Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.N1CCCCC1.[Cl:17][C:18]1[CH:26]=[C:25]2[C:21]([CH2:22][C:23](=[O:27])[NH:24]2)=[CH:20][CH:19]=1>CO>[Cl:17][C:18]1[CH:26]=[C:25]2[C:21](/[C:22](=[CH:5]\[C:4]3[CH:7]=[CH:8][CH:9]=[C:2]([Cl:1])[C:3]=3[F:10])/[C:23](=[O:27])[NH:24]2)=[CH:20][CH:19]=1
Reactant: O=Cc1cccc(Cl)c1F
Reactant: O=C1Cc2ccc(Cl)cc2N1
Solvent: CO
Solvent: C1CCNCC1
Product: O=C1Nc2cc(Cl)ccc2/C1=C\c1cccc(Cl)c1F
Reaction time: 8 h
Yield: 96.1 %

Procedure:
3-Chloro-2-fluorobenzaldehyde (6.24 g, 39.4 mmol) was added to a solution of piperidine (3.88 mL, 39.4 mmol) and 6-chlorooxindole (6.0 g, 35.8 mmol) dissolved in methanol (100 mL). After stirring overnight, the resulting solid was filtered and washed with methanol and hexanes to give 10.6 g of (E)-6-chloro-3-(3-chloro-2-fluorobenzylidene)indolin-2-one (3) as a green solid.
Reaction SMILES: Br[CH:2]1[CH2:5][CH2:4][CH2:3]1.[F:6][C:7]1[C:15]([F:16])=[CH:14][C:13]([OH:17])=[CH:12][C:8]=1[C:9]([OH:11])=[O:10].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH:2]1([O:17][C:13]2[CH:14]=[C:15]([F:16])[C:7]([F:6])=[C:8]([CH:12]=2)[C:9]([O:11][CH:2]2[CH2:5][CH2:4][CH2:3]2)=[O:10])[CH2:5][CH2:4][CH2:3]1
Reactant: BrC1CCC1
Reactant: O=C(O)c1cc(O)cc(F)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C(OC1CCC1)c1cc(OC2CCC2)cc(F)c1F
Temperature: 90 °C
Reaction time: 8 h
Yield: 60.5 %

Procedure:
Bromocyclobutane (150 g, 1.12 mol) was added to a mixture of 2,3-difluoro-5-hydroxybenzoic acid (50 g, 287 mmol), and potassium carbonate (230 g, 1.67 mol) in acetonitrile (1500 mL), and the resulting mixture stirred overnight at 90° C. The reaction mixture was cooled to room temperature, filtered, and concentrated under vacuum. The residue was purified via column chromatography on silica gel (eluting with petroleum ether) to afford cyclobutyl 5-cyclobutoxy-2,3-difluorobenzoate (49 g, 60%) as a yellow green solid. MS (ESI, pos. ion) m/z 283 [M+H]+.
Reaction SMILES: C([N:3]([CH2:14][CH3:15])[C:4](=[O:13])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:6]=1[CH3:12])C.[OH:16][C@@H:17]1[CH2:21][CH2:20][N:19]([CH2:22]CC(N(OC)C)=O)[CH2:18]1>>[Cl:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:5]2[C:6]=1[CH:12]=[C:14]([CH2:15][CH2:22][N:19]1[CH2:20][CH2:21][C@@H:17]([OH:16])[CH2:18]1)[NH:3][C:4]2=[O:13]
Reactant: CCN(CC)C(=O)c1cccc(Cl)c1C
Reactant: CON(C)C(=O)CCN1CC[C@@H](O)C1
Product: O=c1[nH]c(CCN2CC[C@@H](O)C2)cc2c(Cl)cccc12
Yield: 2.3 %

