Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.C1C2C(=O)C3C(=CC=CC=3)C(=O)C=2C=CC=1.[OH:34][S:35](O)(=[O:37])=[O:36].O=S(=O)=O>S([O-])([O-])(=O)=O.[Hg+2]>[C:2]1([S:35]([OH:37])(=[O:36])=[O:34])[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Nc1cccc2c1C(=O)c1ccccc1C2=O
Reactant: O=S(=O)(O)O
Agent: O=C1c2ccccc2C(=O)c2ccccc21
Agent: O=S(=O)([O-])[O-]
Agent: O=S(=O)=O
Product: O=C1c2ccccc2C(=O)c2c1cccc2S(=O)(=O)O

Procedure:
GB-A-1 370 413 discloses a two-step synthesis of 1-aminoanthraquinone, in which anthraquinone is sulfonated with oleum in the presence of mercury sulfate to give anthraquinone-1-sulfonic acid and this is reacted in a second step with ammonia to give 1-aminoanthraquinone.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1Br)([CH3:3])[CH3:2].[CH2:14]1[O:16][CH2:15]1.[NH4+].[Cl-]>CCOCC>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[CH:15]([OH:16])[CH3:14])([CH3:3])[CH3:2]
Reactant: CC(C)c1cccc(C(C)C)c1Br
Reactant: C1CO1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CC(C)c1cccc(C(C)C)c1C(C)O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
2,6 diisopropylbromobenzene (see J. Org. Chem., 42(14):2426-2431 (1977) for preparation) (30 g, 124.4 mmol) was added to a suspension of Li powder (1.9 g, 273.6 mmol) in ether (100 nIL) heated under reflux, the heating was continued for another 4 hours, cooled, and the mixture was poured into ethylene oxide which was precooled to -78° C. The mixture was warmed slowly to room temperature, saturated NH4Cl solution was added slowly with caution, the ether layer was separated and washed with brine, dried over MgSO4, filtered, and the solvent was evaporated to dryness. After column chromatography (3:1 hexane:ethyl acetate) pure 2,6-diisopropylphenylethanol was obtained (17 g, 66.3%); NMR (CDCl3):δ 1.2-1.3 (m, 12H), 3.05 (t, 3.15-3.35 (m, 2H), 3.7-3.8 (t, 2H), 7.1-7.3 (m, 3H) ppm.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]1[CH2:11][CH:12]3[NH:17][CH:16]([C:5]2=1)[CH2:15][CH2:14][CH2:13]3.[CH3:18][C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:20]=1[CH:26]=[CH2:27]>>[CH3:18][C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:20]=1[CH2:26][CH2:27][N:7]1[C:8]2[C:4](=[CH:3][C:2]([CH3:1])=[CH:10][CH:9]=2)[C:5]2[C@@H:16]3[NH:17][C@H:12]([CH2:11][C:6]1=2)[CH2:13][CH2:14][CH2:15]3
Reactant: Cc1ccc2[nH]c3c(c2c1)C1CCCC(C3)N1
Reactant: C=Cc1cc(C)ccc1C
Product: Cc1ccc(C)c(CCn2c3c(c4cc(C)ccc42)[C@H]2CCC[C@@H](C3)N2)c1

Procedure:
The coupling of 2-methyl-6,7,8,9,10,11-hexahydro-5H-7,11-epiminocycloocta[b]indole (110 mg, 0.486 mmol; Example 118A) and 1,4-dimethyl-2-vinylbenzene (129 mg, 0.972 mmol; Aldrich) was performed according to the procedure described in Example 114B to afford the title compound as a racemic mixture. Individual enantiomers were obtained by preparative chiral supercritical fluid chromatography (ChiralPak® OD-H 5 μm column, 21×250 mm, 35° C., 10-50% gradient of CH3OH—CO2 containing 0.1% diethylamine, 20 minutes) to afford the title compound as the second-eluting enantiomer: 1H NMR (300 MHz, methanol-d4) δ ppm 1.07-1.32 (m, 3H), 1.62 (dd, J=13, 2 Hz, 1H), 1.70-1.95 (m, 3H), 2.00 (s, 3H), 2.15 (s, 3H), 2.40 (s, 3H), 2.79 (dd, J=17, 7 Hz, 1H), 2.94-3.16 (m, 2H), 3.34-3.40 (m, 1H), 4.19 (ddd, J=14, 9, 5 Hz, 1H), 4.28-4.39 (m, 2H), 6.69 (s, 1H), 6.85-6.97 (m, 3H), 7.13 (s, 1H), 7.26 (d, J=8 Hz, 1H); MS (DCI/NH3) m/z 359 (M+H)+.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:2].[Cl-].[CH3:19][C:20]1[CH:31]=[CH:30][CH:29]=[CH:28][C:21]=1[CH:22]=[N+:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1>>[CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH:22]([N:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[C:21]2[CH:28]=[CH:29][CH:30]=[CH:31][C:20]=2[CH3:19])=[C:4]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:2]
Reactant: CCn1c(-c2ccccc2)cc2ccccc21
Reactant: Cc1ccccc1C=[N+]1CCCC1
Agent: [Cl-]
Product: CCn1c(-c2ccccc2)c(C(c2ccccc2C)N2CCCC2)c2ccccc21

