Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[C:21]([C:23]2[N:27]=[C:26]([CH3:28])[O:25][N:24]=2)[CH:20]=[CH:19][C:3]=1[CH2:4][NH:5][C:6](=[O:18])[C:7]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([CH3:15])=[C:9]([O:16][CH3:17])[CH:8]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:36][CH2:37][O:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>CN(C=O)C>[CH3:28][C:26]1[O:25][N:24]=[C:23]([C:21]2[CH:20]=[CH:19][C:3]([CH2:4][NH:5][C:6](=[O:18])[C:7]3[CH:12]=[C:11]([O:13][CH3:14])[C:10]([CH3:15])=[C:9]([O:16][CH3:17])[CH:8]=3)=[C:2]([NH:1][CH2:36][CH2:37][O:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[CH:22]=2)[N:27]=1
Reactant: BrCCOc1ccccc1
Reactant: COc1cc(C(=O)NCc2ccc(-c3noc(C)n3)cc2N)cc(OC)c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(C(=O)NCc2ccc(-c3noc(C)n3)cc2NCCOc2ccccc2)cc(OC)c1C
Temperature: 80 °C

Procedure:
To a solution of compound 1g (38 mg, 0.099 mmol) in DMF was added potassium carbonate (28 mg, 0.20 mmol) and 2-bromoethoxybenzene (20 mg, 0.1 mmol). The reaction mixture was heated at 80° C. in a pressure tube for seven days. During this time, two additional portions of 2-bromoethoxybenzene (20 mg each) were added. The reaction mixture was concentrated and purified by preparative thin layer chromatography in 1:1 hexane/ethyl acetate to give compound 42a. ESI-MS m/e 503.3 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:14]=[C:13]2[C:5]([N:6]3[C:11](=[CH:12]2)[C:10](=[O:15])[NH:9][CH2:8][CH2:7]3)=[N:4][CH:3]=1.O[CH:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)(C)C)=O)=O)(C)C>>[C:26]([O:25][C:23]([N:20]1[CH2:21][CH2:22][CH:17]([O:1][C:2]2[CH:14]=[C:13]3[C:5]([N:6]4[C:11](=[CH:12]3)[C:10](=[O:15])[NH:9][CH2:8][CH2:7]4)=[N:4][CH:3]=2)[CH2:18][CH2:19]1)=[O:24])([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: O=C1NCCn2c1cc1cc(O)cnc12
Agent: CC(C)(C)OC(=O)/N=N/C(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(C)(C)OC(=O)N1CCC(Oc2cnc3c(c2)cc2n3CCNC2=O)CC1
Yield: 70 %

Procedure:
The title compound was synthesized in analogy to example 1, from 7-hydroxy-3,4-dihydro-2H-2,4a,5-triaza-fluoren-1-one (example 84, intermediate a)), tert-butyl 4-hydroxy-1-piperidinecarboxylate (commercially available), triphenylphosphine and di-tert-butylazodicarboxylate, to give the desired product as a light brown solid (70%).
Reaction SMILES: C[O:2][C:3]1[C:10]([CH3:11])=[C:9]([O:12][CH3:13])[CH:8]=[CH:7][C:4]=1[CH:5]=[O:6].[Cl-].[Be+2].[Cl-].Cl>C1(C)C=CC=CC=1>[OH:2][C:3]1[C:10]([CH3:11])=[C:9]([O:12][CH3:13])[CH:8]=[CH:7][C:4]=1[CH:5]=[O:6]
Reactant: COc1ccc(C=O)c(OC)c1C
Agent: Cl
Agent: [Be+2]
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: COc1ccc(C=O)c(O)c1C
Yield: 98.4 %

