Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:6]1[CH:10]=[C:9]([C:11](=[O:16])[CH2:12][CH:13]([CH3:15])[CH3:14])[CH:8]=[C:7]1[C:17]([C:19]1[CH:20]=[CH:21][C:22]([O:35][CH2:36][CH2:37][CH:38]([CH3:40])[CH3:39])=[C:23]([CH2:25][CH2:26][C:27]([O:29]CCC(C)C)=[O:28])[CH:24]=1)=[O:18])[CH2:2][CH:3]([CH3:5])[CH3:4].[OH-].[Na+].O.Cl>C(O)C.C(Cl)(Cl)Cl>[CH2:1]([N:6]1[CH:10]=[C:9]([C:11](=[O:16])[CH2:12][CH:13]([CH3:15])[CH3:14])[CH:8]=[C:7]1[C:17]([C:19]1[CH:20]=[CH:21][C:22]([O:35][CH2:36][CH2:37][CH:38]([CH3:40])[CH3:39])=[C:23]([CH2:25][CH2:26][C:27]([OH:29])=[O:28])[CH:24]=1)=[O:18])[CH2:2][CH:3]([CH3:5])[CH3:4]
Reactant: CC(C)CCOC(=O)CCc1cc(C(=O)c2cc(C(=O)CC(C)C)cn2CCC(C)C)ccc1OCCC(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: CC(C)CCOc1ccc(C(=O)c2cc(C(=O)CC(C)C)cn2CCC(C)C)cc1CCC(=O)O
Temperature: 50 °C
Reaction time: 1 h
Yield: 95.7 %

Procedure:
To a solution of 0.67 g of isopentyl 3-[5-{[1-isopentyl-4-(3-methylbutanoyl)-1H-pyrrol-2-yl]carbonyl}-2-(isopentyloxy)phenyl]propanoate in 14 ml of ethanol is added 3.6 ml of 1 mol/L sodium hydroxide solution. The mixture thus obtained is stirred at 50° C. for one hour. Water and chloroform are added to the reaction mixture, pH is adjusted to 2 with 6 mol/L hydrochloric acid, and the organic layer is separated. The organic layer is washed with water and saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. Thus, 0.56 g of 3-[5-{[1-isopentyl-4-(3-methylbutanoyl)-1H-pyrrol-2-yl]carbonyl}-2-(isopentyloxy)phenyl]propanoic acid is obtained as a white solid product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][C:9]2[N:13]([CH3:14])[CH:12]=[N:11][C:10]=2[C:15]2[CH:20]=[CH:19][C:18]([C@H:21]3[CH2:23][C@@H:22]3[CH2:24][OH:25])=[CH:17][CH:16]=2)=[N:6][CH:7]=1.[H-].[Na+].[CH3:28]I>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][C:9]2[N:13]([CH3:14])[CH:12]=[N:11][C:10]=2[C:15]2[CH:20]=[CH:19][C:18]([C@H:21]3[CH2:23][C@@H:22]3[CH2:24][O:25][CH3:28])=[CH:17][CH:16]=2)=[N:6][CH:7]=1
Reactant: CI
Reactant: Cn1cnc(-c2ccc([C@H]3C[C@@H]3CO)cc2)c1Sc1ccc(Cl)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC[C@H]1C[C@@H]1c1ccc(-c2ncn(C)c2Sc2ccc(Cl)cn2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
[(1S,2S)-2-(4-{5-[(5-Chloropyridin-2-yl)thio]-1-methyl-1H-imidazol-4-yl}phenyl)cyclopropyl]methanol (product of Example 23, 20 mg, 0.054 mmol) was dissolved in DMF (1 mL), to which was added NaH (0.25 mmol) and MeI (0.25 mmol) at 0° C. The reaction was warmed to rt and stirred for 30 min. The reaction was quenched with 1 mL of aqueous NH4Cl and diluted with 5 mL of EtOAc. The mixture was washed with water (two times) and brine. The organic layer was dried and concentrated to give the crude product that was purified by column (60-100% EtOAc in hexanes) to afford the title compound. 1H NMR (500 MHz, (CDCl3): 9.82 (s, 1H), 8.37 (s, 1H), 7.88 (d, 2H), 7.58 (d, 1H), 7.15 (d, 2H), 7.07 (d, 1H), 3.97 (s, 3H), 3.42 (d, 2H), 3.39 (s, 3H), 1.82 (m, 1H), 1.44 (m, 1H), 0.99 (m, 2H). LCMS: m/z 386 (M+H)+. Human FAAH lysate assay: IC50=35.5 nM.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([C:20]([O:22][CH2:23][CH3:24])=[O:21])([CH2:16][CH2:17][CH:18]=[CH2:19])[C:13](O)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.ClC(OCC)=O.[BH4-].[Na+].Cl>O1CCCC1.O.C(OCC)(=O)C>[CH2:1]([O:8][C:9]([NH:11][C:12]([CH2:13][OH:14])([CH2:16][CH2:17][CH:18]=[CH2:19])[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=CCCC(NC(=O)OCc1ccccc1)(C(=O)O)C(=O)OCC
Agent: CCOC(=O)Cl
Agent: Cl
Agent: [BH4-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=CCCC(CO)(NC(=O)OCc1ccccc1)C(=O)OCC
Reaction time: 0.5 h
Yield: 47.4 %

