Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]([CH2:25][OH:26])([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:13][CH:12]=1)[CH2:3][O:4][P:5](=[O:8])([OH:7])[OH:6].C(N([CH2:43][C:44]([OH:46])=O)CC(O)=O)CN(CC(O)=O)CC(O)=O.B(O)(O)O.Cl>C(O)C>[OH:26][CH2:25][C:2]([N:1]1[CH2:12][C:11]2[C:43](=[CH:3][CH:2]=[CH:9][CH:10]=2)[C:44]1=[O:46])([CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:15][CH:16]=1)[CH2:3][O:4][P:5](=[O:6])([OH:7])[OH:8]
Reactant: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CC(=O)O
Reactant: CCCCCCCCc1ccc(CCC(N)(CO)COP(=O)(O)O)cc1
Agent: Cl
Agent: OB(O)O
Solvent: CCO
Product: CCCCCCCCc1ccc(CCC(CO)(COP(=O)(O)O)N2Cc3ccccc3C2=O)cc1
Reaction time: 1 h

Procedure:
The endproduct of step d) ((R/S)-FTY720-phosphate) (50 mg; 0.125 mmol) is suspended in a solution of EDTA (0.5 ml; 10 mM in water) and aqueous boric acid (0.5 ml; 3% in water; adjusted to pH 10.5 with aqueous KOH10%). After addition of OPA (33 mg, 0.25 mmol), dissolved in ethanol (0.5 ml), the reaction is kept at RT for 1 hour (ultrasound). After that the pH is adjusted to 3.5 (aqueous HCl; 1N) and extracted with ethylacetate (three times). The organic layer is dried over Na2SO4 and the compound is purified on silica gel using methylenechloride/methanol (95/5→0/100) as mobile phase.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])[C:5]([Cl:20])=[CH:4][N:3]=1.[N:21]([C:24]1[CH:36]=[CH:35][C:27]([CH2:28][N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)=[CH:26][C:25]=1[O:37][CH3:38])=[C:22]=S>>[Cl:20][C:5]1[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])=[C:7]2[N:8]=[C:22]([NH:21][C:24]3[CH:36]=[CH:35][C:27]([CH2:28][N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)=[CH:26][C:25]=3[O:37][CH3:38])[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: COc1cc(CN2CCOCC2)ccc1N=C=S
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Product: COc1cc(CN2CCOCC2)ccc1Nc1nc2c(N[C@H]3[C@@H](C(N)=O)[C@@H]4C=C[C@H]3C4)c(Cl)cnc2[nH]1
Yield: 11 %

Procedure:
In a similar fashion as for the synthesis of Compound LXVII, (1S,2S,3R,4R)-3-(2,3-Diamino-5-chloro-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide was reacted with 4-(4-isothiocyanato-3-methoxybenzyl)-morpholine to afford the title compound as a tan solid (11%). 1H NMR (d-6 DMSO): 10.0 (br m, 1H), 8.78 (m, 1H), 8.62 (m, 1H), 7.86 (m, 2H), 7.36 (m, 1H), 7.25 (m, 1H), 7.10 (m, 1H), 6.43 (m, 2H), 5.08 (m, 1H), 4.34 (m, 2H), 3.98 (s, 3H), 3.29 (m, 4H), 3.12 (m, 4H), 2.92 (s, 1H), 2.86 (s, 1H), 2.62 (m, 1H), 2.21 (m, 1H), 1.69 (m, 1H), 1.44 (m, 1H). MS: 524.02 (M+H). HPLC retention time: 1.74 minutes (G Method).
Reaction SMILES: C1(CCCN)C=CC=CC=1.[CH2:11]1[C:19]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[CH2:13][N:12]1[C:20]([NH:22][C@H:23]1[CH2:26][C@H:25]([C:27]([OH:29])=O)[CH2:24]1)=[O:21].[CH2:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)C[N:31]1C(NC1C=CC(C(O)=O)=CC=1)=O>>[CH2:30]([NH:31][C:27]([C@H:25]1[CH2:24][C@H:23]([NH:22][C:20]([N:12]2[CH2:11][C:19]3[CH:18]=[CH:17][N:16]=[CH:15][C:14]=3[CH2:13]2)=[O:21])[CH2:26]1)=[O:29])[C:38]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: O=C(O)c1ccc(NC(=O)N2Cc3ccccc3C2)cc1
Reactant: O=C(N[C@H]1C[C@H](C(=O)O)C1)N1Cc2ccncc2C1
Agent: NCCCc1ccccc1
Product: O=C(N[C@H]1C[C@H](C(=O)NCc2ccccc2)C1)N1Cc2ccncc2C1