Procedure:
In the same manner as in Example 16b and using N,N-diethyl-3-chloro-2-methylbenzamide (3.43 g) and (R)-3-(3-hydroxypyrrolidin-1-yl)-N-methoxy-N-methylpropanamide (3.08 g), (R)-5-chloro-3-[2-(3-hydroxypyrrolidin-1-yl)ethyl]-2H-isoquinolin-1-one (102 mg) was obtained.
Reaction SMILES: F[C:2](F)(F)[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]([N:15](C)[CH2:16][C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)=[O:14])=[CH:8][CH:7]=1)=O.[CH2:26](I)C.CC(C)=O>O>[CH2:3]([NH:5][C:6]1[CH:7]=[CH:8][C:9]([NH:12][C:13]([NH:15][CH2:16][C:17]2([CH3:26])[CH:18]=[CH:19][N:20]=[CH:21][CH2:22]2)=[O:14])=[CH:10][CH:11]=1)[CH3:2]
Reactant: CN(Cc1ccncc1)C(=O)Nc1ccc(NC(=O)C(F)(F)F)cc1
Reactant: CCI
Solvent: CC(C)=O
Solvent: O
Product: CCNc1ccc(NC(=O)NCC2(C)C=CN=CC2)cc1
Reaction time: 8 h

Procedure:
To 2.89 gms. (0.01 mole) of 1-(p-trifluoroacetamidophenyl)-3-methyl-3-(4-pyridylmethyl)urea [prepared by reacting 1-(p-aminophenyl)-3-methyl-3- (4-pyridylmethyl)urea (Example 6., supra.) with trifluoroacetic anhydride (method of Hickenbottom, Reactions of Organic Compounds, Longmans, London, 1963)] there is added 6.24 gms. (0.04 mole) of ethyl iodide in 50 ml. of dry acetone. The acetone is then stripped and the residue added to 50 ml. of water. The aqueous mixture is warmed to reflux for about 30 minutes and then allowed to stand overnight. The mixture is then stripped of water to give 1-(p-ethylaminophenyl)-4-methyl-3-(4-pyridylmethyl)urea.
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:11][CH:10]=1)=[N+]=[N-].O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[NH2:1][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:11][CH:10]=1
Reactant: [N-]=[N+]=NCCCCCc1ccc(Oc2ccccc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: NCCCCCc1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 84 h

Procedure:
To a solution of the product from Step 2 (360 mg, 1.28 mmol) in 10 mL of THF at room temperature was added water (0.025 mL), followed by triphenylphosphine (364 mg, 1.41 mmol). The solution was stirred at room temperature. After 84 hours, the reaction was concentrated in vacuo to provide the titled compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH:10]([NH:18][C:19]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:20]=1[CH:21]=[CH:22][C:23](=[O:29])[NH:24]2)[C:11]1([C:14]([F:17])([F:16])[F:15])[CH2:13][O:12]1.C([O-])([O-])=O.[Cs+].[Cs+].[CH2:36]([SH:38])[CH3:37].O>CN(C=O)C>[CH2:36]([S:38][CH2:13][C:11]([OH:12])([C:14]([F:16])([F:15])[F:17])[CH:10]([NH:18][C:19]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:20]=1[CH:21]=[CH:22][C:23](=[O:29])[NH:24]2)[C:3]1[CH:4]=[CH:5][C:6]([O:8][CH3:9])=[CH:7][C:2]=1[F:1])[CH3:37]
Reactant: COc1ccc(C(Nc2cccc3[nH]c(=O)ccc23)C2(C(F)(F)F)CO2)c(F)c1
Reactant: CCS
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCSCC(O)(C(Nc1cccc2[nH]c(=O)ccc12)c1ccc(OC)cc1F)C(F)(F)F
Reaction time: 4 h
Yield: 35.4 %

