Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:18]=3[CH:19]=[CH:20][N+:21]([O-])=[CH:22]4)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].P(Cl)(Cl)([Cl:30])=O>>[Cl:30][C:22]1[C:23]2[C:18](=[C:17]([C:14]3[N:13]=[C:12]([C:4]4[CH:5]=[CH:6][C:7]([O:8][CH:9]([CH3:11])[CH3:10])=[C:2]([Cl:1])[CH:3]=4)[O:16][N:15]=3)[CH:26]=[CH:25][CH:24]=2)[CH:19]=[CH:20][N:21]=1
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c[n+]([O-])ccc34)no2)cc1Cl
Reactant: O=P(Cl)(Cl)Cl
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c(Cl)nccc34)no2)cc1Cl
Temperature: 65 °C
Yield: 92.2 %

Procedure:
5-(5-{3-Chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)isoquinoline 2-oxide (D6; 1.18 g, 3.09 mmol) and phosphorus oxychloride (5.76 ml, 61.8 mmol) was stirred under an atmosphere of argon at room temperature for 4 hours. The mixture was then heated to 65° C. for 15 minutes, the phosphorus oxychloride evaporated under reduced pressure, and the residue, azeotroped with toluene and dried under vacuum overnight. The pale yellow solid residue was dissolved in dichloromethane (50 ml) and stirred with 2M NaOH (10 ml). The organic layer was separated, dried with MgSO4 and evaporated to dryness under reduced pressure to give a pale yellow solid (1.14 g) which was chromatographed over silica eluting with dichloromethane to give the title compound as a white solid (0.85 g).
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][OH:18])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.[C:21](Cl)(=[O:31])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].[C:33]([OH:40])(=[O:39])/[CH:34]=[CH:35]/[C:36]([OH:38])=[O:37]>C(Cl)Cl.C(O)C>[C:33]([OH:40])(=[O:39])/[CH:34]=[CH:35]/[C:36]([OH:38])=[O:37].[C:21]([O:18][CH2:17][CH2:16][CH2:15][N:12]1[CH2:13][CH2:14][CH:9]([C:6]2[C:5]3[CH:19]=[CH:20][C:2]([F:1])=[CH:3][C:4]=3[O:8][N:7]=2)[CH2:10][CH2:11]1)(=[O:31])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: OCCCN1CCC(c2noc3cc(F)ccc23)CC1
Reactant: CCCCCCCCCC(=O)Cl
Agent: O=C(O)/C=C/C(=O)O
Solvent: CCO
Solvent: ClCCl
Product: CCCCCCCCCC(=O)OCCCN1CCC(c2noc3cc(F)ccc23)CC1
Reaction time: 0.33 h

Procedure:
To a solution 3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propanol (1.81 g, 6.5 mmol) triethylamine (0.9 g, 9.0 mmol) in DCM (45 ml) was added decanoyl chloride (1.5 g, 7.8 mmol) dropwise at room temperature. The mixture was stirred for 20 minutes, then concentrated down to a crude solid. The solid was extracted into EtOAc (20 ml), and the insoluble salts were filtered. The EtOAc was removed. The crude oil was purified by flash choursomatography (Sorbsil C-30, 30 g; eluted with MeOH:DCM). The oil thus obtained (2.54 g, 90%) was converted to a fumarate salt with fumaric acid (670 mg) in ethanol. The crystals collected weighed 1.61 g, m.p.=100°-102° C.
Reaction SMILES: [C:1]([NH:8][CH2:9][C:10]([OH:12])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN1CCOCC1.C(OC(Cl)=O)C(C)C.[NH2:28][C@H:29]([C:37]([CH:39]1[CH:46]2[CH2:47][CH:42]3[CH2:43][CH:44]([CH2:48][C:40]1([NH2:49])[CH2:41]3)[CH2:45]2)=[O:38])[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C(Cl)Cl>[C:1]([NH:8][CH2:9][C:10]([NH:28][C@H:29]([C:37]([CH:39]1[CH:46]2[CH2:47][CH:42]3[CH2:43][CH:44]([CH2:48][C:40]1([NH2:49])[CH2:41]3)[CH2:45]2)=[O:38])[CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)=[O:12])([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: N[C@@H](Cc1ccccc1)C(=O)C1C2CC3CC(C2)CC1(N)C3
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC(=O)N[C@@H](Cc1ccccc1)C(=O)C1C2CC3CC(C2)CC1(N)C3
Temperature: -20 °C
Reaction time: 8 h