Procedure:
A mixture of 2,4-dimethoxy 3-methyl benzaldehyde (3.75 g, 20.8 mmole) and beryllium chloride (5.0 g, 62.5 mmole) in anhydrous toluene (50 mL) was heated to reflux for 3.5 hour. The solvent was evaporated under reduced pressure to yield an orange residue, which was treated with 2 N HCl. The compound was extracted with methylene chloride and the organic layer was dried over anhydrous MgSO4. The filtrate was evaporated and dried in vacuo to give an orange solid (3.4 g, 99%): LCMS m/z 168.05 (M+H). 1H NMR (CDCl3/300 MHz) 11.45 (s, 1H), 9.72 (s, 1H), 7.37 (d, 1H, J=8.7 Hz), 6.57 (d, 1H, J=8.7 Hz), 3.92 (s, 3H), 2.10 (s, 3H).
Reaction SMILES: CS([O:5][CH2:6][C:7]1[C:8]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([F:24])[CH:17]=2)=[N:9][S:10][C:11]=1[C:12]([F:15])([F:14])[F:13])(=O)=O.O[C:26]1[C:31]([F:32])=[CH:30][C:29]([CH2:33][CH2:34][C:35]([O:37]CC)=[O:36])=[CH:28][C:27]=1[F:40]>>[F:32][C:31]1[CH:30]=[C:29]([CH2:33][CH2:34][C:35]([OH:37])=[O:36])[CH:28]=[C:27]([F:40])[C:26]=1[O:5][CH2:6][C:7]1[C:8]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([F:24])[CH:17]=2)=[N:9][S:10][C:11]=1[C:12]([F:15])([F:14])[F:13]
Reactant: COc1ccc(-c2nsc(C(F)(F)F)c2COS(C)(=O)=O)cc1F
Reactant: CCOC(=O)CCc1cc(F)c(O)c(F)c1
Product: COc1ccc(-c2nsc(C(F)(F)F)c2COc2c(F)cc(CCC(=O)O)cc2F)cc1F

Procedure:
The title compound was prepared according to the procedure described in Example 1 starting following Step 5 and 6 coupling (3-(3-fluoro-4-methoxyphenyl)-5-(trifluoromethyl)isothiazol-4-yl)methyl methanesulfonate and ethyl 3-(4-hydroxy-3,5-difluorophenyl)propanoate followed by hydrolysis to afford the desired product as an off-white solid. 1H NMR (400 MHz, CD3OD) δ 7.55-7.63 (m, 2H), 7.22 (t, J=8.8 Hz, 2H), 6.86-6.91 (m, 2H), 5.22 (s, 2H), 3.97 (s, 3H), 2.88 (t, J=7.2 Hz, 2H), 2.60 (t, J=7.5 Hz, 2H). Mass spectrum (ESI, m/z): Calcd. for C21H15F6NO4S, 490.1 (M−H). found 489.9.
Reaction SMILES: [Na+].[CH2:2]([O:7][C:8]1[CH:13]=[CH:12][C:11]([S:14]([O-:17])(=O)=[O:15])=[CH:10][CH:9]=1)[CH:3]=[C:4]=[CH:5][CH3:6].P(Cl)(Cl)([Cl:20])=O.O>C(#N)C.S1(CCCC1)(=O)=O>[CH2:2]([O:7][C:8]1[CH:13]=[CH:12][C:11]([S:14]([Cl:20])(=[O:17])=[O:15])=[CH:10][CH:9]=1)[CH:3]=[C:4]=[CH:5][CH3:6]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC=C=CCOc1ccc(S(=O)(=O)[O-])cc1
Agent: [Na+]
Solvent: CC#N
Solvent: O
Solvent: O=S1(=O)CCCC1
Product: CC=C=CCOc1ccc(S(=O)(=O)Cl)cc1
Temperature: 62.5 °C
Reaction time: 0.25 h
Yield: 64.7 %