Procedure:
The title compound was prepared as described in Example 1C, substituting benzylamine for 3-phenylpropan-1-amine and trans-3-(2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-2-carboxamido)cyclobutanecarboxylic acid for 4-(isoindoline-2-carboxamido)benzoic acid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.56 (s, 1H), 8.47 (d, J=5.0 Hz, 1H), 8.26 (t, J=5.9 Hz, 1H), 7.39 (d, J=5.1 Hz, 1H), 7.36-7.28 (m, 2H), 7.27-7.20 (m, 3H), 6.60 (d, J=7.6 Hz, 1H), 4.65-4.59 (m, 4H), 4.45-4.29 (m, 1H), 4.28 (d, J=5.9 Hz, 2H), 2.96-2.84 (m, 1H), 2.41-2.29 (m, 2H), 2.30-2.15 (m, 2H); MS (ESI(+)) m/e 351 (M+H)+.
Reaction SMILES: [C:1]1([S:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21])=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.OO.O.O.O.O.O.S([O-])([O-])(=[O:31])=S.[Na+].[Na+]>C(O)(=O)C.O.C(OCC)(=O)C.C1(C)C=CC=CC=1>[C:1]1([S:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21])=[CH:10][CH:9]=2)=[O:31])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COCCOCCOc1ccc(Sc2ccccc2)cc1
Reactant: O=S([O-])([O-])=S
Agent: OO
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: O
Product: COCCOCCOc1ccc(S(=O)c2ccccc2)cc1
Reaction time: 18 h
Yield: 993.8 %

Procedure:
In 770 g of acetic acid was dissolved 109.3 g of 4-[2-(2-methoxyethoxy)ethoxy]phenyl phenyl sulfide obtained in Synthesis Example 1-38. While the solution was maintained at an internal temperature of 30° C., 34.5 g of 35 wt % aqueous hydrogen peroxide was added dropwise. The reaction solution was aged at room temperature for 18 hours, after which under ice cooling, a mixture of 8.8 g sodium thiosulfate pentahydrate and 80 g water was added dropwise to quench the reaction. The solution was combined with 200 g of toluene, 200 g of ethyl acetate and 200 g of water. The organic layer was separated, washed with water, and concentrated in vacuum, obtaining 112.9 g of the target compound, 4-[2-(2-methoxyethoxy)ethoxy]phenyl phenyl sulfoxide as oily matter. Yield 92%.
Reaction SMILES: N(OCCC(C)C)=O.[Br:9][C:10]1[CH:16]=[CH:15][C:13](N)=[C:12]([C:17]([F:20])([F:19])[F:18])[CH:11]=1.[CH3:21][S:22]C>C(#N)C>[Br:9][C:10]1[CH:16]=[CH:15][C:13]([S:22][CH3:21])=[C:12]([C:17]([F:20])([F:19])[F:18])[CH:11]=1
Reactant: CSC
Reactant: Nc1ccc(Br)cc1C(F)(F)F
Agent: CC(C)CCON=O
Solvent: CC#N
Product: CSc1ccc(Br)cc1C(F)(F)F

Procedure:
Isopentyl nitrite (0.67 ml) was added dropwise to a solution of 4-bromo-2-(trifluoromethyl)aniline (1.2 g) and dimethyl sulfide (0.45 ml) in acetonitrile (12 ml). The reaction was slowly heated to reflux and then refluxed until gas evolution ceased. The volatiles were evaporated, the residue absorbed onto silica and the product eluted off with isohexane. Yield 0.8 g.
Reaction SMILES: [C:1]1([CH3:9])[CH:6]=[CH:5][C:4]([CH:7]=[O:8])=[CH:3][CH:2]=1.[CH2:10](I)[CH:11]=[CH2:12].O>CN1C(=O)N(C)CC1>[C:1]1([CH3:9])[CH:6]=[CH:5][C:4]([CH:7]([OH:8])[CH2:12][CH:11]=[CH2:10])=[CH:3][CH:2]=1
Reactant: C=CCI
Reactant: Cc1ccc(C=O)cc1
Solvent: O
Solvent: CN1CCN(C)C1=O
Product: C=CCC(O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.5 %