Procedure:
A solution of 1.42 g of Boc-glycine and 0.90 ml of N-methylmorpholine in 10 ml of dry methylene chloride under nitrogen is allowed to react with 1.05 ml of isobutylchloroformate at -45° C. The reaction mixture is allowed to warm to -20° C. then recooled to -40° C. To this solution is added 2.38 g of L-phenylalanyl-1-aminoadamantane. The cooling bath is removed and the reaction mixture is allowed to stand overnight at room temperature. The reaction mixture is filtered, diluted with 20 ml of methylene chloride and washed with 10 ml of cold 1 M potassium bisulfate solution followed by washing with 10 ml of cold 2 M potassium carbonate solution and 10 ml of saturated sodium chloride solution. The reaction mixture is dried over sodium sulfate, filtered and concentrated. The product separates as crystals upon addition of ether. The crystalline material is collected to give Boc-glycyl-L-phenylalanyl-1-aminoadamantane. A dry solution of 2.8 g of Boc-glycol-L-phenylalanyl-1-aminoadamantane in 15 ml of methylene chloride under a nitrogen atmosphere at 5° C. is allowed to react with 10 ml of trifluoroacetic acid. The reaction mixture is allowed to stand for 30 minutes at room temperature. The solution is concentrated under reduced pressure then diluted with 10 ml of 5 M potassium carbonate solution and extracted with methylene chloride. The reaction mixture is dried over sodium sulfate, filtered and evaporated to dryness under reduced pressure to give glycyl-L-phenylalanyl-1-aminoadamantane which is represented by the following formula ##STR37##
Reaction SMILES: Cl.[NH2:2][C@H:3]1[C:9](=[O:10])[N:8]([CH3:11])[C:7]2[CH:12]=[CH:13][CH:14]=[CH:15][C:6]=2[C:5]2[CH:16]=[CH:17][CH:18]=[CH:19][C:4]1=2.[C:20](O)(=[O:24])[C@H:21]([CH3:23])[OH:22]>>[OH:22][C@@H:21]([CH3:23])[C:20]([NH:2][C@H:3]1[C:9](=[O:10])[N:8]([CH3:11])[C:7]2[CH:12]=[CH:13][CH:14]=[CH:15][C:6]=2[C:5]2[CH:16]=[CH:17][CH:18]=[CH:19][C:4]1=2)=[O:24]
Reactant: C[C@H](O)C(=O)O
Reactant: CN1C(=O)[C@H](N)c2ccccc2-c2ccccc21
Agent: Cl
Product: C[C@H](O)C(=O)N[C@H]1C(=O)N(C)c2ccccc2-c2ccccc21

Procedure:
The title compound, MS: m/e=311.3 (M+H+), was prepared in analogy to example 1a) from (+)-(R)-7-amino-5-methyl-5H,7H-dibenzo[b,d]azepin-6-one hydrochloride and L-(+)-lactic acid.
Reaction SMILES: CO.[H-].[Na+].[C:5]([N:9]=[N:10][C:11]1([N:17]=[C:18]=[O:19])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)([CH3:8])([CH3:7])[CH3:6].[N-]=[C:21]=[O:22]>O>[C:5]([N:9]=[N:10][C:11]1([NH:17][C:18]([O:22][CH3:21])=[O:19])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)([CH3:8])([CH3:6])[CH3:7]
Reactant: CC(C)(C)N=NC1(N=C=O)CCCCC1
Reactant: [N-]=C=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)NC1(N=NC(C)(C)C)CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 30 ml of methanol in a 100 ml 3 neck round bottom flask equipped with a thermometer and magnetic stirrer was slowly added 2.1 grams (0.05 moles) of 57% sodium hydride. After the temperature came back to 25° C., 10.5 grams (0.05 moles) of 1-t-butylazo-1-isocyanatocyclohexane was added dropwise over 5 minutes. There was a 2° C. rise in temperature during the addition. After the addition was complete, the reaction was stirred an additional 30 minutes at room temperature. Gas chromatography indicated that the 1-t-butylazo-1-isocyanatocyclohexane had reacted almost immediately. The reaction mixture was poured into 300 ml water and the product extracted with 100 ml methylene chloride. The methylene chloride extract was separated, washed with water, 100 ml 10% NaHCO3 solution, dried over anhydrous Na2SO4, filtered and the methylene chloride evaporated under reduced pressure to leave 11.0 grams (91% crude yield) of a yellow liquid. The product had a strong carbonyl band at 1730 cm-1 and a sharp NH band at 3400 cm-1 in its infrared spectrum and the isocyanate band at 2225 cm-1 was absent.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:7]2[S:8][C:9](=S)[S:10][C:6]=2[C:5](=[O:12])[C:4](=[O:13])[O:3]1.C(Cl)Cl.C(Cl)Cl.CC(O)=[O:23]>C([O-])(=O)C.[Hg+]>[CH3:1][C:2]1([CH3:14])[C:7]2[S:8][C:9](=[O:23])[S:10][C:6]=2[C:5](=[O:12])[C:4](=[O:13])[O:3]1
Reactant: CC1(C)OC(=O)C(=O)c2sc(=S)sc21
Reactant: CC(=O)O
Agent: CC(=O)[O-]
Agent: [Hg+]
Solvent: ClCCl
Product: CC1(C)OC(=O)C(=O)c2sc(=O)sc21