Procedure:
To 50 mg (0.12 mmol) 5-{[(2-Fluoro-4-methoxyphenyl)(2-trifluoromethyl-oxiranyl)methyl]amino}-1H-quinolin-2-one and 80 mg Cs2CO3 in 0.5 ml DMF are added 14 μl (0.18 mmol) of ethyl mercaptan in DMF. The mixture is stirred vigorously for 4 hours and water is added. The aqueous layer is extracted with ethyl acetate, the organic phases washed with brine and dried over sodium sulphate. After removal of the solvent thin layer chromatography on silica gel (acetone in hexane 50%) yields 20 mg of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C:15]([O-])([O-])=O.[K+].[K+].IC>CC(C)=O>[CH3:15][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:9][CH2:10][C:11](=[O:14])[CH2:12][CH2:13]2)=[CH:6][CH:7]=1
Reactant: O=C1CCC(c2ccc(O)cc2)CC1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1ccc(C2CCC(=O)CC2)cc1
Temperature: 65 °C
Yield: 99.4 %

Procedure:
A solution of 4-(4-hydroxyphenyl)cyclohexanone (5.0 g, 26.3 mmol) in acetone (100 mL) was treated with K2CO3 (14.5 g, 105 mmol, 4 equiv) and iodomethane (4.9 mL, 11.2 g, 78.6 mmol, 3 equiv.). The reaction was heated at 65° C. overnight. After the solvent was removed, the residue was treated with H2O and extracted with EtOAc. The organic extracts were combined and washed with brine, dried over Na2SO4 and concentrated in vacuum to give the spectroscopically pure 4-(4-methoxyphenyl)cyclohexanone (5.34 g, 100%). 1H NMR(CDCl3) 7.16 (dt, 2H), 6.87 (dt, 2H), 3.78 (s, 3H), 2.99 (tt, 1H), 2.47-2.53 (m, 4H), 2.20 (m, 2H) and 1.83-1.98 (m, 2H); MS (electrospray) m/e, 205 (M+1)+, Calcd for C13H16O2, 204.
Reaction SMILES: [C:1]([C:4]1[C:5]([OH:17])=[C:6]([O:15][CH3:16])[C:7]2[O:11][CH:10]=[CH:9][C:8]=2[C:12]=1[O:13][CH3:14])(=[O:3])[CH3:2].Cl[CH2:19][CH2:20][CH2:21][N:22]([CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([O:34][CH3:35])[CH:27]=1)[CH3:23]>C(C(C)=O)C>[C:1]([C:4]1[C:5]([O:17][CH2:19][CH2:20][CH2:21][N:22]([CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([O:34][CH3:35])[CH:27]=2)[CH3:23])=[C:6]([O:15][CH3:16])[C:7]2[O:11][CH:10]=[CH:9][C:8]=2[C:12]=1[O:13][CH3:14])(=[O:3])[CH3:2]
Reactant: COc1c(C(C)=O)c(O)c(OC)c2occc12
Reactant: COc1ccc(CCN(C)CCCCl)cc1OC
Solvent: CCC(C)=O
Product: COc1ccc(CCN(C)CCCOc2c(C(C)=O)c(OC)c3ccoc3c2OC)cc1OC

Procedure:
39 g of 5-acetyl-6-hydroxy-4,7-dimethoxybenzofuran are refluxed with 40 g of 3-chloropropyl-(2-(3,4-dimethoxyphenyl)-ethyl)-methylamine in 250 ml of methyl ethyl ketone for 14 hours. The mixture is filtered, the solvent is stripped off and the oily residue is dissolved in dilute HCl. The aqueous phase is washed with ether, rendered alkaline with dilute sodium hydroxide solution and extracted with ether. Stripping off the solvent gives 45 g of crude oily product which is further reacted without purification.
Reaction SMILES: [C:1]([OH:9])(=[S:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:10]([N:13]1[C:25]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:19]2[C:14]1=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:11]=[CH2:12].C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.O>[CH:15]1[C:14]2[N:13]([CH2:10][CH2:11][CH2:12][S:8][C:1](=[O:9])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]=2[CH:18]=[CH:17][CH:16]=1
Reactant: OC(=S)c1ccccc1
Reactant: C=CCn1c2ccccc2c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(SCCCn1c2ccccc2c2ccccc21)c1ccccc1