Procedure:
A solution of 2-(benzyloxycarbonylamino)-2-(ethoxycarbonyl)hex-5-enoic acid (1.54 g, 4.6 mmol) and triethylamine (557 mg, 5.52 mmol, 0.76 mL) in tetrahydrofuran (10 mL) was cooled to −30° C. and treated with ethyl chloroformate (522 mg, 4.82 mmol, 0.46 mL) and stirred for 30 minutes. A solution of sodium borohydride (175 mg, 4.6 mmol) in water (2 mL) was added and the mixture was stirred for 30 minutes. Once the reaction was complete, 3 N hydrochloric acid (1 mL) was added and the mixture was diluted with ethyl acetate (50 mL), washed with water (1×50 mL) and extracted with ethyl acetate (1×50 mL). The combined organic layers were concentrated and purified using a combiflash system (2×12 g silica gel column, eluting with 10-50% ethyl acetate in heptanes) to give ethyl 2-(benzyloxycarbonylamino)-2-(hydroxymethyl)hex-5-enoate (700 mg, 48%). 1H NMR (CDCl3) δ 7.29 (m, 5H), 5.82 (bs, 1H), 5.68-5.62 (m, 1H), 5.03 (s, 1H), 4.94-4.86 (m, 2H), 4.17 (m, 2H) 3.76 (dd, J=11.4 Hz, 1H), 1.97 (m, 2H), 1.77 (m, 2H), 1.21 (t, J=7.2 Hz, 3H). MS found for C17H23NO5 m/z [322 (M+1)].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[S:10])=[CH:4][C:3]=1[N:11]=[C:12]=[S:13].[CH:14]([NH:17][CH:18]([CH3:20])[CH3:19])([CH3:16])[CH3:15]>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([N:17]([CH:18]([CH3:20])[CH3:19])[CH:14]([CH3:16])[CH3:15])=[S:10])=[CH:4][C:3]=1[NH:11][C:12]([N:17]([CH:18]([CH3:20])[CH3:19])[CH:14]([CH3:16])[CH3:15])=[S:13]
Reactant: S=C=Nc1ccc(Cl)c(N=C=S)c1
Reactant: CC(C)NC(C)C
Solvent: CC#N
Product: CC(C)N(C(=S)Nc1ccc(Cl)c(NC(=S)N(C(C)C)C(C)C)c1)C(C)C