Procedure:
Mercury acetate (181 mg, 0.568 mmol) was added to a stirred solution of 4,4-dimethyl-2-thioxo-4H-[1,3]dithiolo[4,5-c]pyran-6,7-dione (6) (100 mg, 0.406 mmol) in CH2Cl2/AcOH (3:1). The reaction was followed by TLC (silica, CH2Cl2) and after ca. 30 min the mixture is filtered through a celite pad to remove the mercury salts. The resulting solution was washed first with water (3×15 mL) and then with sat. aqueous NaHCO3 (5×10 mL), and dried over MgSO4. Removal of the solvent under reduced pressure afforded pure 4,4-dimethyl-4H-[1,3]dithiolo[4,5-c]pyran-2,6,7-trione (5) a pale beige solid. Yield: 65 mg (70%). 1H-NMR spectrum in CDCl3 (ppm): 1.88 (s, 6H). 13C-NMR spectrum in CDCl3 (ppm): 184.5, 163.5, 160.4, 153.5, 128.3 84.2, 31.8. Selected IR (neat, cm−1): 1746, 1693, 1641, 1552, 1453. MS-ESI calculated for C7H8O4S2 [M+H]+ 230.98. found 230.78; calculated for C7H8O4S2Na [M+Na]+) 252.96. found 252.79.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:13][C:14]([NH:16][C@@H:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C@H:20]([O:27][C:28]3[CH:29]=[CH:30][C:31]4[N:32]([C:34]([N:37]5[CH2:42][CH2:41][O:40][CH2:39][C@@H:38]5[CH3:43])=[N:35][N:36]=4)[CH:33]=3)[CH2:19][CH2:18]2)=[O:15])[N:8]([CH2:10][CH2:11][OH:12])[N:9]=1)([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[CH3:53][S:54](Cl)(=[O:56])=[O:55]>C(Cl)Cl>[C:1]([C:5]1[CH:6]=[C:7]([NH:13][C:14]([NH:16][C@@H:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C@H:20]([O:27][C:28]3[CH:29]=[CH:30][C:31]4[N:32]([C:34]([N:37]5[CH2:42][CH2:41][O:40][CH2:39][C@@H:38]5[CH3:43])=[N:35][N:36]=4)[CH:33]=3)[CH2:19][CH2:18]2)=[O:15])[N:8]([CH2:10][CH2:11][O:12][S:54]([CH3:53])(=[O:56])=[O:55])[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: C[C@H]1COCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4CCO)c4ccccc43)cn12
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1COCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4CCOS(C)(=O)=O)c4ccccc43)cn12
Reaction time: 1 h