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 1-ethyl-2-phenyl-1H-indole and 1-(2-methyl-benzylidene)-pyrrolidinium chloride
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1([CH3:23])[CH2:8][CH2:7][N:6]([CH2:9][C@@H:10]([C:12]2[CH:21]=[CH:20][C:15]3[C:16](=[O:19])[O:17][CH2:18][C:14]=3[C:13]=2[CH3:22])[OH:11])[CH2:5]1.Cl[C:25]1[N:30]=[CH:29][C:28]([C:31]#[N:32])=[CH:27][CH:26]=1>>[OH:11][C@H:10]([C:12]1[C:13]([CH3:22])=[C:14]2[C:15](=[CH:20][CH:21]=1)[C:16](=[O:19])[O:17][CH2:18]2)[CH2:9][N:6]1[CH2:7][CH2:8][C:4]([CH2:3][NH:2][C:25]2[CH:26]=[CH:27][C:28]([C:31]#[N:32])=[CH:29][N:30]=2)([C:23]2[CH:14]=[CH:13][CH:12]=[CH:10][CH:9]=2)[CH2:5]1
Reactant: N#Cc1ccc(Cl)nc1
Reactant: Cc1c([C@@H](O)CN2CCC(C)(CN)C2)ccc2c1COC2=O
Agent: Cl
Product: Cc1c([C@@H](O)CN2CCC(CNc3ccc(C#N)cn3)(c3ccccc3)C2)ccc2c1COC2=O

Procedure:
6-((1-((R)-2-Hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)-3-phenylpyrrolidin-3-yl)methylamino)nicotinonitrile was prepared in a similar fashion to that described for the synthesis of EXAMPLE 18 starting from 5-[(R)-2-[3-(Aminomethyl)-3-methylpyrrolidin-1-yl]-1-hydroxyethyl}-4-methyl-2-benzofuran-1(3H)-one hydrochloride [INTERMEDIATE 7] and 6-chloropyridine-3-carbonitrile.
Reaction SMILES: C(O[C:4]1([O:14]CC)[NH:8][C:7](=[O:9])[C:6]2=[CH:10][CH:11]=[CH:12][CH:13]=[C:5]12)C.Cl.[C:18](OCC)(=[O:20])[CH3:19]>O1CCCC1>[O:14]=[C:4]1[C:5]2[C:6](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:7](=[O:9])[N:8]1[CH2:19][CH:18]=[O:20]
Reactant: CCOC1(OCC)NC(=O)c2ccccc21
Reactant: CCOC(C)=O
Agent: Cl
Solvent: C1CCOC1
Product: O=CCN1C(=O)c2ccccc2C1=O
Temperature: 75 °C

Procedure:
To a solution of phthalimide diethylacetal (15 g) in tetrahydrofuran (THF) (30 mL) was added 10% aqueous HCl (18 mL). After heating at 75° C. for 5 hrs, the solution was allowed to cool to RT, and ethyl acetate (100 mL) was added. The solution was extracted with saturated sodium carbonate solution (100 mL), brine (100 mL), and the organic layer was separated and dried over magnesium sulfate (MgSO4). The solution was filtered and evaporated to provide 11.2 g of the titled compound.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[C:12]([OH:17])(=[O:16])/[CH:13]=[CH:14]/[CH3:15].O.[OH-].[Na+]>C1(C)C=CC=CC=1>[N:7]1[C:8]2[C:3](=[C:2]([NH:1][CH:14]([CH3:15])[CH2:13][C:12]([OH:17])=[O:16])[CH:11]=[CH:10][CH:9]=2)[CH:4]=[CH:5][CH:6]=1
Reactant: C/C=C/C(=O)O
Reactant: Nc1cccc2ncccc12
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(CC(=O)O)Nc1cccc2ncccc12
Yield: 51 %