Procedure:
To a suspension of product from Example 9 (740 mg, 2.48 mmol) in acetonitrile (2 ml) and sulfolane (2 ml) was added phosphoryl chloride (0.9 ml, 9.93 mmol) and the resulting mixture was heated at 60-65° C. for 2 hours. The mixture was cooled in ice and cold water was added, dropwise, while stirring was continued for an additional 15 minutes. The reaction mixture was extracted with ethyl acetate and the organic layer was dried over anhydrous sodium sulfate. The crude residue was purified by flash chomatography to give 415 mg (65%) of the product.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH2:15][O:16][CH2:17][CH2:18][OH:19])[C:13]([CH3:20])=[N:12][C:11]=2[CH:21]([CH3:23])[CH3:22])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[CH3:24][O:25][C:26]1(OC)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>>[CH3:8][C:6]1[CH:5]=[C:4]([S:9][C:10]2[N:14]([CH2:15][O:16][CH2:17][CH2:18][O:19][C:26]3([O:25][CH3:24])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)[C:13]([CH3:20])=[N:12][C:11]=2[CH:21]([CH3:23])[CH3:22])[CH:3]=[C:2]([CH3:1])[CH:7]=1
Reactant: Cc1cc(C)cc(Sc2c(C(C)C)nc(C)n2COCCO)c1
Reactant: COC1(OC)CCCCCC1
Product: COC1(OCCOCn2c(C)nc(C(C)C)c2Sc2cc(C)cc(C)c2)CCCCCC1
Yield: 69.5 %

Procedure:
The compound 1 (301 mg, 0.9 mmol) was converted to the acetal with 1,1-dimethoxycycloheptane (1.30 g, 9 mmol) in the same manner as the example 1 to give the compound 4 (288 mg, 67%). Rf 0.68 (Al2O3 60-type E, 2:1 hexane -EtOAc).
Reaction SMILES: [OH:1][CH:2]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:3][C:4]#[C:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10].CCOCC.CO>CC(C)=O>[O:1]=[C:2]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:3][C:4]#[C:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10]
Reactant: CCCCCCCCCCCCC(O)CC#CCCCC(=O)O
Solvent: CO
Solvent: CCOCC
Solvent: CC(C)=O
Product: CCCCCCCCCCCCC(=O)CC#CCCCC(=O)O
Reaction time: 0.5 h

Procedure:
A solution of 4.22 g of 8-hydroxy-5-eicosynoic acid, the product of Example 1d, in 200 ml of acetone with vigorous stirring at 5° was added 5.5 ml of Jone's reagent (2.67M). The reaction mixture was stirred for 30 min and then 700 ml of Et2O and 2 ml of MeOH was added and stirred for additional 3 min. The resulting reaction mixture was washed with H2O, saturated NaCl solution and dried over MgSO4. The crude product after removal of solvent was recrystallized in cyclohexane to yield the title compound, mp 79°-80.5°.
Reaction SMILES: [C:1]([C:5]1[S:6][C:7]2[CH:13]=[C:12]([N:14]=[C:15]=[S:16])[C:11]([N:17]3[CH2:22][CH2:21][CH:20]([CH3:23])[CH2:19][CH2:18]3)=[CH:10][C:8]=2[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[C:24]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)(=[O:26])[CH3:25]>C(Cl)(Cl)Cl>[C:24]([N:27]1[CH2:32][CH2:31][N:30]([C:15]([NH:14][C:12]2[C:11]([N:17]3[CH2:22][CH2:21][CH:20]([CH3:23])[CH2:19][CH2:18]3)=[CH:10][C:8]3[N:9]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[S:6][C:7]=3[CH:13]=2)=[S:16])[CH2:29][CH2:28]1)(=[O:26])[CH3:25]
Reactant: CC(=O)N1CCNCC1
Reactant: CC1CCN(c2cc3nc(C(C)(C)C)sc3cc2N=C=S)CC1
Solvent: ClC(Cl)Cl
Product: CC(=O)N1CCN(C(=S)Nc2cc3sc(C(C)(C)C)nc3cc2N2CCC(C)CC2)CC1