Procedure:
A mixture of 11.1 g. of 4-chloro-1,3-diisothiocyanatobenzene and 10.2 g. of diisopropylamine is refluxed in 250 ml. of acetonitrile for 4 hours. The reaction mixture is cooled and the acetonitrile is removed in vacuo. The residue is crystallized twice from ether to yield 5.0 g. of the title compound, melting point 122°-123° C.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][O:8][C:9]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=1[C:17]1[CH:22]=[CH:21][C:20]([C:23]([OH:25])=O)=[CH:19][C:18]=1[CH3:26].O[N:28]=[C:29]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[O:37][C:38]([F:41])([F:40])[F:39])[NH2:30].CCN(C(C)C)C(C)C>>[CH3:7][O:8][C:9]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=1[C:17]1[CH:22]=[CH:21][C:20]([C:23]2[O:25][N:30]=[C:29]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[O:37][C:38]([F:39])([F:40])[F:41])[N:28]=2)=[CH:19][C:18]=1[CH3:26]
Reactant: COc1ccc(-c2ccc(C(=O)O)cc2C)c(OC)c1
Reactant: NC(=NO)c1ccccc1OC(F)(F)F
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-c2ccc(-c3nc(-c4ccccc4OC(F)(F)F)no3)cc2C)c(OC)c1

Procedure:
Oxalyl chloride (112 μL; 1.32 mmol; 3 eq.), Intermediate 28 (120 mg; 0.44 mmol; 1 eq.), Intermediate 2 (97 mg; 0.44 mmol, 1 eq.) and DIEA (228 μL; 1.32 mmol; 3 eq.) were reacted according to general procedure 2. Purification by column chromatography c-hexane/ethyl acetate, 95/5) afforded the title compound as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6].[NH:12]1[CH:16]=[CH:15][CH:14]=[N:13]1.CN[C@@H]1CCCC[C@H]1NC.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.[Cu]I.O>[N:12]1([C:2]2[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=2)[C:5]([O:7][CH3:8])=[O:6])[CH:16]=[CH:15][CH:14]=[N:13]1
Reactant: COC(=O)c1ccnc(Br)c1
Reactant: c1cn[nH]c1
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)c1ccnc(-n2cccn2)c1
Temperature: 25 °C

Procedure:
A mixture of commercially available methyl 2-bromoisonicotinate (500 mg; 2.31 mmol), 1H-pyrazole (157 mg; 2.31 mmol), trans-N,N′-dimethylcyclohexane-1,2-diamine (67 mg; 0.46 mmol), K2CO3 (685 mg; 4.86 mmol), and CuI (22 mg; 0.11 mmol) in anh. toluene (8 ml) was heated at reflux for 16 h. After cooling to rt, water was added, and the mixture was extracted with AcOEt. The mixed organic layers were dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Purification by FC (DCM/MeOH=20/1) afforded methyl 2-(1H-pyrazol-1-yl)isonicotinate as an off-white solid. LC-MS (conditions A): tR=0.67 min.; [M+H]+: 204.04 g/mol.
Reaction SMILES: Br.F[C:3]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:4]=1[C:5]([NH:7][C:8]1[CH:13]=[CH:12][NH:11][C:10](=[O:14])[CH:9]=1)=[O:6].C(=O)([O-])[O-].[K+].[K+].[F:29][C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[C:32]([CH3:37])[CH:31]=1.CC1CCCO1>CN1C(=O)CCC1.O>[F:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][C:3]2[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:4]=2[C:5]([NH:7][C:8]2[CH:13]=[CH:12][NH:11][C:10](=[O:14])[CH:9]=2)=[O:6])=[C:32]([CH3:37])[CH:31]=1
Reactant: O=C(Nc1cc[nH]c(=O)c1)c1ccc(C(F)(F)F)cc1F
Reactant: Cc1cc(F)ccc1O
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CC1CCCO1
Product: Cc1cc(F)ccc1Oc1cc(C(F)(F)F)ccc1C(=O)Nc1cc[nH]c(=O)c1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 78.3 %