Procedure:
A mixture of 5-aminoquinoline (9.9 g, 0.069 mol) and crotonic acid (8.9 g, 0.103 mol) in toluene (35 ml) was stirred at reflux for 48 h. The reaction mixture was allowed to cool to ambient, added to water (500 ml) and the pH adjusted to 9 to 10 by the addition of 2N sodium hydroxide. The reaction mixture was screened and the filtrate extracted with diethyl ether (3×100 ml). The pH of the aqueous layer was first adjusted to pH2 with concentrated HCl and then to pH7 with calcium hydroxide. The precipitate which formed was collected by filtration, washed first with water (200 ml) and then with acetone (200 ml) before being dried to give 8.1 g of a cream solid.
Reaction SMILES: C([O:4][CH:5]([CH3:20])[C:6]([C:8]1[C:9]([CH:17]([CH3:19])[CH3:18])=[N:10][N:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=12)=[O:7])(=O)C.[OH-].[Na+].C(OCC)(=O)C.C([O-])(O)=O.[Na+]>C1COCC1>[OH:4][CH:5]([CH3:20])[C:6]([C:8]1[C:9]([CH:17]([CH3:19])[CH3:18])=[N:10][N:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=12)=[O:7]
Reactant: CC(=O)OC(C)C(=O)c1c(C(C)C)nn2ccccc12
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(O)C(=O)c1c(C(C)C)nn2ccccc12
Yield: 96.6 %

Procedure:
A solution of 1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)-1-oxopropan-2-yl acetate (0.33 g, 1 equivalent) and 1M NaOH (1.5 mL, 1.25 equivalents) in 3 mL of THF was stirred at room temperature for 24 hours. The solution was worked up with ethyl acetate and saturated NaHCO3. The crude solid obtained was recrystallized from ethyl acetate and hexane to provide 2-hydroxy-1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)propan-1-one (0.27 g, 96% yield) as a white solid. Compound 1068.
Reaction SMILES: [C:1]([C:3]1[C:8]2[C:9]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)=[N:10][O:11][C:7]=2[C:6]([OH:19])=[C:5]([C:20](OCC)=[O:21])[N:4]=1)#[N:2].[NH2:25][CH2:26][C:27]([OH:29])=[O:28].C[O-].[Na+].Cl>>[C:1]([C:3]1[C:8]2[C:9]([C:12]3[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=3)=[N:10][O:11][C:7]=2[C:6]([OH:19])=[C:5]([C:20]([NH:25][CH2:26][C:27]([OH:29])=[O:28])=[O:21])[N:4]=1)#[N:2]
Reactant: NCC(=O)O
Reactant: CCOC(=O)c1nc(C#N)c2c(-c3ccc(F)cc3)noc2c1O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Product: N#Cc1nc(C(=O)NCC(=O)O)c(O)c2onc(-c3ccc(F)cc3)c12
Temperature: 25 °C
Yield: 66.3 %