Procedure:
To an ice-bath cooled solution of Example 139 (54 mg, 0.092 mmol) in DCM (2.0 mL) was added DIPEA (65 μL, 0.37 mmol) followed by methanesulfonyl chloride (14 μL, 0.18 mmol). The reaction mixture was stirred for 1 h and then quenched with water. The aqueous phase was extracted with DCM (×3) and the combined organic layers were washed with brine, dried (MgSO4) and concentrated in vacuo to afford the title compound (Quantitative). Product used in the following step without further purification. LCMS (Method 4): Rt 3.04 min, m/z 667 [MH+].
Reaction SMILES: [C:1]([OH:22])(=O)[CH2:2][CH2:3][CH2:4]/[CH:5]=[CH:6]\[CH2:7]/[CH:8]=[CH:9]\[CH2:10]/[CH:11]=[CH:12]\[CH2:13]/[CH:14]=[CH:15]\[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].C(N(CC)CC)C.ClC(OCCCC)=O.Cl.C(N(CC)CC)C.[NH2:46][CH2:47][CH2:48][OH:49].Cl>C(#N)C.CO>[C:1]([NH:46][CH2:47][CH2:48][OH:49])(=[O:22])[CH2:2][CH2:3][CH2:4]/[CH:5]=[CH:6]\[CH2:7]/[CH:8]=[CH:9]\[CH2:10]/[CH:11]=[CH:12]\[CH2:13]/[CH:14]=[CH:15]\[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: NCCO
Reactant: CCCCC/C=C\C/C=C\C/C=C\C/C=C\CCCC(=O)O
Agent: CCCCOC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Solvent: CC#N
Product: CCCCC/C=C\C/C=C\C/C=C\C/C=C\CCCC(=O)NCCO
Temperature: -15 °C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
Arachidonic acid (152 mg, 0.5 mmol) and triethylamine (52 mg, 0.51 mmol) were dissolved in 3 ml of dry acetonitrile and chilled to −15° C., and 70 mg (0.51 mmol) of butyl chloroformate was added. After 30 min, the mixture free of the precipitated triethylamine hydrochloride was pipetted in a solution of 2-aminoethanol (61 mg, 1 mmol) in 1 ml of methanol, stirring was continued for 15 min at −15° C., then the mixture obtained was allowed to warm to room temperature. After 2 h, 0.5 M HCl was added, and the mixture was extracted with ether (20 ml). The extract was washed with water, then dried with Na2SO4, and evaporated under reduced pressure. The residue was dissolved in 2 ml of chloroform and purified by column (2×2 cm) chromatography on aluminum oxide (basic, Brockmann II). Elution of the column with chloroform-methanol (9:1 v/v) and evaporation of the appropriate fractions gave 165 mg (95%) of desired N-arachidonoylaminoethan-2-ol as oil: TLC (system A) Rf 0.4.
Reaction SMILES: [C:1]([N:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:15])[C:10]=2[Br:14])[CH:5]1[CH2:16][C:17]([O:19]C)=O)(=[O:3])[CH3:2].C([N:24]1C=CC2C(=CC=C(F)C=2Br)C1CC(OC)=O)(=O)C.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCCl>[Br:14][C:10]1[C:9]([F:15])=[CH:8][CH:7]=[C:6]2[C:11]=1[CH2:12][CH2:13][N:4]1[C:1](=[O:3])[CH2:2][NH:24][C:17](=[O:19])[CH:16]=[C:5]12
Reactant: COC(=O)CC1c2ccc(F)c(Br)c2C=CN1C(C)=O
Reactant: COC(=O)CC1c2ccc(F)c(Br)c2CCN1C(C)=O
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: O=C1C=C2c3ccc(F)c(Br)c3CCN2C(=O)CN1
Temperature: 25 °C