Procedure:
5.90 ml (50 mmol) p-tolualdehyde was dissolved in 150 ml of DMI, and 5.5 ml (60 mmol, 1.2 eq.) allyl iodide and 10.34 g (66 mmol, 1.3 eq.) SnF2 were added. The reaction became warm to the touch and much precipitate formed as the reaction progressed. After stirring for 1 hour at room temperature, 200 ml of H2O was added, the mixture was extracted with Et2O (1×250 ml, 2 ×100 ml), the combined Et2O layers were washed with sat. NH4Cl (3×50 ml, to remove excess DMI), dried over MgSO4, and evaporated in vacuo to an oil. Flash chromatography (1:4 EtOAc:hexanes, Rf 0.56) yielded 7.5 g (93%) of product as a clear oil. 1H NMR (CDCl3): 7.25 and 7.15 (4H, phenyl), 5.8 and 5.15 (3H, vinyl), 4.65 (1H, CHOH), 2.5 (2H, CH2), 2.35 (2H, CH2), 2.35 (3H, CH3), and 2.15 (1H, OH) ppm.
Reaction SMILES: [CH:1]([C:4]1[CH:18]=[C:17]([O:19]C)[C:16]([C:21]#[C:22][Si](C)(C)C)=[CH:15][C:5]=1[O:6][C:7]1[C:8]([NH2:14])=[N:9][C:10]([NH2:13])=[N:11][CH:12]=1)([CH3:3])[CH3:2].B(Br)(Br)Br.C([O-])(O)=O.[Na+]>C(Cl)Cl>[NH2:13][C:10]1[N:9]=[C:8]([NH2:14])[C:7]([O:6][C:5]2[C:4]([CH:1]([CH3:3])[CH3:2])=[CH:18][C:17]([OH:19])=[C:16]([C:21]#[CH:22])[CH:15]=2)=[CH:12][N:11]=1
Reactant: COc1cc(C(C)C)c(Oc2cnc(N)nc2N)cc1C#C[Si](C)(C)C
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: C#Cc1cc(Oc2cnc(N)nc2N)c(C(C)C)cc1O
Reaction time: 1.5 h
Yield: 20.7 %

Procedure:
5-(2-Isopropyl-4-methoxy-5-trimethylsilanylethynyl-phenoxy)-pyrimidine-2,4-diamine (0.65 g, 1.75 mmol) was added to 40 mL methylene chloride at ice bath temperature and under nitrogen. Boron tribromide (7 mL) was added and the reaction mixture was stirred at ice bath temperature for 1.5 hours, and then for 20 hours at room temperature. The reaction mixture was added to saturated aqueous NaHCO3, and the resulting mixture was extracted with chloroform. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was chromatographed on 50 g of flash silica (2%-6% MeOH/CH2Cl2) to give 103 mg of 4-(2,4-diamino-pyrimidin-5-yloxy)-2-ethynyl-5-isopropyl-phenol, MS (M+H)=285.
Reaction SMILES: [C:1]1([C:7]2[O:11][C:10]([C:12]([OH:14])=O)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][C:24]#[N:25])[CH:19]=[CH:20][CH:21]=1>>[C:24]([CH:23]=[CH:22][C:18]1[CH:17]=[C:16]([NH:15][C:12]([C:10]2[O:11][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:8][CH:9]=2)=[O:14])[CH:21]=[CH:20][CH:19]=1)#[N:25]
Reactant: O=C(O)c1ccc(-c2ccccc2)o1
Reactant: N#CC=Cc1cccc(N)c1
Product: N#CC=Cc1cccc(NC(=O)c2ccc(-c3ccccc3)o2)c1