Procedure:
To a 50 liter jacketed glass reactor fitted with an N2 inlet and a mechanical stirrer was added 1-methyl-2-pyrrolidinone (NMP) (3.75 liters). The solution was stirred, 2-fluoro-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide hydrobromide salt (1500.2 g, 3.94 moles, 1.0 eq) was added and chased with NMP (1 liter), and the jacket temperature was adjusted to 35° C. Potassium carbonate (1631.9 g, 11.8 moles, 3.0 eq, 325 mesh) was then added portionwise over 10 minutes, during which time the reaction temperature increased to 40° C. The resulting suspension was treated with a solution of 4-fluoro-2-methylphenol (5, 546.1 g, 4.33 moles, 1.1 eq, AK Scientific) in NMP (2.25 liters) with stirring, and the addition funnel was then rinsed with NMP (0.75 liters) to give an orange suspension. The jacket temperature was raised to 61° C. over 30 minutes and the suspension was stirred overnight under nitrogen, at which time the reaction was judged to be complete by HPLC analysis. To the reaction mixture was added 2-methyltetrahydrofuran (15 liters) and water (15 liters) and the mixture stirred until all solids dissolved. Stirring was stopped, the orange aqueous layer drained off, and the organic layer washed with water (7.5 liters) while stirring and a jacket temperature of ˜52° C.). The aqueous wash procedure was repeated 4 times (3×7.5 liter water washes, then 1×4.5 liter water wash). The resulting organic slurry was stirred at a jacket temperature of 50.8° C., and isopropyl acetate (6 liters, Sigma Aldrich) was added. The jacket temperature was ramped down to 20° C. over 30 minutes, and the slurry was stirred overnight before collecting the precipitated solid by filtration. The collected solid was returned to the reactor, slurried in isopropyl acetate with stirring for about 2 hours, then filtered, rinsed with isopropyl acetate (1.5 liters) and dried in vacuo at 65° C. to give 1253.1 g (78%) of 2-(4-fluoro-2-methylphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide (9a) as an off-white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:8]([C:11]2[CH:16]=[CH:15][C:14](F)=[CH:13][C:12]=2[N+:18]([O-:20])=[O:19])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[NH:21]1[CH2:27][CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.C(=O)([O-])[O-].[K+].[K+].O>C(#N)C.C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([N:21]3[CH2:27][CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)=[CH:13][C:12]=2[N+:18]([O-:20])=[O:19])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1cc(F)ccc1S(=O)(=O)c1cccc(F)c1
Reactant: C1CNCCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Solvent: CC#N
Product: O=[N+]([O-])c1cc(N2CCCNCC2)ccc1S(=O)(=O)c1cccc(F)c1
Temperature: 60 °C
Reaction time: 4 h
Yield: 99.6 %

Procedure:
A mixture of 4-fluoro-2-nitrophenyl 3-fluorophenyl sulfone (5.00 g, 16.7 mmol), homopiperazine (2.09 g, 20.9 mmol), and potassium carbonate (3.46 g, 25.1 mmol) in 140 mL of dry acetonitrile is stirred vigorously for 4 h at 60° C. After cooling to room temperature, water and CH2Cl2 (140 mL each) are added and the layers separated. The aqueous layer extracted with CH2Cl2 (3×50 mL). The combined organics are dried over MgSO4, filtered, and concentrated to give an orange solid. The crude product is triturated with a hot Et2O:CH2Cl2 mixture (4:1) until solid. Further trituration with hot EtOAc/hexane gave 6.31 g (99%) of the title compound as bright yellow solid.
Reaction SMILES: [C:1]([NH:9][CH2:10][CH:11]([C:16](=[O:18])[CH3:17])[C:12]([O:14][CH3:15])=[O:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(CC)CC>C(Cl)Cl.[Ru]>[C:1]([NH:9][CH2:10][C@@H:11]([C@H:16]([OH:18])[CH3:17])[C:12]([O:14][CH3:15])=[O:13])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C(CNC(=O)c1ccccc1)C(C)=O
Agent: [Ru]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@@H](CNC(=O)c1ccccc1)[C@@H](C)O
Temperature: 50 °C
Reaction time: 20 h
Yield: 89.5 %