Procedure:
methyl 2-(2-acetyl-5-bromo-6-fluoro-1,2,3,4-tetrahydroisoquinolin-1-yl)acetate. A stirred solution of methyl 2-(2-acetyl-5-bromo-6-fluoro-1,2-dihydroisoquinolin-1-yl)acetate (70.6 g, 206 mmol), triethylsilane (176 g, 1517 mmol) and trifluoroacetic acid (121 mL, 1568 mmol) in 1,2-dichloroethane (500 mL) was stirred at 80° C. for 3.5 h. The reaction mixture was cooled to rt and the solvent was evaporated under reduced pressure. The remaining volatile components were evaporated under high vacuo and 40° C. bath temperature. To the resulting yellow residue saturated aqueous NaHCO3 (500 mL) was added while stirring and the mixture was extracted with DCM (3×400 mL). The organic layer was washed with saturated aqueous NaHCO3 (250 mL) and brine (200 mL). The organic layer was treated with charcoal, then dried with sodium sulfate, filtered through a pad of Hyflo and the solvent was removed under reduced pressure. The crude product was crystallized from diethyl ether (200 mL) to yield the title compound as white crystals (47.6 g). UPLC-MS: MS 344.1/346.1 (M+H+); UPLC rt 0.95 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[N:10]([CH3:19])[C:9]2=[O:20])=[C:4]([F:21])[CH:3]=1.[N+:22]([O-])([OH:24])=[O:23]>S(=O)(=O)(O)O>[Cl:1][C:2]1[C:7]([N+:22]([O-:24])=[O:23])=[CH:6][C:5]([N:8]2[C:13](=[O:14])[CH:12]=[C:11]([C:15]([F:18])([F:16])[F:17])[N:10]([CH3:19])[C:9]2=[O:20])=[C:4]([F:21])[CH:3]=1
Reactant: O=[N+]([O-])O
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc(Cl)cc2F)c1=O
Agent: O=S(=O)(O)O
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2cc([N+](=O)[O-])c(Cl)cc2F)c1=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 3.0 grams (9.4 mmole) of 3-(4-chloro-2-fluorophenyl)-1-methyl-6-trifluoromethyl-2,4-(1H,3H)pyrimidinedione in 30 mL of concentrated sulfuric acid was stirred and cooled in an ice bath. During 15 minutes, 0.75 mL (12 mmole) of aqueous 70% nitric acid was added dropwise, after which the reaction mixture was allowed to warm to ambient temperature, where it stirred for two hours. The reaction mixture was then poured into 150 mL of ice-water. The resulting precipitate was collected by filtration, washed with water, and dried under reduced pressure, yielding 3.0 grams of 3-(4-chloro-2-fluoro-5-nitrophenyl)-1-methyl-6-trifluoromethyl-2,4-(1H,3H)-pyrimidinedione. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: C(O)=O.[CH3:4][N:5]([CH2:7][C:8]1[CH:25]=[CH:24][C:11]([O:12][CH:13]2[CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14]2)=[C:10]([CH3:26])[CH:9]=1)[CH3:6]>Cl.CO>[NH:15]1[CH2:14][CH:13]([O:12][C:11]2[CH:24]=[CH:25][C:8]([CH2:7][N:5]([CH3:6])[CH3:4])=[CH:9][C:10]=2[CH3:26])[CH2:16]1
Reactant: Cc1cc(CN(C)C)ccc1OC1CN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: O=CO
Solvent: CO
Product: Cc1cc(CN(C)C)ccc1OC1CNC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.1 %

Procedure:
Intermediate 16A (1.9 g, 5.93 mmol) was dissolved in a 4.0 M solution of HCl in MeOH (30 mL) and the reaction mixture was stirred at RT overnight. The mixture was concentrated and the residue was dissolved in water. The aqueous solution was basified to pH=10 with aqueous NaOH (1.0 M) and then extracted with DCM (4×30 mL). The combined organic phases were filtered through a phase separator and the solvent was removed by evaporation. There was obtained 1.02 g (78%) of 16B as a colorless oil. 1H NMR (500 MHz, CDCl3): δ 2.21 (s, 6H), 2.33 (s, 3H), 3.30 (s, 2H), 3.73-3.84 (m, 2H), 3.85-3.96 (m, 2H), 4.91-5.03 (m, 1H), 6.52 (d, 1H), 6.58 (s, 1H), 7.11 (d, 1H).
Reaction SMILES: [C:1]([C:5]1[CH:30]=[CH:29][C:8]([CH2:9][CH:10]2[CH:15]=[C:14]([CH2:16][O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[CH:13]=[CH:12][N:11]2[C:25]([O:27][CH3:28])=[O:26])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]>C(OCC)(=O)C.[Pt](=O)=O>[C:1]([C:5]1[CH:30]=[CH:29][C:8]([CH2:9][CH:10]2[CH2:15][CH:14]([CH2:16][O:17][Si:18]([C:21]([CH3:23])([CH3:24])[CH3:22])([CH3:19])[CH3:20])[CH2:13][CH2:12][N:11]2[C:25]([O:27][CH3:28])=[O:26])=[CH:7][CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)N1C=CC(CO[Si](C)(C)C(C)(C)C)=CC1Cc1ccc(C(C)(C)C)cc1
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Product: COC(=O)N1CCC(CO[Si](C)(C)C(C)(C)C)CC1Cc1ccc(C(C)(C)C)cc1
Reaction time: 20 h
Yield: 95.6 %