Procedure:
Ethyl 4-cyano-3-(4-fluorophenyl)-7-hydroxyisoxazolo[4,5-c]pyridine-6-carboxylate (101 mg, 0.309 mmol) and glycine (468 mg, 6.18 mmol) were added to sodium methoxide solution (9.3 mL, 4.63 mmol, 0.5 M in MeOH) and the mixture was refluxed for 3 days. The mixture was cooled to room temperature and 0.25 M hydrochloric acid was added until pH was 3. The precipitate was isolated by filtration and dried under vacuum to give 73 mg of the title compound. MS: (−) m/z 355.31 (M−1).
Reaction SMILES: [Cl-].[Li+].C(OP([CH2:11][C:12]#[N:13])(=O)OCC)C.C1CCN2C(=NCCC2)CC1.[CH:25]1([N:28]([CH2:36][C:37]2[CH:42]=[C:41]([CH2:43][CH:44]=O)[CH:40]=[C:39]([Cl:46])[C:38]=2[Cl:47])[C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:27][CH2:26]1>C1COCC1>[CH:25]1([N:28]([CH2:36][C:37]2[CH:42]=[C:41]([CH2:43]/[CH:44]=[CH:11]/[C:12]#[N:13])[CH:40]=[C:39]([Cl:46])[C:38]=2[Cl:47])[C:29](=[O:35])[O:30][C:31]([CH3:32])([CH3:34])[CH3:33])[CH2:27][CH2:26]1
Reactant: CCOP(=O)(CC#N)OCC
Reactant: CC(C)(C)OC(=O)N(Cc1cc(CC=O)cc(Cl)c1Cl)C1CC1
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)OC(=O)N(Cc1cc(C/C=C/C#N)cc(Cl)c1Cl)C1CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a THF (0.1 M) suspension of anhydrous lithium chloride (1.2 eq.) was added sequentially diethyl(cyanomethyl)phosphonate (1.2 eq.) and DBU (1 eq.). The resulting suspension was stirred at RT for 15 min before 1,1-dimethylethyl cyclopropyl{[2,3-dichloro-5-(2-oxoethyl)phenyl]methyl}carbamate (1 eq.) from the previous step was added dropwise as a THF (0.1 M) solution. The resulting pink suspension was allowed to stir at RT for 12 h before it was carefully quenched with 1 N aq. HCl and then extracted with ether. The combined organic extracts were washed further with water and brine, dried over Na2SO4, filtered and the filtrate concentrated in vacuo. Purification of the crude product thus obtained by way of flash chromatography (SiO2, Hex→3:7 (v/v) Hex:EtOAc) afforded the title compound as a colorless oil.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:17]([CH:18]=[O:19])[O:16][C@H:15]2[C@H:11]([N:12]=[C:13]([N:20]([CH3:22])[CH3:21])[S:14]2)[C@H:10]1[O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-].[C:49]([Si](C)(C)C)([F:52])([F:51])[F:50]>C1COCC1>[CH2:1]([O:8][C@@H:9]1[C@@H:17]([C@@H:18]([OH:19])[C:49]([F:52])([F:51])[F:50])[O:16][C@H:15]2[C@H:11]([N:12]=[C:13]([N:20]([CH3:22])[CH3:21])[S:14]2)[C@H:10]1[O:23][CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)C1=N[C@@H]2[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@@H](C=O)O[C@@H]2S1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CN(C)C1=N[C@@H]2[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@@H]([C@@H](O)C(F)(F)F)O[C@@H]2S1
Reaction time: 0.5 h
Yield: 48.9 %

Procedure:
A mixture of the aldehyde (95) (3.0 g, 7 mmol) (Prepared according to the synthesis of Example 149 step 3) TBAF (1.06 g, 3 mmol) and 4 Å molecular sieves (2.0 g) in THF (60 mL) was stirred for 30 min followed by the addition of CF3SiMe3 (5.8 g, 40 mmol) at −30° C. The mixture was kept overnight at room temperature, additional TBAF (20 g, 63 mmol) was added. After stirred additional 1 hour, the reaction was quenched by brine (40 mL) and extracted with ethyl acetate (3×50 mL). The organic layers combined, washed with brine (3×50 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue, which was purified by a silica gel column, eluted with 5%-25% ethyl acetate in petroleum ether to afford 110 as a light yellow syrup (1.7 g, 49%). (ES, m/z): [M+H]+ 497.7; 1H NMR (300 MHz, CDCl3) δ 7.31-7.40 (m, 10H), 6.29 (d, J=6.6 Hz, 1H), 4.57-4.78 (m, 4H), 4.30-4.43 (m, 2H), 3.80-4.17 (m, 4H), 3.01 (s, 6H).
Reaction SMILES: CC([O:5][C:6](=[O:23])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17](=[O:22])[C:18]([F:21])([F:20])[F:19])=[CH:11][CH:10]=1)(C)C.FC(F)(F)C(O)=O>>[F:19][C:18]([F:20])([F:21])[C:17](=[O:22])[CH2:16][CH2:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:6]([OH:23])=[O:5])=[CH:10][CH:11]=1
Reactant: CC(C)(C)OC(=O)COc1ccc(CCC(=O)C(F)(F)F)cc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)COc1ccc(CCC(=O)C(F)(F)F)cc1
Yield: 100 %