Procedure:
A solution of 2.0 g of 2-tert-butyl-6-isothiocyanato-5-(4-methylpiperidin-1-yl)benzothiazole and 0.78 g of 1-acetyl-piperazine in 30 ml of chloroform is stirred for 30 minutes and the product triturated with petroleum ether to obtain 6-[(4-acetyl-piperazin-1-yl)thiocarbonylamino]-2-tert-butyl-5-(4-methylpiperidin-1-yl)benzothiazole, melting at 187°-190°.
Reaction SMILES: C(Cl)(OC(F)F)C(F)(F)[F:3].Cl.[CH:12]([F:21])([O:17][CH:18]([F:20])[F:19])[C:13]([F:16])([F:15])[F:14]>O=[Cr]O[Cr]=O>[CH:12]([F:21])([O:17][CH:18]([F:20])[F:19])[C:13]([F:16])([F:15])[F:14].[FH:3]
Reactant: FC(F)OC(Cl)C(F)(F)F
Agent: O=[Cr]O[Cr]=O
Agent: Cl
Agent: FC(F)OC(F)C(F)(F)F
Product: F

Procedure:
A 6-ft×2-inch tube was charged with chromia catalyst and isoflurane and 5 mole equivalents of HF were introduced in vapor form at a pressure of 150 psig. The by-product HCl, desflurane, unreacted isoflurane and unreacted HF that exited the tube were collected and distilled at 150 psig to remove HCl. After HCl was removed, the reaction mixture was heated at total reflux. At a pressure of 150 psig, the material collected overhead at 82° C. was the desflurane/hydrogen fluoride azeotrope. The composition of the azeotrope, after analysis was determined to be 85% desflurane and 15% HF, by weight. The table below shows the boiling point and composition of the azeotrope at different pressures.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([NH:15][CH2:16][CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])(=[O:14])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].[H-].[Na+].I[CH3:28]>CN(C)C=O.C(OCC)(=O)C>[C:21]([O:20][C:18](=[O:19])[CH2:17][CH2:16][N:15]([S:12]([C:9]1[CH:8]=[CH:7][C:6]([O:5][CH2:1][C:2]#[C:3][CH3:4])=[CH:11][CH:10]=1)(=[O:14])=[O:13])[CH3:28])([CH3:24])([CH3:23])[CH3:22]
Reactant: CC#CCOc1ccc(S(=O)(=O)NCCC(=O)OC(C)(C)C)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC#CCOc1ccc(S(=O)(=O)N(C)CCC(=O)OC(C)(C)C)cc1
Yield: 96.2 %

Procedure:
To a solution of tert-butyl 3-({[4-(2-butynyloxy)phenyl]-sulfonyl}amino)propanoate (1.0 g, 2.83 mmol) in dimethylformamide (5 mL) at 0° C. was added sodium hydride (3.39 mmol) followed by iodomethane (211 uL, 3.39 mmol). After 72 hours the reaction mixture was diluted with ethyl acetate and washed with water and brine and dried over anhydrous sodium sulfate. Filtration and concentration in vacuo gave tert-butyl-3-[{[4-(2-butynyloxy)phenyl]-sulfonyl}(methyl)amino]propanoate (1.0 g) as a colorless oil. Electrospray Mass Spec 368.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:42]=[CH:41][C:5]([C:6]2[C:11]([C:12]3[CH:21]=[CH:20][C:19]4[C:14](=[CH:15][C:16]([F:40])=[C:17]([C:22]5[N:26]([CH:27]6[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]6)[C:25]6[CH:33]=[CH:34][C:35]([C:37](O)=[O:38])=[CH:36][C:24]=6[N:23]=5)[CH:18]=4)[N:13]=3)=[CH:10][CH:9]=[CH:8][CH:7]=2)=[CH:4][CH:3]=1.[OH:43][CH:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1>>[Cl:1][C:2]1[CH:42]=[CH:41][C:5]([C:6]2[C:11]([C:12]3[CH:21]=[CH:20][C:19]4[C:14](=[CH:15][C:16]([F:40])=[C:17]([C:22]5[N:26]([CH:27]6[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]6)[C:25]6[CH:33]=[CH:34][C:35]([C:37]([N:47]7[CH2:48][CH2:49][CH:44]([OH:43])[CH2:45][CH2:46]7)=[O:38])=[CH:36][C:24]=6[N:23]=5)[CH:18]=4)[N:13]=3)=[CH:10][CH:9]=[CH:8][CH:7]=2)=[CH:4][CH:3]=1
Reactant: OC1CCNCC1
Reactant: O=C(O)c1ccc2c(c1)nc(-c1cc3ccc(-c4ccccc4-c4ccc(Cl)cc4)nc3cc1F)n2C1CCCCC1
Product: O=C(c1ccc2c(c1)nc(-c1cc3ccc(-c4ccccc4-c4ccc(Cl)cc4)nc3cc1F)n2C1CCCCC1)N1CCC(O)CC1