Procedure:
Carboxylic acid (56) (120 mg, 0.64 mmol) was coupled to aniline (88) (92 mg, 0.64 mmol), using Method C to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([C:11]([CH:22]([CH3:24])[CH3:23])(C(OCC)=O)[C:12]([O:14]CC)=[O:13])[N:4]=1.[OH-].[Na+].O>CO>[CH3:10][O:9][C:7]1[CH:8]=[C:3]([O:2][CH3:1])[N:4]=[C:5]([CH:11]([CH:22]([CH3:24])[CH3:23])[C:12]([OH:14])=[O:13])[N:6]=1
Reactant: CCOC(=O)C(C(=O)OCC)(c1nc(OC)cc(OC)n1)C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1cc(OC)nc(C(C(=O)O)C(C)C)n1
Yield: 75.1 %

Procedure:
10 g of diethyl 2-(4,6-dimethoxypyrimidin-2-yl)- 2-isopropylmalonate, 5,0 g of sodium hydroxide, 20 ml of water and 50 ml of methanol were placed in a round bottomed flask, and were stirred under heat-refluxing for 6 hours. The reaction liquor was concentrated, and 100 ml of water was added thereto. The reaction liquor was adjusted to a pH of from 3 to 4 with a dilute hydrochloric acid under cooling with ice, and was extracted twice with 100 ml of diethyl ether. The extracted liquor was washed with water, and was dried with anhydrous sodium sulfate for one night. After filtrating the inorganic salt, the solvent was distilled off under reduced pressure to obtain 5.8 g of a crude crystal. The crude crystal thus obtained was recrystallized from ether-hexane to obtain 5.3 g of the aimed product of white powder (yield=75.1%) having a melting point of 99°-101° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:20]([NH2:23])(=[O:22])=[O:21])[CH:5]=[CH:6][C:7]=1[O:8][C@H:9]1[CH2:13][CH2:12][CH2:11][C@@H:10]1[C:14]1[N:18]([CH3:19])[N:17]=[CH:16][CH:15]=1.[F:24][C:25]1[CH:30]=[C:29](F)[N:28]=[CH:27][N:26]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([S:20]([NH:23][C:29]2[CH:30]=[C:25]([F:24])[N:26]=[CH:27][N:28]=2)(=[O:21])=[O:22])[CH:5]=[CH:6][C:7]=1[O:8][C@H:9]1[CH2:13][CH2:12][CH2:11][C@@H:10]1[C:14]1[N:18]([CH3:19])[N:17]=[CH:16][CH:15]=1
Reactant: Cn1nccc1[C@H]1CCC[C@@H]1Oc1ccc(S(N)(=O)=O)cc1F
Reactant: Fc1cc(F)ncn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1nccc1[C@H]1CCC[C@@H]1Oc1ccc(S(=O)(=O)Nc2cc(F)ncn2)cc1F
Yield: 61.2 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 16d by using the 3-fluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}benzenesulfonamide (0.07 g, 0.21 mmol) prepared in Example 16c, 4,6-difluoropyrimidine (0.07 g, 0.62 mmol), potassium carbonate (0.11 g, 0.83 mmol) and DMF (2.0 mL), to yield the title compound (56 mg, 63%) as a colorless solid.
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[O:13]C(=O)C)[CH:8]=O)(=O)C.[NH:17]1[CH2:22][CH:21]=[CH:20][CH2:19][CH2:18]1>CO>[OH:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[OH:13])[CH2:8][N:17]1[CH2:18][CH:19]=[CH:20][CH2:21][CH2:22]1
Reactant: C1=CCNCC1
Reactant: CC(=O)Oc1ccc(C=O)cc1OC(C)=O
Solvent: CO
Product: Oc1ccc(CN2CC=CCC2)cc1O

Procedure:
Using a similar procedure to that described in Example 7, but starting from 3,4-diacetoxybenzaldehyde (18.6 g.) and 1,2,3,6-tetrahydropyridine (13.9 g.) in methanol (150 ml.), there was obtained 1-(3,4-dihydroxybenzyl)-1,2,3,6-tetrahydropyridine as the free base (0.45 g.), m.p. >300° C.; microanalysis,
Reaction SMILES: [Cl-].[CH2:2]([N+:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])([CH3:14])[CH3:13])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[C:25]1([CH3:35])[CH:30]=[CH:29][C:28]([S:31]([OH:34])(=[O:33])=[O:32])=[CH:27][CH:26]=1.[OH-].[Na+]>O>[C:25]1([CH3:35])[CH:26]=[CH:27][C:28]([S:31]([O-:34])(=[O:32])=[O:33])=[CH:29][CH:30]=1.[CH2:15]([N+:12]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])([CH3:14])[CH3:13])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: CCCCCCCCCC[N+](C)(C)CCCCCCCCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Temperature: 40 °C
Reaction time: 2 h