Procedure:
Thiobenzoic acid (30 g, 0.20 mol) was added to 9-allylcarbazole (11.9 g, 0.057 mol) in 100 mL toluene, and the reaction was carried out at 90° C. with argon purge via radical mechanism using AIBN as the initiator (1.8 g, 11 mmol, in 300 mg increments at 1 hr intervals). After 6 hrs the reaction mixture was poured into a 1 L separatory funnel containing 20 g sodium bicarbonate (NaHCO3, 0.24 mol) in 250 mL water, extracted with 100 mL chloroform, and the organic phase was washed twice with 200 mL water before solvent removal under reduced pressure. The crude product was subsequently washed in 100 mL hot hexane, 150 mL ethanol, and finally 150 mL of 15:1 ethanol:chloroform. Evaporation of leftover solvent at 80° C. under reduced pressure yielded compound 16 in ca. 90% purity as a dark brown, viscous syrup which solidified upon cooling (9.35 g, 0.024 mol, 42% yield, ˜10% wt dibenzoyl disulfide). 1H NMR (300 MHz, CDCl3): δ=8.10 (d, 2 carbazole H, J=8.1 Hz), 8.00-7.95 (m, 2 aromatic H ortho to COS), 7.62-7.41 (m, 3 aromatic H meta and para to COS plus 4 carbazole H), 7.27-7.19 (m, 2 carbazole H), 4.43 (t, NCH2, J=6.9 Hz), 3.06 (t, SCH2, J=6.9 Hz), 2.26 (tt, NCH2CH2CH2S, J=6.9, 6.9 Hz). 13C NMR (300 MHz, CDCl3): δ=191.56, 140.25, 136.88, 133.50, 128.65, 127.23, 125.75, 122.91, 120.41, 119.00, 108.55, 41.65, 28.95, 26.41.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH2:11])[CH:6]=1)[CH3:2].[N:13]([O-])=O.[Na+].O.O.Cl[Sn]Cl>Cl>[NH:11]([C:7]1[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=1)[C:4]([O:3][CH2:1][CH3:2])=[O:12])[NH2:13]
Reactant: O=N[O-]
Reactant: CCOC(=O)c1cccc(N)c1
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: CCOC(=O)c1cccc(NN)c1
Reaction time: 1 h