Procedure:
The title compound was synthesized from Compound 408 and 4-hydroxypiperidine using standard HBTU activation.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC(=O)[NH:14][CH2:15][C:16]1[O:20][N:19]=[C:18]([C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)[N:17]=1)(C)(C)C>C(Cl)Cl>[N:24]1[CH:23]=[CH:22][C:21]([C:18]2[N:17]=[C:16]([CH2:15][NH2:14])[O:20][N:19]=2)=[CH:26][CH:25]=1
Reactant: CC(C)(C)OC(=O)NCc1nc(-c2ccncc2)no1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCc1nc(-c2ccncc2)no1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Trifluoroacetic acid (6.5 ml) was added to a solution of (3-pyridin-4-yl-[1,2,4]oxadiazol-5-ylmethyl)carbamic acid tert-butyl ester (Preparation 8, 420 mg, 1.52 mmol in CH2Cl2 (10 ml) and the mixture stirred at rt for 2 h. The solvent was evaporated and the residue dissolved in EtOAc (100 ml). After washing with saturated aqueous Na2CO3 (25 ml), the aqueous phase was re-extracted with 5% MeOH in CH2Cl2 (7×25 ml) and the combined organic phases dried (MgSO4). The solvent was removed to afford the title compound: RT=0.25 min; m/z (ES+)=177.1 [M+H]+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl.[Cl:8][C:9]1[CH:25]=[CH:24][C:12]([O:13][C:14]2[CH:23]=[CH:22][C:17]([O:18][CH2:19][CH2:20][NH2:21])=[CH:16][CH:15]=2)=[CH:11][CH:10]=1.[CH2:26]([O:28][C:29](Cl)=[O:30])[CH3:27]>CC(C)=O>[CH2:26]([O:28][C:29](=[O:30])[NH:21][CH2:20][CH2:19][O:18][C:17]1[CH:22]=[CH:23][C:14]([O:13][C:12]2[CH:24]=[CH:25][C:9]([Cl:8])=[CH:10][CH:11]=2)=[CH:15][CH:16]=1)[CH3:27]
Reactant: NCCOc1ccc(Oc2ccc(Cl)cc2)cc1
Reactant: CCOC(=O)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)NCCOc1ccc(Oc2ccc(Cl)cc2)cc1
Reaction time: 7 h
Yield: 81.6 %