Procedure:
0.015 mol of didecyldimethylammonium chloride, 0.01 mol of p-toluenesulfonic acid, 0.01 mol of NaOH and 100 mL of distilled water were charged to a round bottomed flask and heated. The mixture was stirred for 2 h at 40° C., whence the phases were allowed to separate. The organic layer was then washed three times with distilled water. The aqueous phases were tested for the presence of chloride ion using silver nitrate solution. Finally, the organic layer was vacuum stripped to remove water. The obtained didecyldimethylammoniump-toluenesulfonate with 95% yield is soluble in chloroform, acetone, DMSO, and insoluble in water and hexane.
Reaction SMILES: [CH3:1][C:2]1([C:45]([F:48])([F:47])[F:46])[CH2:7][C:6]([C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH2:14][N:13]3[C:21]([C:24]([N:26]4[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]4)=[O:25])=[CH:22][CH:23]=[C:12]3[CH2:11]2)=[O:9])=[CH:5][CH:4]=[C:3]1[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.C(OCC)(=O)C.[ClH:55]>C(OCC)C>[ClH:55].[CH3:1][C:2]1([C:45]([F:47])([F:46])[F:48])[CH2:7][C:6]([C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH2:14][N:13]3[C:21]([C:24]([N:26]4[CH2:27][CH2:28][NH:29][CH2:30][CH2:31]4)=[O:25])=[CH:22][CH:23]=[C:12]3[CH2:11]2)=[O:9])=[CH:5][CH:4]=[C:3]1[C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc3n2Cc2ccccc2N(C(=O)C2=CC=C(c4ccccc4)C(C)(C(F)(F)F)C2)C3)CC1
Agent: Cl
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CC1(C(F)(F)F)CC(C(=O)N2Cc3ccc(C(=O)N4CCNCC4)n3Cc3ccccc32)=CC=C1c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
The 4-[[10,11-dihydro-10-[[2-methyl-2-(trifluoromethyl)[1,1-biphenyl]-4-yl]carbonyl]-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl]carbonyl]-1-piperazinecarboxylic acid, tert-butyl ester of Step B (0.85 g, 1.29 mmol) was then added in one portion to stirred ethyl acetate (10 mL) saturated with hydrogen chloride gas at 0° C. The reaction mixture was stirred for 90 minutes under anhydrous conditions. A precipitate formed after several minutes. The reaction was then warmed to room temperature and diluted with diethyl ether. The precipitated product was collected by filtration and dried under high vacuum to provide 0.65 g of the desired title compound hydrochloride salt as an off-white foam.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([O:8]N=C(C1C=CC=CC=1)C#N)=O)([CH3:4])[CH3:3].[NH2:19][C@H:20]([C:24]([OH:26])=[O:25])[CH:21]([CH3:23])[CH3:22].C(N(CC)CC)C>C(OCC)(=O)C.O.O1CCOCC1>[C:2]([O:5][C:6]([NH:19][C@H:20]([C:24]([OH:26])=[O:25])[CH:21]([CH3:23])[CH3:22])=[O:8])([CH3:1])([CH3:3])[CH3:4]
Reactant: CC(C)[C@H](N)C(=O)O
Reactant: CC(C)(C)OC(=O)ON=C(C#N)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reaction time: 1 h