Procedure:
To a solution of m-aminobenzoic acid ethyl ester (200 g, 1.21 mmol) in conc. HCl (200 mL) was added an aqueous solution (250 mL) of NaNO2 (102 g, 1.46 mmol) at 0° C. and the reaction mixture was stirred for 1 h. A solution of SnCl2.2H2O (662 g, 2.92 mmol) in conc. HCl (2 L) was then added at 0° C. The reaction solution was stirred for 2 h at RT. The precipitate was filtered and washed with ethanol and ether to yield ethyl 3-hydrazinobenzoate, which was used for the next reaction without further purification.
Reaction SMILES: [C:1]([NH:6][C:7]1[C:8]2[N:9]=[CH:10][N:11]([C:43]=2[N:44]=[CH:45][N:46]=1)[C@:12]1(C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[O:23][C@H:18]([CH2:19][O:20]OC)[C@@H:16]([OH:17])[C@H:13]1[O:14][CH3:15])(=[O:5])[CH2:2][CH2:3][CH3:4].[C:47](Cl)(=[O:54])[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1>N1C=CC=CC=1>[C:47]([O:17][C@@H:16]1[C@@H:18]([CH2:19][OH:20])[O:23][C@@H:12]([N:11]2[C:43]3[N:44]=[CH:45][N:46]=[C:7]([NH:6][C:1](=[O:5])[CH2:2][CH2:3][CH3:4])[C:8]=3[N:9]=[CH:10]2)[C@@H:13]1[O:14][CH3:15])(=[O:54])[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCCC(=O)Nc1ncnc2c1ncn2[C@]1(C(c2ccccc2)(c2ccccc2)c2ccccc2)O[C@H](COOC)[C@@H](O)[C@H]1OC
Solvent: c1ccncc1
Product: CCCC(=O)Nc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](OC(=O)c2ccccc2)[C@H]1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
N-Butyryl-5′-O-monomethoxytrityl-2′-O-methyladenosine 7 (100 mg, 0.16 mmol) was dried by evaporation of added dry pyridine (5 mL) under reduced pressure and finally by keeping on a vacuum pump for 30 min. Dry pyridine was added (2 mL) and the solution was put into ice-bath whereupon benzoyl chloride was added (1.2 eq, 0.19 mmol, 22.2 μL) and after 10 min the ice-bath was removed and the reaction was allowed to warm up and was then left stirring overnight at room temperature. A small amount of NaHCO3 (aq. sat.) was added and the solvent was evaporated under reduced pressure. Dichloromethane was added and the organic phase was washed with NaHCO3 (aq. sat. 2×). The organic phase was collected, dried (MgSO4), filtered and concentrated. Evaporation of added toluene (2×) and dichloromethane (2×) was done to remove traces of pyridine. The remaining crude material of compound 8 was dissolved in 80% acetic acid (10 mL) and allowed to react at room temperature for 4 h. after which deprotection of 5′-monomethoxytrityl was complete (TLC, mass). The solution was concentrated and added toluene (2×) and dichloromethane (2×) evaporated under reduced pressure to remove excess acetic acid. The compound was purified on silica gel column chromatography using a gradient of methanol in dichloromethane (0-5%). Yield 80% of compound 9. 1H NMR (CDCl3) δ 1.04 (3H, t, J=7.4 Hz), 1.80 (2H, m), 2.92 (2H, t, J=7.4 Hz), 3.31 (3H, s), 3.96 (2H, m), 4.51 (1H, s), 4.87 (1H, m), 5.90 (1H, d, J=4.9 Hz), 6.01 (1H, d, J=7.9 Hz), 6.32 (1H, d, J=9.9 Hz), 7.27 (2H, m), 7.51 (1H, m), 8.12 (2H, m), 8.18 (1H, s), 8.70 (1H, s), 9.27 (1H, s), 13C NMR δ 13.9, 18.4, 40.0, 59.3, 63.1, 72.7, 77.4, 81.4, 86.8, 89.9, 123.7, 128.1, 128.9, 129.8, 133.7, 143.5, 150.2, 152.1, 165.8, 173.5, MS (ES-TOF) m/z calculated: 455.18. found: 455.38.
Reaction SMILES: C([O:8][C:9]1[C:10]([F:24])=[C:11]([C:15]2(O)[CH2:20][CH2:19][N:18]([CH2:21][CH3:22])[CH2:17][CH2:16]2)[CH:12]=[CH:13][CH:14]=1)C1C=CC=CC=1.FC(F)(F)C(O)=O>>[CH2:21]([N:18]1[CH2:17][CH:16]=[C:15]([C:11]2[C:10]([F:24])=[C:9]([OH:8])[CH:14]=[CH:13][CH:12]=2)[CH2:20][CH2:19]1)[CH3:22]
Reactant: CCN1CCC(O)(c2cccc(OCc3ccccc3)c2F)CC1
Solvent: O=C(O)C(F)(F)F
Product: CCN1CC=C(c2cccc(O)c2F)CC1

Procedure:
Preparation according to preparation 2: 4-[3-(benzyloxy)-2-fluorophenyl]-1-ethylpiperidin-4-ol (1.9 g, 5.77 mmol), trifluoroacetic acid (5 ml). Yield: 1.1 g. MS m/z (rel. intensity, 70 eV) 221 (M+, bp), 220 (43), 206 (95), 163 (10), 110 (14).
Reaction SMILES: [F:1][C:2]1[C:3]([N:9]=[CH:10][N:11]([CH3:13])[CH3:12])=[N:4][C:5]([OH:8])=[N:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[F:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Br)=[CH:23][CH:22]=1>CN(C)C=O>[F:1][C:2]1[C:3]([N:9]=[CH:10][N:11]([CH3:13])[CH3:12])=[N:4][C:5](=[O:8])[N:6]([CH2:25][C:24]2[CH:27]=[CH:28][C:21]([F:20])=[CH:22][CH:23]=2)[CH:7]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: CN(C)C=Nc1nc(O)ncc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(C)C=Nc1nc(=O)n(Cc2ccc(F)cc2)cc1F
Temperature: 70 °C
Reaction time: 16 h