Procedure:
18.4 g of potassium carbonate, 8.0 g of 2-[p-(p-chlorophenoxy)phenoxy]ethylamine hydrochloride and 16.0 g of chloroformic acid ethyl ester in 210 ml of acetone are heated to reflux with stirring for 7 hours. Undissolved salt is vacuum filtered and washed well with acetone. The filtrate is evaporated in vacuo. The crystalline residue remaining is dissolved in ethyl acetate, washed with water and saturated sodium chloride solution, dried over magnesium sulfate and concentrated. The residue is recrystallized from diisopropyl ether to yield 7.3 g (81.5%) of 2-[p-(p-chlorophenoxy)phenoxy]ethylcarbamic acid ethyl ester, m.p.--99°-100° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:21])[CH:5]=[CH:6][CH:7]=1.[O:22]1[C:24]2([CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[CH2:23]1.C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O>[OH:22][C:24]1([CH2:23][O:1][C:2]2[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]3[C:19](=[O:20])[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[C:12]3=[O:21])[CH:5]=[CH:6][CH:7]=2)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: C1CCCC2(CCC1)CO2
Reactant: O=C1c2ccccc2C(=O)N1CCCc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: O=C1c2ccccc2C(=O)N1CCCc1cccc(OCC2(O)CCCCCCC2)c1
Temperature: 120 °C

Procedure:
A suspension of the phenol 58 (1.0 g, 3.5 mmol), 1-oxa-spiro[2.7]decane (0.5 g, 3.2 mmol) and Cs2CO3 (1.14 g, 3.5 mmol) in DMSO (4 mL) was heated at 120° C. for 16 h. After completion of reaction, the mixture was quenched by the addition of 1N HCl and extracted with DCM. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. Purification by flash chromatography (0 to 10% 7N NH3/methanol —CH2Cl2) afforded 2-(3-(3-((1-hydroxycyclooctyl)methoxy)phenyl)propyl)isoindoline-1,3-dione as yellow oil. Yield (1.057 g, 72%): 1H NMR (400 MHz, CDCl3) δ 7.10-7.36 (m, 2H), 6.40-6.80 (m, 6H), 3.69 (s, 2H), 2.10-2.45 (m, 2H), 1.30-2.0 (m, 18H).
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH2:9][C:10]#[CH:11])[C:7]2[CH:12]=[CH:13][CH:14]=[CH:15][C:6]=2[O:5][C@H:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C@@H:3]1[NH:22]C(=O)OC(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:22][C@@H:3]1[C:2](=[O:1])[N:8]([CH2:9][C:10]#[CH:11])[C:7]2[CH:12]=[CH:13][CH:14]=[CH:15][C:6]=2[O:5][C@@H:4]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: C#CCN1C(=O)[C@@H](NC(=O)OC(C)(C)C)[C@@H](c2ccccc2)Oc2ccccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C#CCN1C(=O)[C@@H](N)[C@@H](c2ccccc2)Oc2ccccc21
Yield: 99 %

Procedure:
tert-Butyl [(2R,3S)-4-oxo-2-phenyl-5-prop-2-yn-1-yl-2,3,4,5-tetrahydro-1,5-benzoxazepin-3-yl]carbamate (67b) (125 mg, 0.318 mmol) was dissolved in 5:1 (v/v) dichloromethane:trifluoroacetic acid (4 mL) and kept at ambient temperature for 90 min. The solution was evaporated and the residue was dissolved in ethyl acetate and extracted with saturated aqueous sodium bicarbonate. The organic solution was dried and evaporated to afford the title compound (92 mg, 99%) as a white solid. 1H NMR (300 MHz, CDCl3) δ1.36 (br s, 2H), 2.29 (t, 1H, J=2.3 Hz), 4.10 (m, 1H), 4.56 and 4.61 (dd, 1H, J=2.4 Hz), 4.76 and 4.81 (dd, 1H, J=2.4 Hz), 5.46 (d, 1H, J=7.4 Hz), 7.27 (m, 3H), 7.38 (m, 3H), 7.47 (m, 3H). MS APCI, m/z=293 (M+1). LC/MS: 1.63 min.
Reaction SMILES: N1CCOCC1.[CH:7](=[O:14])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[C:15]([O:19][CH3:20])(=[O:18])[CH:16]=[CH2:17].O.O.O.C([O-])(=O)C.[Na+]>O.C(O)(=O)C.C1CCCCC1>[CH:7]([CH:8]([CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH2:17][CH2:16][C:15]([O:19][CH3:20])=[O:18])=[O:14]
Reactant: CCCCCCC=O
Reactant: C=CC(=O)OC
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: C1CCCCC1
Solvent: O
Solvent: C1COCCN1
Product: CCCCCC(C=O)CCC(=O)OC
Temperature: 40 °C
Reaction time: 12 h
Yield: 99.3 %