Procedure:
To a solution of methyl 2-(4-tert-butylbenzyl)-4-((tert-butyldimethylsilyloxy)methyl)-pyridine-1(2H)-carboxylate (6.5 g, 15.13 mmol) in ethyl acetate (50 mL) was added platinum(IV) oxide (0.07 g, 0.31 mmol). The suspension was hydrogenated at 6 bar H2 atmosphere for 20 h. The mixture was filtered through Celite and the solvents were evaporated to give the product (6.27 g, 96%) as an oil. 1H NMR (400 MHz, cdcl3) δ −0.07-0.18 (m, 6H), 0.77-1.01 (m, 9H), 1.28-1.37 (m, 9H), 1.36-1.87 (m, 4H), 2.58-2.74 (m, 1H), 2.88-3.06 (m, 2H), 3.40-3.55 (m, 3H), 3.60-3.72 (m, 3H), 3.78-4.10 (m, 2H), 7.14-7.32 (m, 4H). MS m/z 434 (M+H)+.
Reaction SMILES: C[O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:15]([CH3:16])=[CH:14][C:13]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[F:26])=[C:12]([Br:27])[C:11]2=[O:28])=[C:6]([Cl:29])[CH:5]=1.Cl>C1COCC1.O>[Br:27][C:12]1[C:11](=[O:28])[N:10]([C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:30])=[O:2])=[CH:5][C:6]=2[Cl:29])[C:15]([CH3:16])=[CH:14][C:13]=1[O:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=1[F:26]
Reactant: COC(=O)c1ccc(-n2c(C)cc(OCc3ccc(F)cc3F)c(Br)c2=O)c(Cl)c1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)n1-c1ccc(C(=O)O)cc1Cl
Reaction time: 8 h
Yield: 67.1 %

Procedure:
Methyl-4-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-3-chlorobenzoate (2.30 g, 4.61 mmol) was taken up in THF (20 ml) and H2O (4 ml). 2.5 N NAOH (9.2 ml) was added to the vessel and the reaction stirred overnight to completion. Concentrated HCl was added dropwise until reaction was made acidic (pH=1). H2O (100 ml) and THF (100 ml) were added to the mixture. The contents were poured into a separatory funnel and the aqueous layer was extracted with ethyl acetate. The organic layer was dried over Na2SO4, the solvent removed in vacuo, and the residue was taken up in a 50% mixture of ethyl acetate/hexane. The precipitate was collected on a filter pad to yield a white powder (1.5 g, 67%). 1H NMR (300 MHz, DMSO) δ 13.59 (1H), 8.16 (d, J=1.81 Hz, 1H), 8.06 (dd, J=6.24, 1.81 Hz, 1H), 7.73 (app q, J=8.46, 1H), 7.68 (d, J=8.26 Hz, 1H), 7.38 (dt, J=9.48, 2.62 Hz, 1H) 7.26-7.18 (m, 1H), 6.80 (s, 1H), 5.39 (s, 2H), 3.93 (s, 3H), 1.96 (s, 3H); ES-MS m/z 483 (M+H). ES-HRMS m/z 483.9749 (M+H calcd for C20H14BrClF2NO4 requires 483.9757).
Reaction SMILES: C[O:2][C:3](=[O:32])[C:4]([CH3:31])([CH3:30])[CH2:5][NH:6][C:7]([C:9]1[N:10]=[C:11]([C:28]#[N:29])[C:12]2[C:17]([C:18]=1[OH:19])=[CH:16][CH:15]=[C:14]([CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH:13]=2)=[O:8].[OH-].[Na+].Cl>CO>[C:28]([C:11]1[C:12]2[C:17](=[CH:16][CH:15]=[C:14]([CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:13]=2)[C:18]([OH:19])=[C:9]([C:7]([NH:6][CH2:5][C:4]([CH3:31])([CH3:30])[C:3]([OH:32])=[O:2])=[O:8])[N:10]=1)#[N:29]
Reactant: COC(=O)C(C)(C)CNC(=O)c1nc(C#N)c2cc(CCc3ccccc3)ccc2c1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(CNC(=O)c1nc(C#N)c2cc(CCc3ccccc3)ccc2c1O)C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 70 %