Procedure:
In a 100 ml-volume stainless steel-made autoclave whose atmosphere had been displaced with nitrogen was charged a solution of 2.5 g (10 mmole) of methyl 2-(N-benzoylamino)methyl-3-oxobutanoate and 84.5 mg (0.05 mmole) of the ruthenium-optically active phosphine complex as synthesized in Reference Example 1 [Ru2Cl4 ((+)-BINAP)2 (NEt3)] in 17.5 ml of methylene chloride, and the mixture was stirred at 50° C. under a hydrogen pressure of 100 kg/cm2 for 20 hours to conduct a hydrogenation reaction. The solvent was removed from the reaction mixture by distillation, and the residue was purified by silica gel column chromatography using a mixed solvent of n-hexane and ethyl acetate as an eluent to obtain 2.25 g (yield: 90%) of methyl (2S, 3R)-2-(N-benzoylamino)methyl-3-hydroxybutanoate having an optical purity of 98 %ee.
Reaction SMILES: [Br:1][CH:2]([CH2:14]Br)[CH2:3][CH:4]([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=1[F:13])[OH:5].[OH-].[Ca+2].[OH-].[Br-].[Ca+2].[Br-].O>C(OCC)(=O)C.CO>[Br:1][CH:2]1[CH2:14][O:5][CH:4]([C:6]2[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=2[F:13])[CH2:3]1
Reactant: OC(CC(Br)CBr)c1ccc(F)cc1F
Agent: [Br-]
Agent: [Ca+2]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: Fc1ccc(C2CC(Br)CO2)c(F)c1
Temperature: 85 °C
Yield: 57 %

Procedure:
A mixture of 4.5 g of product from Example 164, 1.67 g of calcium hydroxide, 7.5 g of calcium bromide, 25 ml of water and 12 ml of methyl alcohol is stirred and heated at 85° C. overnight. The reaction mixture is cooled, diluted with ethyl acetate and filtered through diatomaceous earth. The layers are separated and the organic layer is washed with saturated sodium chloride, dried, filtered and concentrated in vacuo. The residue is purified by chromatography (silica gel: 3-5% ethyl acetate/hexane) to give 1.96 g of the desired product as a mixture of isomers.
Reaction SMILES: [NH2:1][C@H:2]([C:5]([OH:7])=[O:6])[CH2:3][OH:4].[CH:8](=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[BH4-].[Na+]>[OH-].[Na+]>[CH2:8]([NH:1][C@H:2]([C:5]([OH:7])=[O:6])[CH2:3][OH:4])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: N[C@@H](CO)C(=O)O
Reactant: O=Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)[C@H](CO)NCc1ccccc1
Temperature: 5 °C
Reaction time: 1 h
Yield: 89.1 %

Procedure:
Racemic serine (14.7 g, 140 mmol) was dissolved in 2M NaOH (70 mL) and benzaldehyde (14.64 g, 14.0 mL, 138 mmol) added with stirring. The mixture was stirred at r.t. for 1 h before cooling to 5° C. Sodium borohydride (1.5 g, 40 mmol) was added portionwise such that an internal temperature of between 6 and 10° C. was maintained. After addition the reaction mixture was allowed to stir at 5° C. for 30 minutes and then at r.t. for 1 h. The reaction mixture was cooled to 5° C. and a further portion of sodium borohydride (1.5 g, 40 mmol) added portionwise such that an internal temperature <10° C. was maintained. The ice bath was removed on completion of addition and the reaction stirred at r.t. for 16 h. The reaction mixture was extracted with Et2O (3×100 mL) and the aqueous phase acidified to pH 5 with concentrated hydrochloric acid. The resultant white precipitate was filtered and washed with water. The product was dried in vacuo to give the title compound (24.0 g, 88%). δH (DMSO-d6) 7.45-7.30 (5H, m), 4.04-3.91 (2H, m), 3.70-3.61 (3H, m), 3.17 (1H, t, J 5.8 Hz). Some exchangeable protons were not observed.
Reaction SMILES: O[C:2]1[N:3]=[N+:4]([O-:13])[C:5]2[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:6]=2[N:7]=1.CN(C=O)C.O=P(Cl)(Cl)[Cl:21]>>[Cl:21][C:2]1[N:3]=[N+:4]([O-:13])[C:5]2[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: [O-][n+]1nc(O)nc2ccc(O)cc21
Solvent: CN(C)C=O
Product: [O-][n+]1nc(Cl)nc2ccc(O)cc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
1 g of 3,7-dihydroxybenzo[e][1,2,4]triazine 1-oxide was suspended in POCl3 (20 mL) and DMF (0.1 mL) and stirred at 100° C. for 2 h. The solution was cooled, poured into ice/water (200 mL), stirred for 30 min, filtered, washed with water (3×10 mL) and dried.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[N:11]=[C:10]([CH2:21][CH2:22][CH:23]=O)[CH:9]=2)=[CH:4][CH:3]=1.Cl.[NH2:26][OH:27].N1C=CC=CC=1>CCO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[N:11]=[C:10]([CH2:21][CH2:22][CH:23]=[N:26][OH:27])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: NO
Reactant: COc1ccc(-n2nc(CCC=O)cc2-c2ccc(Cl)cc2)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: COc1ccc(-n2nc(CCC=NO)cc2-c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.2 %