Procedure:
To an 8 mL screw-cap vial was added N,N-dimethylformamide (DMF; 1.5 mL), N′-(5-fluoro-2-hydroxypyrimidin-4-yl)-N,N-dimethylformamidine (100 mg, 0.54 mmol), anhydrous potassium carbonate (K2CO3; 138 mg, 1.0 mmol), and 4-fluorobenzyl bromide (113 mg, 0.60 mmol). The mixture was shaken and heated to 70° C. for 2 h and then at room temperature for an additional 16 h. The crude reaction mixture was filtered and placed directly onto a reverse phase chromatography column. After elution, the title compound was isolated as a white solid (30 mg, 20%): mp 134-136° C.; 1H NMR (300 MHz, CDCl3) δ 8.68 (s, 1H), 8.07 (d, J=2.5 Hz, 1H), 7.49-7.43 (m, 2H), 7.10-7.01 (m, 2H), 5.33 (s, 2H), 3.20 (s, 3H), 3.18 (s, 3H); ESIMS m/z 293 ([M+H]+).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[CH2:6][O:7][C:8]1[CH:20]=[CH:19][C:11]([O:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:10][CH:9]=1.[OH-].[Na+].[C:23]([O:27]C)(=[O:26])[CH:24]=[CH2:25].Cl>O1CCOCC1.ClCCl>[N:16]1[CH:17]=[CH:18][C:13]([O:12][C:11]2[CH:10]=[CH:9][C:8]([O:7][CH2:6][C@H:2]3[CH2:3][CH2:4][CH2:5][N:1]3[CH2:25][CH2:24][C:23]([OH:27])=[O:26])=[CH:20][CH:19]=2)=[CH:14][CH:15]=1
Reactant: C=CC(=O)OC
Reactant: c1cc(Oc2ccc(OC[C@H]3CCCN3)cc2)ccn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=C(O)CCN1CCC[C@@H]1COc1ccc(Oc2ccncc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The product from Example 144 (50 mg, 0.15 mmol) was treated with 20% NaOH (5 ml) and extracted with EtOAc, dried over Na2SO4 and dried down to give the free base. Dichloromethane (3 ml) and methyl acrylate (0.4 ml, 2.8 mmol) were added and the mixture was stirred at rt overnight. The reaction mixture was dried down to give an oil. Excess 4.0M HCl in dioxane was added and the mixture was stirred overnight at rt. The solvent was removed in vacuo to give the title compound. (15 mg, 23%); LC/MS; m/z 343 (M+H) 99%; 1H NMR (DMSO-d6, 400 MHz) δ 1.79-2.29 (4H, m), 2.89 (2H, m), 3.16 (1H, m), 3.56-3.71 (3H, m), 3.97 (1H, m) 4.34-4.51 (2H, m), 7.18 (2H, d, J=8.8 Hz), 7.33 (2H, d, J=9.6 Hz), 7.43 (2H, d, J=7.2 Hz), 8.80 (2H, d, J=7.2 Hz)
Reaction SMILES: [CH2:1]([NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]2[CH:27]=[CH:26][C:18]([O:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:17][CH:16]=2)[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:28]([O:35][C:36]1[CH:41]=[CH:40][C:39]([O:42][CH2:43][C@H:44]2[O:46][CH2:45]2)=[CH:38][C:37]=1[N:47](C(OC(C)(C)C)=O)[S:48]([CH3:51])(=[O:50])=[O:49])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.Cl>C(O)C>[CH2:1]([N:8]([CH2:45][C@H:44]([OH:46])[CH2:43][O:42][C:39]1[CH:40]=[CH:41][C:36]([O:35][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[C:37]([NH:47][S:48]([CH3:51])(=[O:50])=[O:49])[CH:38]=1)[C@H:9]1[CH2:10][CH2:11][C@H:12]([C:15]2[CH:27]=[CH:26][C:18]([O:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:17][CH:16]=2)[CH2:13][CH2:14]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)COc1ccc([C@H]2CC[C@H](NCc3ccccc3)CC2)cc1
Reactant: CC(C)(C)OC(=O)N(c1cc(OC[C@@H]2CO2)ccc1OCc1ccccc1)S(C)(=O)=O
Agent: Cl
Solvent: CCO
Product: CCOC(=O)COc1ccc([C@H]2CC[C@H](N(Cc3ccccc3)C[C@H](O)COc3ccc(OCc4ccccc4)c(NS(C)(=O)=O)c3)CC2)cc1
Temperature: 50 °C