Procedure:
Boc-ON (13.55 g, 55 mmol) was added portionwise to a mixture of L-valine (5.86 g, 50 mmol), triethylamine (7.59 g, 10.4 ml, 75 mmol), H2O (30 ml) and p-dioxane (30 ml). A clear solution (yellowish) was obtained after stirring the suspension at 25° for 1 hour. After stirring for 4 hours more, water (75 ml) and ethyl acetate (100 ml) were added. The aqueous layer was separated and washed with ethyl acetate (150 ml). The colorless aqueous phase was acidified to pH 3 with cold 1 N HCl. Boc-Val was extracted with ethyl acetate (3×75 ml). The combined extracts were washed with saturated NaCl and then dried (Na2SO4 /MgSO4). Solvent removal on a rotary evaporator under reduced pressure followed by drying under high vacuum gave a highly viscous oil: 10.51 g (96.8%).
Reaction SMILES: [N+:1]([CH:4]=[C:5](SC)[NH:6][CH2:7][CH2:8][S:9][CH2:10][C:11]1[NH:15][CH:14]=[N:13][C:12]=1[CH3:16])([O-:3])=[O:2].[CH2:19]([NH2:22])[C:20]#[CH:21]>C(#N)C>[N+:1]([CH:4]=[C:5]([NH:22][CH2:19][C:20]#[CH:21])[NH:6][CH2:7][CH2:8][S:9][CH2:10][C:11]1[NH:15][CH:14]=[N:13][C:12]=1[CH3:16])([O-:3])=[O:2]
Reactant: C#CCN
Reactant: CSC(=C[N+](=O)[O-])NCCSCc1[nH]cnc1C
Solvent: CC#N
Product: C#CCNC(=C[N+](=O)[O-])NCCSCc1[nH]cnc1C
Yield: 87 %

Procedure:
A mixture of 1-nitro-2-methylthio-2-{2-[(4-methyl-1H-imidazol-5-yl)methylthio]ethylamino}ethylene prepared according to Belgian Pat. No. 814,941 (4.0 g, 0.014 mole) and distilled propargylamine (7.74 g, 0.14 mole) in acetonitrile (60 ml) was stirred at reflux temperature under a positive pressure of nitrogen for 18 hours. The reaction mixture was cooled, evaporated to dryness and then triturated under 20 ml of isopropyl alcohol to give the title compound (3.58 g, 87%). Column chromatography on silica gel by gradient elution using methylene chloride-methanol gave a pure sample; mp 159°-160° dec.
Reaction SMILES: [CH:1]([C:3]1([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:7][CH2:6][CH2:5][CH2:4]1)=O.[O:16]([C:18]1[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:19]=1[CH2:20][NH2:21])[CH3:17].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+].[Na+].[Cl-]>C1COCC1.CCOC(C)=O>[CH3:17][O:16][C:18]1[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:19]=1[CH2:20][NH:21][CH2:1][C:3]1([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: CC(C)(C)OC(=O)NC1(C=O)CCCC1
Reactant: COc1ccc(CN)c(OC)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc(CNCC2(NC(=O)OC(C)(C)C)CCCC2)c(OC)c1
Reaction time: 0.17 h

Procedure:
To a solution of tert-butyl 1-formylcyclopentylcarbamate (1.87 g, 8.78 mmol) in anhydrous THF (9 mL) was added 2,4-dimethoxylbenzylamine (1.98 mL, 13.17 mmol). The reaction was stirred for 10 min, treated with sodium triacetoxyborohydride (2.98 g, 14.04 mmol), and stirred for an additional 2 h at room temperature under an atmosphere of nitrogen. Saturated aqueous NaHCO3 solution was added and the mixture stirred until gas evolution ceased. The mixture was diluted with EtOAc, and the separated aqueous layer was saturated with NaCl and extracted into EtOAc once more. The combined organics were dried over Na2SO4, filtered, and concentrated in vacuo to afford the product.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:13]([CH2:24]Cl)=[C:12]2[O:26][CH2:27][CH2:28][CH2:29][CH3:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:31]1(=[O:41])[NH:35][C:34](=[O:36])[C:33]2=[CH:37][CH:38]=[CH:39][CH:40]=[C:32]12.[K].O>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:13]([CH2:24][N:35]1[C:31](=[O:41])[C:32]3[C:33](=[CH:37][CH:38]=[CH:39][CH:40]=3)[C:34]1=[O:36])=[C:12]2[O:26][CH2:27][CH2:28][CH2:29][CH3:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CCCCOc1c(CCl)n(CC(C)C)c(=O)c2ccc(OCc3ccccc3)cc12
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCOc1c(CN2C(=O)c3ccccc3C2=O)n(CC(C)C)c(=O)c2ccc(OCc3ccccc3)cc12
Yield: 82.2 %