Procedure:
418.0 g (4.80 mol) of morpholine and 344.0 g of cyclohexane are placed in a four-liter round-bottomed flask with a magnetic stirrer, a water separator, a thermometer and an addition funnel. The mixture is brought to a temperature of 65° C. to 70° C. 444.2 g (3.89 mol) of heptanal are added over five hours. The boiling point (80° C.-84° C. at the start of addition and then 87° C. toward the end of the operation) is thus rapidly obtained. The water formed during the reaction is recovered in a water separator. The reaction medium is then cooled and the cyclohexane and the excess morpholine are distilled off under reduced pressure (about 4400 Pa) without exceeding 80° C. in the bulk. The mixture is cooled to 40° C., brought to ambient pressure and 4.0 g of potassium hydroxide in 40 ml of methanol are added to the 4-hept-1(E/Z)-enylmorpholine. The mixture is brought to 60° C. and 237.5 g (2.76 mol) of methyl acrylate are then added over 4 hours. The mixture is stirred for 12 hours at 60° C. and a further 165.3 g (1.92 mol) of methyl acrylate are then added over two hours thirty minutes. At the end of the addition, the temperature of the reaction medium is increased to 80° C. and stirring is continued for 12 hours. An aqueous solution of acetic acid buffered to pH 4 (587.3 g of acetic acid, 215.3 g of sodium acetate trihydrate and 697.5 g of water) is added dropwise over two hours at this temperature. Stirring is continued for a further four hours. The phases are allowed to settle and are separated. The aqueous phase is extracted twice with 200 ml of cyclohexane. The organic phases are combined and washed once with 100 ml of water, once with 100 ml of saturated sodium bicarbonate solution and once with 150 ml of brine. The resulting organic phase is dried over magnesium sulfate. After evaporating off the solvent under reduced pressure (3990 Pa), without exceeding 50° C. in the bulk, 890.0 g of crude oxo ester are obtained, and are blanched under high vacuum (80° C. to 95° C. at 80 Pa) to give 663.0 g of 82.7% methyl 4-formylnonanoate (yield: 2.74 mol; 70%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:14]([OH:16])=O)[CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:18][C@@H:19]([CH2:28][CH:29]([CH3:31])[CH3:30])[CH:20]([OH:27])[C:21]([O:23][CH:24]([CH3:26])[CH3:25])=[O:22].C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(CC)CC)C>CN(C)C=O>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:14]([NH:18][C@@H:19]([CH2:28][CH:29]([CH3:31])[CH3:30])[CH:20]([OH:27])[C:21]([O:23][CH:24]([CH3:25])[CH3:26])=[O:22])=[O:16])[CH3:13])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CC(C)C[C@H](N)C(O)C(=O)OC(C)C
Agent: Cl
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)C[C@H](NC(=O)[C@H](C)NC(=O)OCc1ccccc1)C(O)C(=O)OC(C)C
Yield: 50.2 %