Procedure:
A mixture of 3.22 g of ethyl trans-{4-[4-(benzylamino)cyclohexyl]phenoxy}acetate (8.7 mmol) and 5 g of 4-benzyloxy-3-(N-(tert-butoxycarbonyl)-N-(methylsulfonyl)amino)-1-((2S)-2,3-epoxypropoxy)benzene (11.2 mmol) in ethanol (72 ml) is brought to reflux for 40 h. A 3N solution of hydrochloric acid in ethanol is added and the reaction medium is heated at 50° C. for 19 h. The solvents are evaporated under reduced pressure and then water, dichloromethane and a saturated aqueous sodium carbonate solution are added. The aqueous phase is extracted once with dichloromethane. The organic phases are combined, washed with water and then dried over magnesium sulfate. The solvents are evaporated under reduced pressure and ethyl trans-(4-{4-[Benzyl((2S)-3-{4-(benzyloxy)-3-[(methylsulfonyl)amino]phenoxy}-2-hydroxypropyl)amino]cyclohexyl}phenoxy)acetate is obtained in the form of an oil (2.7 g, 43%) after purification on silica gel (eluent: ethyl acetate/heptane 30/70 to 50/50 gradient in 40 min). [M+H+]=717.6
Reaction SMILES: [CH:1]1([CH:4]([O:20][CH3:21])[CH:5]([N:7]2[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[C:9]([C:16]([OH:18])=O)=[C:8]2[CH3:19])[CH3:6])[CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[NH2:47][CH2:48][C:49]1[C:50](=[O:58])[NH:51][C:52]([CH3:57])=[CH:53][C:54]=1[O:55][CH3:56]>ClCCl>[CH:1]1([CH:4]([O:20][CH3:21])[CH:5]([N:7]2[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[C:9]([C:16]([NH:47][CH2:48][C:49]3[C:50](=[O:58])[NH:51][C:52]([CH3:57])=[CH:53][C:54]=3[O:55][CH3:56])=[O:18])=[C:8]2[CH3:19])[CH3:6])[CH2:3][CH2:2]1
Reactant: COC(C1CC1)C(C)n1c(C)c(C(=O)O)c2cccnc21
Reactant: COc1cc(C)[nH]c(=O)c1CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: COc1cc(C)[nH]c(=O)c1CNC(=O)c1c(C)n(C(C)C(OC)C2CC2)c2ncccc12
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
To a solution of 1-(1-cyclopropyl-1-methoxypropan-2-yl)-2-methyl-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid (100 mg, 0.35 mmol) in dichloromethane (2 mL) was added HATU (192 mg, 0.52 mmol), TEA (105.28 mg, 1.04 mmol). After stirred for 50 min at room temperature, 3-(aminomethyl)-4-methoxy-6-methylpyridin-2(1H)-one hydrochloride (87.5 mg, 0.52 mmol) was added. The mixture was stirred at room temperature for 3 hours. After the reaction completed, the solution was partitioned between EtOAc and H2O. The organic was separated, dried over Na2SO4 and evaporated under vacuum.
Reaction SMILES: C(OC[C:5]([CH2:27]OCC)([OH:26])[CH:6]([NH:18]C(OC(C)(C)C)=O)[CH2:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1)C.[ClH:31]>>[ClH:31].[NH2:18][C@H:6]1[CH2:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10][C:9]=2[C@H:27]([Cl:31])[C@H:5]1[OH:26]
Reactant: CCOCC(O)(COCC)C(Cc1cccc2ccccc12)NC(=O)OC(C)(C)C
Agent: Cl
Product: N[C@H]1Cc2c(ccc3ccccc23)[C@H](Cl)[C@H]1O
Temperature: 100 °C
Reaction time: 0.05 h

