brown oil which crystallised on standing. The brown solid was purified by flash silica-gel chromatography and eluted with 3%MeOH/CHCl3 to yield the title compound as a lemon solid (0.22 g;74%), mp=157°-159° C.
Reaction SMILES: I[C:2]1[C:3]([CH3:17])=[N:4][N:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][OH:16])=[CH:10][CH:9]=2)[C:6]=1[CH3:7].[F:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[C:23]([F:25])[CH:24]=1>>[F:18][C:19]1[CH:20]=[C:21]([C:2]2[C:3]([CH3:17])=[N:4][N:5]([C:8]3[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][OH:16])=[CH:10][CH:9]=3)[C:6]=2[CH3:7])[CH:22]=[C:23]([F:25])[CH:24]=1
Reactant: OB(O)c1cc(F)cc(F)c1
Reactant: Cc1nn(-c2ccc(CCO)cc2)c(C)c1I
Product: Cc1nn(-c2ccc(CCO)cc2)c(C)c1-c1cc(F)cc(F)c1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 12 from 2-[4-(4-iodo-3,5-dimethyl-1H-pyrazol-1-yl)phenyl]ethanol (step 2 of Example 11) and 3,5-difluorobenzeneboronic acid: MS (ESI) m/z 329 [M+H]+, 1H-NMR (CDCl3) δ 7.70-7.63 (1H, m), 7.55-7.33 (4H, m), 6.87-6.73 (2H, m), 3.89 (2H, t, J=6.2 Hz), 2.93 (2H, t, J=6.6 Hz), 2.33 (3H, s), 2.30 (3H, s).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]([OH:19])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[C-:20]#[N:21].[Na+]>CN(C=O)C.C(OCC)C>[OH:19][CH:13]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:20]#[N:21]
Reactant: CCCCCC(O)CCCCCCCCCCCBr
Reactant: [C-]#N
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCCCCC(O)CCCCCCCCCCCC#N
Temperature: 90 °C
Yield: 91.8 %

Procedure:
To 17-bromoheptadecan-6-ol (1.0 g, 2.98 mmol) in dry DMF, was added NaCN (175 mg, 3.58 mmol) and the resulting reaction mixture heated at 90° C. for 16 hours. After cooling to room temperature, the mixture was diluted with diethyl ether (100 ml), the organic layer was washed with cold water (3×20 ml), brine solution, dried over MgSO4 and concentrated. The crude product was purified over a silica gel column (10% EtOAc in hexane) to give 13-hydroxyoctadecanenitrile as a colorless liquid (0.77 g, 92%).
Reaction SMILES: C(O[C@H:5]1[NH:8][C:7](=[O:9])[C@@H:6]1[C@H:10]([O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[CH3:11])(=O)C.[Na].[C:21]([OH:24])(=[S:23])[CH3:22]>O1CCOCC1.C(OCC)(=O)C.O.[Br-].[Zn+2].[Br-]>[C:21]([S:23][C@H:5]1[NH:8][C:7](=[O:9])[C@@H:6]1[C@H:10]([O:12][Si:13]([C:16]([CH3:17])([CH3:18])[CH3:19])([CH3:14])[CH3:15])[CH3:11])(=[O:24])[CH3:22]
Reactant: CC(O)=S
Reactant: CC(=O)O[C@H]1NC(=O)[C@@H]1[C@@H](C)O[Si](C)(C)C(C)(C)C
Agent: [Br-]
Agent: [Na]
Agent: [Zn+2]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(=O)S[C@H]1NC(=O)[C@@H]1[C@@H](C)O[Si](C)(C)C(C)(C)C
Temperature: 40 °C
Reaction time: 4 h
Yield: 89.1 %

Procedure:
To a solution of 4-(R)acetoxy-3(R)-[1(R)t-butyldimethylsilyloxyethyl]azetidin-2-one (2.87 g) in dioxane (40 ml) the sodium salt of thioacetic acid (1.2 g) was added. Zinc bromide (2.7 g) was added to the resulting suspension and the reaction mixture was stirred for 4 hours at 40° C. The reaction mixture was then cooled at room temperature and poured in a mixture of ethyl acetate and water. The organic layer was separated, washed twice with water, dried over anhydrous sodium sulfate, and evaporated in vacuo. The residue was purified by column chromatography to give 2.7 g of the title product (89% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]#[CH:20])=[CH:15][C:14]=1[CH3:21])[O:8][CH:7]([C:22]([F:25])([F:24])[F:23])[C:6]([C:26]([O:28]CC)=[O:27])=[CH:5]2.[OH-].[Li+].C(O)C>O1CCCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]#[CH:20])=[CH:15][C:14]=1[CH3:21])[O:8][CH:7]([C:22]([F:25])([F:23])[F:24])[C:6]([C:26]([OH:28])=[O:27])=[CH:5]2
Reactant: C#Cc1ccc(Oc2cc3c(cc2Cl)C=C(C(=O)OCC)C(C(F)(F)F)O3)c(C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: C#Cc1ccc(Oc2cc3c(cc2Cl)C=C(C(=O)O)C(C(F)(F)F)O3)c(C)c1
Temperature: 80 °C
Yield: 32.3 %

Procedure:
The product of step 1 (230 mg, 0.53 mmol) was dissolved in 3 ml of tetrahydrofuran. To the resulting solution was added a solution of lithium hydroxide (111 mg, 2.6 mmol) in 3 mL of water, followed by addition of 3 mL of ethanol. The resulting solution was heated to 80° C. for one hr, LC-MS indicated that the reaction was complete. The volatiles were removed. The residue was diluted with water, and acidified at 0° C. with dilute hydrochloric acid to pH=1.0. The product was extracted with ethyl acetate, and dried over anhydrous magnesium sulfate. After removing the volatiles, the crude product was purified by reverse phase HPLC. The product was obtained 70 mg (28.8%) of a light yellow solid: 1H NMR (CDCl3/300 MHz) 7.82 (s, 1H), 7.48(s, 1H), 7.42-7.40(m, 2H), 6.93(d, J=8.1 Hz, 1H), 6.36(s, 1H), 5.66(q, J=6.9 Hz, 1H), 3.11(s, 1H), 2.23(s, 3H). MS (ESI+) 409.0(M+1, 100). MS(ES−) 407.0(M−H, 100). HRMS (ES−) m/z calcd for (M−H; C20H11ClF3O4): 407.0292, found: 407.0317