Procedure:
4-(4,4,4-trifluoro-3-oxo-1-butyl)phenoxyacetic acid 1,1-dimethylethyl ester (0.450 g, 1.35 mmol) was treated with trifluoroacetic acid as described in example (133) to give 0.373 g (100%) of the material as a white solid.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[C:10]([NH:11][C:12](=[O:14])[CH3:13])=[CH:9][C:8]([CH2:15][S:16](/[CH:19]=[CH:20]/[C:21]2[C:26]([O:27][CH3:28])=[CH:25][C:24]([O:29][CH3:30])=[CH:23][C:22]=2[O:31][CH3:32])(=[O:18])=[O:17])=[CH:7][N:6]=1.I[CH2:34][CH3:35]>C1COCC1>[CH2:34]([N:11]([C:10]1[C:5]([O:4][CH3:3])=[N:6][CH:7]=[C:8]([CH2:15][S:16](/[CH:19]=[CH:20]/[C:21]2[C:26]([O:27][CH3:28])=[CH:25][C:24]([O:29][CH3:30])=[CH:23][C:22]=2[O:31][CH3:32])(=[O:18])=[O:17])[CH:9]=1)[C:12](=[O:14])[CH3:13])[CH3:35]
Reactant: CCI
Reactant: COc1cc(OC)c(/C=C/S(=O)(=O)Cc2cnc(OC)c(NC(C)=O)c2)c(OC)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCN(C(C)=O)c1cc(CS(=O)(=O)/C=C/c2c(OC)cc(OC)cc2OC)cnc1OC
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 74.9 %

Procedure:
Sodium hydride (0.6 mg, 0.025 mmol) was added into the solution of (E)-N-(2-methoxy-5-((2,4,6-trimethoxystyrylsulfonyl)methyl)pyridin-3-yl)acetamide (10 mg, 0.023 mmol) in dry THF (5 mL). The mixture was stirred at room temperature for 45 min. Iodoethane (15 μL, 0.05 mmol) was added dropwise into the mixture and stirred at room temperature for another 2 h. After evaporated to dryness, the residue was diluted with H2O (10 mL) and extracted (2×20 mL CH2Cl2). The combined extracts were extracted with sat. Na2CO3, washed with brine, dried on MgSO4, and filtered. The residue was purified by silica gel chromatography, eluting with PE/EtOAc (1:1, v/v) to afford pure product as a white powder (8 mg, 75%). 1H-NMR (CDCl3): δ 1.02 (t, 3H, J=7.2 Hz, CH3), 1.74 (s, 3H, CH3), 3.42 (m, 2H, CH2), 3.86 (s, 6H, 2×OCH3), 3.87 (s, 3H, OCH3), 3.99 (s, 3H, OCH3), 4.23 (s, 2H, CH2), 6.10 (s, 2H, Ph-H), 7.07 (d, 1H, J=15.6 Hz, CH), 7.05 (d, 1H, J=2.0 Hz, Py-H), 7.77 (d, 1H, J=15.6 Hz, CH), 8.15 (d, 1H, J=2.0 Hz, Py-H); HR-MS (ESI+) m/z: 465.1762 [M+H]+, C22H28N2O7S, requires 464.1617.
Reaction SMILES: [N:1](=[C:3]1[N:7]=[C:6]([CH3:8])[C:5]([CH3:11])([CH2:9][CH3:10])[S:4]1)[OH:2].[CH3:12][N:13]=[C:14]=[O:15]>>[CH3:12][NH:13][C:14]([O:2][N:1]=[C:3]1[N:7]=[C:6]([CH3:8])[C:5]([CH3:11])([CH2:9][CH3:10])[S:4]1)=[O:15]
Reactant: CN=C=O
Reactant: CCC1(C)SC(=NO)N=C1C
Product: CCC1(C)SC(=NOC(=O)NC)N=C1C

Procedure:
2-oxo-4,5-dimethyl-5-ethyl-3-thiazoline-oxime was reacted with methyl isocyanate as described in Example 4 to yield 2-oxo-4,5-dimethyl-5-ethyl-3-thiazoline-O-(methylcarbamoyl)-oxime, m.p. 115°-117° C. The 2-oxo-4,5-dimethyl-5-ethyl-3-thiazoline-oxime starting material melts at 143.5°-144.5° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([NH:11][CH2:12][C:13]([CH3:16])([NH2:15])[CH3:14])[C:5]([CH3:17])=[C:4]([CH3:18])[N:3]=1.C(N(CC)CC)C.[C:26](OC(=O)C)(=[O:28])[CH3:27]>C(Cl)Cl>[Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([NH:11][CH2:12][C:13]([NH:15][C:26](=[O:28])[CH3:27])([CH3:14])[CH3:16])[C:5]([CH3:17])=[C:4]([CH3:18])[N:3]=1
Reactant: Cc1nc(Cl)c([N+](=O)[O-])c(NCC(C)(C)N)c1C
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NC(C)(C)CNc1c(C)c(C)nc(Cl)c1[N+](=O)[O-]
Reaction time: 2 h
Yield: 83.1 %