Procedure:
A suspension of α, α-diethoxymethyl-β-tert-butoxycarbonylamino-1-naphthalenepropanol (252 mg), isomer B w as stirred in 37% aqueous hydrochloric acid at 0° C. for 50 minutes. The resulting suspension was then stirred at 100° C. for 3 minutes. The reaction flask was cooled at 0° C. and the precipitate was filtered, washed with water and dried in vacuo. The title compound (156 mg) was obtained as a white solid.
Reaction SMILES: [C:1]1(=[O:17])[N:5]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]O)[C:4](=[O:12])[C:3]2=[CH:13][CH:14]=[CH:15][CH:16]=[C:2]12.P(Br)(Br)[Br:19].C(=O)([O-])O.[Na+]>C(OCC)C>[Br:19][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][N:5]1[C:4](=[O:12])[C:3]2=[CH:13][CH:14]=[CH:15][CH:16]=[C:2]2[C:1]1=[O:17]
Reactant: BrP(Br)Br
Reactant: O=C1c2ccccc2C(=O)N1CCCCCO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Product: O=C1c2ccccc2C(=O)N1CCCCCBr
Temperature: 25 °C
Reaction time: 9 h
Yield: 45 %

Procedure:
Then, 16.2 g of 5-phthalimido-1-pentanol was dissolved in 350 ml of diethyl ether, and 4.3 ml of phosphorus tribromide was added dropwise at 0° C. The reaction solution was stirred at room temperature for 9 hours and neutralized with saturated aqueous sodium hydrogen carbonate, and the organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated in vacuo for removal of the solvent. The residue was purified by silica gel column chromatography (eluent; n-hexane:ethyl acetate=9:1) to give 9.2 g of 1-bromo-5-phthalimidopentane in a yield of 45%.
Reaction SMILES: C(Cl)(Cl)(Cl)Cl.[CH2:6]([O:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH3:21])=[C:16]([O:22][CH2:23][CH2:24][CH2:25][C:26]#[N:27])[CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[Br:28]N1C(=O)CCC1=O>ClCCl>[CH2:6]([O:13][C:14]1[CH:15]=[C:16]([O:22][CH2:23][CH2:24][CH2:25][C:26]#[N:27])[C:17]([CH2:20][CH3:21])=[CH:18][C:19]=1[Br:28])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CCc1ccc(OCc2ccccc2)cc1OCCCC#N
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: CCc1cc(Br)c(OCc2ccccc2)cc1OCCCC#N
Reaction time: 5.5 h
Yield: 47.4 %

Procedure:
Carbon tetrachloride (30 mL) was used to dissolve 4-(Benzyloxy)-2-[(3-cyanopropyl)oxy]-1-ethylbenzene (2.5 g). N-bromosuccinimide (1.66 g) was added to the solution and it was stirred for 5.5 hours. The mixture was diluted with dichloromethane (50 mL), washed with water, dried over magnesium sulfate, filtered, and concentrated under vacuum. The resulting oil was crystallized from hexane/ethyl acetate at −20° C. to afford 1-(benzyloxy)-2-bromo-4-ethyl-5-[(3-cyanopropyl)oxy]-benzene as a white crystalline solid (1.5 g). NMR (CDCl3) 1.14, t (3H); 2.14, m (2H); 2.55, m (4H); 3.98, t (2H); 5.12, s (2H); 6.45, s (1H); 7.37, m (6H).