Procedure:
A mixture of 3-[(1-cyano-4-hydroxy-7-phenethyl-isoquinoline-3-carbonyl)-amino]-2,2-dimethyl-propionic acid methyl ester (55 mg, 0.13 mmol), 2 M NaOH (2 mL) and MeOH (2 mL) was stirred at r.t. for 3 h. 1 M HCl was added until pH was ˜2, and the resulting suspension was extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated. The crude product was purified by column chromatography (0-30% EtOAc/hexanes+2% AcOH) to give 38 mg of the title compound. MS: (−) m/z 416.14 (M−1).
Reaction SMILES: C(=O)(O)[O-].[Na+].[CH2:6]([S:9][C:10](=[N:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[NH:11]C(OC(C)(C)C)=O)[CH:7]=[CH2:8].[I:27]I.O>ClCCl>[I:27][CH2:8][CH:7]1[CH2:6][S:9][C:10]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[N:11]1
Reactant: C=CCSC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Reactant: II
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)NC1=NC(CI)CS1
Yield: 74.6 %

Procedure:
17 g of sodium bicarbonate are added, at a temperature in the region of 20° C., to a suspension of 25.4 g of tert-butyl allylsulphanyl-[(tert-butoxycarbonyl)amino]methylidenecarbamate in 650 cm3 of dichloromethane, followed by addition of a solution of 24.4 g of iodine predissolved in 850 cm3 of dichloromethane. After 72 hours at a temperature in the region of 20° C., 500 cm3 of water and 500 cm3 of saturated sodium bicarbonate solution are added to the reaction medium and the resulting mixture is then extracted with twice 1 dm3 of ethyl acetate. The organic phases are washed with saturated sodium sulphite solution and then with saturated sodium chloride solution, dried over magnesium sulphate, filtered and then concentrated under reduced pressure (1 kPa) at a temperature in the region of 50° C. The residue obtained is crystallized from ethyl acetate. 20.5 g of tert-butyl N-[(4RS)-4-(iodomethyl)-4,5-dihydro-2-thiazolyl]carbamate are obtained in the form of a yellow solid [1H NMR spectrum (300 MHz, (CD3)2SO-d6, δ in ppm): 1.41 (s: 9H); 2.97 (dd, J=11.5 and 7 Hz: 1H); from 3.30 to 3.50 (mt: 3H); 4.12 (mt: 1H); 9.89 (unresolved complex: 1H)].
Reaction SMILES: [C:1]1([CH3:20])[CH:6]=[CH:5][C:4]([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14](Br)[CH:15]=3)[C:10]([CH3:19])([CH3:18])[CH2:9][CH:8]=2)=[CH:3][CH:2]=1.[Li]C(C)(C)C.CCCCC.CN(C)[CH:33]=[O:34].C(=O)=O>C1COCC1.C(OC(=O)C)C>[C:1]1([CH3:20])[CH:6]=[CH:5][C:4]([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([CH:33]=[O:34])[CH:15]=3)[C:10]([CH3:19])([CH3:18])[CH2:9][CH:8]=2)=[CH:3][CH:2]=1
Reactant: CN(C)C=O
Reactant: Cc1ccc(C2=CCC(C)(C)c3ccc(Br)cc32)cc1
Agent: O=C=O
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCCCC
Product: Cc1ccc(C2=CCC(C)(C)c3ccc(C=O)cc32)cc1
Temperature: 25 °C

Procedure:
To a cold (-78° C.), stirred solution of 1-(tol-4-yl)3,4-dihydro-4,4-dimethyl-7-bromo-naphthalene (Compound B 1 g, 3.2 mmol), in THF (17 mL) was added t-BuLi in pentane (1.7M solution, 3 mL, 5.1 mmol). After 10 minutes dry dimethylformamide (DMF) (600 mg, 8 mmol) was added and the dry-ice cooling was replaced with ice-water bath. The mixture was gradually warmed to ambient temperature and diluted with ethylacetate (150 mL), washed with water (15 mL). The organic layer was dried with MgSO4 and solvent was removed under reduced pressure. The crude material was purified by silicagel chromatography to afford the title compound as a white solid.