Procedure:
To a solution of 61 mg of N-benzyloxycarbonyl-L-alanine and 79 mg of isopropyl (2RS, 3S)-3-amino-2-hydroxy-5-methylhexanoate hydrochloride in 5 ml of N,N-dimethylformamide were added successively 0.071 ml of diphenylphosphoryl azide and 0.125 ml of triethylamine with stirring under ice-cooling, and the mixture was stirred overnight. The reaction mixture was evaporated under reduced pressure, and to the residue was added a 5% aqueous sodium bicarbonate solution. The mixture was extracted with ethyl acetate and the ethyl acetate layer was washed with water, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified with silica gel flash column chromatography (eluent: chloroform/methanol=20/1 by volume) to obtain 56 mg of isopropyl (2RS, 3S)-3-(N-benzyloxycarbonyl-L-alanyl)amino-2-hydroxy-5-methylhexanoate as a colorless viscous oil.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8](Cl)[C:5]([C:6]#[N:7])=[CH:4][N:3]=1.[CH3:11][CH2:12][OH:13].CN1C(=O)CCC1.[H-].[Na+]>CCOC(C)=O>[NH2:1][C:2]1[CH:9]=[C:8]([O:13][CH2:12][CH3:11])[C:5]([C:6]#[N:7])=[CH:4][N:3]=1
Reactant: CCO
Reactant: N#Cc1cnc(N)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CCOc1cc(N)ncc1C#N
Temperature: 70 °C

Procedure:
6-Amino-4-chloronicotinonitrile (intermediate 16, 40 mg, 0.260 mmol) and EtOH (0.076 ml, 1.302 mmol) were charged into a sealed vial. NMP (1.5 ml) was added to the mixture at room temperature followed by NaH (60% dispersion in mineral oil, 62.5 mg, 1.56 mmol). The mixture was then heated at 70° C. for 2.5 days. The reaction mixture was diluted in EtOAc and washed with water (2×) and brine. The org. layer was dried over Na2SO4, filtered and concentrated under vacuum. The crude material was purified by normal phase chromatography (4 g silica gel cartridge, heptanes/EtOAc 100:0 to 0:100) to give the title compound as a beige solid. (UPLC-MS 1) tR 0.50 min; ESI-MS 164.0 [M+H]+.
Reaction SMILES: Br[C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[C:5]([S:12]([NH:15][C:16]([CH3:19])([CH3:18])[CH3:17])(=[O:14])=[O:13])=[CH:4][CH:3]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH3:28][C:29]1[C:30](B2OC(C)(C)C(C)(C)O2)=[C:31]([C:34]([O:36][CH3:37])=[O:35])[S:32][CH:33]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:16]([NH:15][S:12]([C:5]1[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=2[C:2]([C:30]2[C:29]([CH3:28])=[CH:33][S:32][C:31]=2[C:34]([O:36][CH3:37])=[O:35])=[CH:3][CH:4]=1)(=[O:14])=[O:13])([CH3:19])([CH3:18])[CH3:17]
Reactant: COC(=O)c1scc(C)c1B1OC(C)(C)C(C)(C)O1
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(Br)c2c1CCCC2
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1scc(C)c1-c1ccc(S(=O)(=O)NC(C)(C)C)c2c1CCCC2
Temperature: 75 °C
Reaction time: 20 h
Yield: 7.7 %

Procedure:
4-bromo-N-(tert-butyl)-5,6,7,8-tetrahydronaphthalene-1-sulfonamide (59b, 1.35 g, 3.90 mmol) and Potassium phosphate (0.75 g, 3.54 mmol) were added to a stirred suspension of methyl 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-2-carboxylate (Prepared according to the procedure reported in the literature, J. Org. Chem., 2010, 75, 3855-3858, 1.0 g, 3.54 mmol) in a mixture of 20 ml THF and 4 ml water in a tube under a nitrogen atmosphere at room temperature (about 25° C.). A nitrogen gas was purged to this suspension for 15 minute at room temperature (about 25° C.). To the reaction mixture was then added triphenyl phospine (0.028 g, 0.10 mmol) and) Palladium (II) acetate (0.016 g, 0.07 mmol) at 25° C. and the tube was sealed. The reaction mixture was then stirred at about 75° C. for 20 hours. The progress of the reaction was monitored by TLC. The reaction mixture was then filtered and the cake obtained was washed with ethyl acetate (2×30 ml). The combined filtrate was then concentrated under reduced pressure to obtain crude product, which was then purified by flash column chromatography using 30% ethyl acetate in hexanes as an eluent to obtain the title compound (0.11 g, 7.7%)