Procedure:
A solution of 6-benzyloxy-4-butoxy-3-chloromethyl-2-isobutyl-1(2H)-isoquinolinone (6.85 g, 16 mmol) and potassium phthalimide (4.44 g, 24 mmol) in N,N-dimethylformamide (50 mL) was stirred at room temperature for 6 h. The reaction mixture was poured into water and extracted with ethyl acetate. After washing the extract with water, the extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 2-[(6-benzyloxy-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methyl]-1H-isoindole-1,3(2H)-dione (7.08 g, 82.2%) as an amorphous.
Reaction SMILES: C([O:4][CH2:5][CH2:6][C@:7]([OH:49])([C@@H:11]([C:29](=[O:48])[NH:30][C@H:31]([C:44]([O:46]C)=[O:45])[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([O:39][CH2:40][C:41]#[C:42][CH3:43])=[CH:35][CH:34]=1)/[CH:12]=[CH:13]/[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20](=[O:28])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:8]([OH:10])=[O:9])(=O)C.[Li+].[OH-]>CO>[CH2:40]([O:39][C:36]1[CH:37]=[CH:38][C:33]([CH2:32][C@H:31]([NH:30][C:29]([C@@H:11](/[CH:12]=[CH:13]/[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20](=[O:28])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C@@:7]([OH:49])([CH2:6][CH2:5][OH:4])[C:8]([OH:10])=[O:9])=[O:48])[C:44]([OH:46])=[O:45])=[CH:34][CH:35]=1)[C:41]#[C:42][CH3:43]
Reactant: CC#CCOc1ccc(C[C@H](NC(=O)[C@@H](/C=C/CCCCCCC(=O)CCCCCCC)[C@@](O)(CCOC(C)=O)C(=O)O)C(=O)OC)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CC#CCOc1ccc(C[C@H](NC(=O)[C@@H](/C=C/CCCCCCC(=O)CCCCCCC)[C@@](O)(CCO)C(=O)O)C(=O)O)cc1
Temperature: 25 °C
Yield: 18.1 %

Procedure:
No. 5214354, (E)-(2S,3S)-2-(2-acetoxy-ethyl)-3-[(S)-2-(4-but-2-ynyloxy-phenyl)-1-methoxycarbonyl-ethylcarbamoyl]-2-hydroxy-12-oxo-nonadec-4-enoic acid (120 mg, 0.175 mmol) was dissolved in methanol (10 mL), and an aqueous solution (1 mL) of 2 M LiOH was added, and the mixture was stirred at room temperature. After confirming the consumption of the starting materials by LCMS, methanol was distilled off under reduced pressure. To the residue was added 1 M hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated brine and then dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure. The resulting residue was purified by preparative HPLC and freeze-dried to obtain the title compound (20 mg, 18% yield, white powder).
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=1[O:18][CH2:19][CH3:20])[CH2:3][CH:4]([CH3:10])[C:5]([O:7]CC)=O.[F:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][C:29]=1[O:30][C:31]([F:34])([F:33])[F:32])[CH:25]=O>>[CH2:19]([O:18][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([F:17])[C:11]=1[CH:2]1[N:1]([CH2:25][C:24]2[CH:27]=[CH:28][C:29]([O:30][C:31]([F:32])([F:33])[F:34])=[C:22]([F:21])[CH:23]=2)[C:5](=[O:7])[CH:4]([CH3:10])[CH2:3]1)[CH3:20]
Reactant: CCOC(=O)C(C)CC(N)c1c(F)cccc1OCC
Reactant: O=Cc1ccc(OC(F)(F)F)c(F)c1
Product: CCOc1cccc(F)c1C1CC(C)C(=O)N1Cc1ccc(OC(F)(F)F)c(F)c1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of ethyl 4-amino-4-(2-ethoxy-6-fluorophenyl)-2-methylbutanoate with commercially available 3-fluoro-4-(trifluoromethoxy)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.98 min.; [M+H]+: 429.97 g/mol.