Procedure:
A solution of gave N1-(2-chloro-5,6-dimethyl-3-nitropyridin-4-yl)-2-methylpropane-1,2-diamine (3.14 g, 10.9 mmol) in 50 mL of CH2Cl2 was cooled to 0° C. under N2 and treated with triethylamine (2.84 mL, 20.4 mmol) and acetic anhydride (1.01 mL, 10.7 mmol). After stirring for 2 h, the reaction was quenched by the addition of saturated aqueous NaHCO3. CH2Cl2 (100 mL) was added and the organic layer was separated. The organic layer was then washed with cold H2O (2×) and brine. The organic portion was dried with Na2SO4 and concentrated to give N-{2-[(2-chloro-5,6-dimethyl-3-nitropyridin-4-yl)amino]-1,1-dimethylethyl}acetamide (2.80 g) as a yellow foam.
Reaction SMILES: F[B-](F)(F)F.[CH2:6]([O+](CC)CC)[CH3:7].[F:13][C:14]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:15]=1[C:16]([NH2:18])=[O:17].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[F:13][C:14]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:15]=1[C:16](=[NH:18])[O:17][CH2:6][CH3:7]
Reactant: NC(=O)c1c(F)cccc1F
Reactant: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=N)c1c(F)cccc1F
Temperature: 20 °C
Reaction time: 18 h
Yield: 90.6 %

Procedure:
A mixture of triethyloxonium tetrafluoroborate (8.0 g, 0.042M), 2,6-difluorobenzamide (5.62 g, 0.036M) and methylene chloride was stirred at 20° C. for 18 hours, after which an excess of aqueous sodium bicarbonate solution was added. The methylene chloride phase was separated and dried over anhydrous magnesium sulphate. Evaporation of the solvent under reduced pressure yielded ethyl 2,6-difluorobenzimidate as a pale yellow oil (6.0 g) which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:10]([CH:11]=[N:12][O:13][CH2:14][C:15]#[CH:16])=[C:9]([S:17]([CH3:20])(=[O:19])=[O:18])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH2:21]([N:23]1[C:27]([NH2:28])=[N:26][N:25]=[N:24]1)[CH3:22].C(Cl)(=O)C(Cl)=O.OS([O-])(=O)=O.[K+]>N1C=CC=CC=1.CN(C)C1C=CN=CC=1.O.CN(C=O)C>[Cl:1][C:2]1[C:10]([CH:11]=[N:12][O:13][CH2:14][C:15]#[CH:16])=[C:9]([S:17]([CH3:20])(=[O:19])=[O:18])[CH:8]=[CH:7][C:3]=1[C:4]([NH:28][C:27]1[N:23]([CH2:21][CH3:22])[N:24]=[N:25][N:26]=1)=[O:6]
Reactant: C#CCON=Cc1c(S(C)(=O)=O)ccc(C(=O)O)c1Cl
Reactant: CCn1nnnc1N
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Agent: O=S(=O)([O-])O
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: O
Product: C#CCON=Cc1c(S(C)(=O)=O)ccc(C(=O)Nc2nnnn2CC)c1Cl
Temperature: 70 °C
Reaction time: 3 h

Procedure:
400 mg (1.15 mmol) of 2-chloro-4-(methylsulfonyl)-3-{[(prop-2-yn-1-yloxy)imino]methyl}benzoic acid and 171.60 mg (1.44 mmol) of 1-ethyl-1H-tetrazole-5-amine were dissolved in 4 ml of pyridine, and 10 mg of 4-dimethylaminopyridine and a drop of DMF were added. At RT, 186.65 mg (1.441 mmol) of oxalyl chloride were then added dropwise, and the mixture was stirred at 70° C. for 3 h. 0.5 ml of water was then added to the reaction, which had once more been cooled, and the mixture was stirred for about 30 min, acidified with a saturated KHSO4 solution and extracted three times with in each case 100 ml of ethyl acetate. The combined organic phases were washed once with 20 ml of a saturated NaHCO3 solution, dried over MgSO4, filtered off and concentrated. Yield: 351.60 mg (67%) as an orange solid.
Reaction SMILES: C([O:3][C:4]([CH2:6][C:7](=O)[CH2:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([O:15][C:16]([N:18]2[CH2:27][CH2:26][C:25]3[C:20](=[CH:21][CH:22]=[C:23]([NH:28][C:29]([NH:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=4[F:38])=[O:30])[CH:24]=3)[CH2:19]2)=[O:17])[CH2:11][CH2:10]1)=O)C.C(O)C.O.[NH2:44][NH2:45]>C(OC(C)C)(C)C>[OH:3][C:4]1[CH:6]=[C:7]([CH2:8][C@H:9]2[CH2:10][CH2:11][C@H:12]([O:15][C:16]([N:18]3[CH2:19][CH2:20][C:25]4[C:26](=[CH:21][CH:22]=[C:23]([NH:28][C:29]([NH:31][C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=5[F:38])=[O:30])[CH:24]=4)[CH2:27]3)=[O:17])[CH2:13][CH2:14]2)[NH:44][N:45]=1
Reactant: NN
Reactant: CCOC(=O)CC(=O)C[C@H]1CC[C@H](OC(=O)N2CCc3cc(NC(=O)Nc4ccccc4F)ccc3C2)CC1
Solvent: CC(C)OC(C)C
Solvent: O
Solvent: CCO
Product: O=C(Nc1ccc2c(c1)CCN(C(=O)O[C@H]1CC[C@H](Cc3cc(O)n[nH]3)CC1)C2)Nc1ccccc1F

Procedure:
To a mixture of trans-6-[3-(2-fluoro-phenyl)-ureido]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 4-(3-ethoxycarbonyl-2-oxo-propyl)-cyclohexyl ester (189 mg) obtained in Example (42a) and ethanol (5 mL), hydrazine monohydrate (0.022 mL) was added at 0° C. During the reaction, hydrazine monohydrate was further added thereto, and the mixture was stirred until the reaction substrate was consumed. The reaction mixture was concentrated and purified by column chromatography (dichloromethane/methanol) to obtain a white solid. This white solid was vigorously stirred in isopropyl ether and collected by filtration to obtain the title compound (90 mg, 51%) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[CH2:16][O:17][C:18](=[O:26])[NH:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:29][CH2:30][CH2:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[CH:35][CH:34]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>C(#N)C.O>[C:1]([O:5][C:6](=[O:27])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:29][CH2:30][CH2:31][O:32][C:33]2[CH:38]=[CH:37][C:36]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)=[CH:35][CH:34]=2)=[CH:11][C:10]=1[CH2:16][O:17][C:18](=[O:26])[NH:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: BrCCCOc1ccc(-c2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)CCc1ccc(O)cc1COC(=O)NC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC#N
Product: CC(C)(C)OC(=O)CCc1ccc(OCCCOc2ccc(-c3ccccc3)cc2)cc1COC(=O)NC1CCCCC1
Yield: 65 %

Procedure:
A mixture of 3-(2-cyclohexylcarbamoyloxymethyl-4-hydroxy-phenyl)-propionic acid tert-butyl ester (50 mg, 0.13 mmol; Example 652 Step D), 4-(3-bromo-propoxy)-biphenyl (58 mg, 0.2 mmol; Tetrahedron 1994, 50, 3427, and potassium carbonate (53 mg, 0.39 mmol) in acetonitrile (6 mL) was heated at 80° C. overnight. Ethyl acetate (20 mL) and H2O (20 mL) were added. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (3×). The combined organic layers were dried (MgSO4), filtered, and concentrated. The crude mixture was purified by silica gel column chromatography (hexane/ethyl acetate 4/1) to give the title compound (50 mg, 65%). 1H-NMR (300 MHz, CDCl3): δ 7.54 (m, 4H), 7.42 (t, 2H, J=7.6), 7.32 (d, 1H, J=8.4), 7.12 (d, 1H, J=8.3), 6.99 (d, 2H, J=8.7), 6.93 (d, 1H, J=2.2), 6.82 (dd, 1H, J=8.4, 2.7), 5.09 (s, 2H), 4.74 (d, 1H, J=7.5), 4.18 (m, 4H), 3.56-3.42 (m, 1H), 2.90 (t, 2H, J=7.8), 2.48 (t, 2H, J=7.8), 2.28 (qn, 2H, J=6.0), 1.95-1.88 (m, 2H), 1.75-1.08 (m, 8H), 1.44 (s, 9H).