Procedure:
To a solution of the aldehyde 11 (1.00 g, 2.93 mM) in EtOH (30 ml) was added hydroxylamine hydrochloride (0.31 g, 4.40 mM) and pyridine (0.47 g, 5.87 mM). After stirring overnight at room temperature, the reaction mixture was concentrated in vacuo. The remaining residue was taken up in CH2Cl2, washed with H2O, dried (Na2SO4), filtered, and concentrated in vacuo. Crystallization from Et2O:hexane afforded 26, (0.67 g, 64%) as a white crystalline solid, mp=134°-135° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:22])=[N:4][O:5][C:6]=1[NH:7][S:8]([C:11]1[CH:15]=[CH:14][S:13][C:12]=1[CH:16]1[S:21][CH2:20][CH2:19][CH2:18][S:17]1)(=[O:10])=[O:9].C([Li])CCC.Cl[CH2:29][C:30]1[C:38]([CH3:39])=[CH:37][C:33]2[CH2:34][O:35][CH2:36][C:32]=2[CH:31]=1.C(O)(=O)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O.O1CCCC1>[Cl:1][C:2]1[C:3]([CH3:22])=[N:4][O:5][C:6]=1[NH:7][S:8]([C:11]1[CH:15]=[CH:14][S:13][C:12]=1[C:16]1([CH2:29][C:30]2[C:38]([CH3:39])=[CH:37][C:33]3[CH2:34][O:35][CH2:36][C:32]=3[CH:31]=2)[S:21][CH2:20][CH2:19][CH2:18][S:17]1)(=[O:10])=[O:9]
Reactant: Cc1noc(NS(=O)(=O)c2ccsc2C2SCCCS2)c1Cl
Reactant: Cc1cc2c(cc1CCl)COC2
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc2c(cc1CC1(c3sccc3S(=O)(=O)Nc3onc(C)c3Cl)SCCCS1)COC2
Temperature: -35 °C
Reaction time: 0.33 h
Yield: 54 %

Procedure:
To a mixture of N-(4-chloro-3-methyl-1,2-oxazol-5-yl)-2-formylthiophene-3-sulfonamide described in Production Example 1-3 (4.9 g, 16 mmol) and dichloromethane (100 mL) was successively added boron trifluoride diethyl etherate (8.1 mL, 64 mmol) and 1,3-propanedithiol (1.9 mL, 19 mmol) under ice cooling, followed by stirring at room temperature for 90 minutes. Water was added under ice cooling to the reaction mixture, which was then extracted with dichloromethane. The organic layer was washed with brine, and the solvent was distilled away under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to give N-(4-chloro-3-methyl-1,2-oxazol-5-yl)-2-(1,3-dithian-2-yl)thiophene-3-sulfonamide as a crude product. To a mixture of crude N-(4-chloro-3-methyl-1,2-oxazol-5-yl)-2-(1,3-dithian-2-yl)thiophene-3-sulfonamide and tetrahydrofuran (50 mL) was added dropwise n-butyl lithium (9.7 mL, 16 mmol, 1.6 M n-hexane solution) at −78° C., followed by stirring for 20 minutes at an internal temperature of −35° C. The reaction mixture was cooled to −78° C., and 5-(chloromethyl)-6-methyl-1,3-dihydro-2-benzofuran described in Production Example 1-6 (960 mg, 5.3 mmol) was added at that temperature and stirred for 1 hour at 0° C. The reaction mixture was cooled to −78° C., and a mixture of acetic acid (0.90 mL, 16 mmol) and tetrahydrofuran (7 mL) was added at that temperature. The reaction mixture was gradually returned to room temperature, water and an aqueous citric acid solution were added at that temperature, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, and the solvent was distilled away under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:heptane=4:1) to give the title compound (1.6 g, 54% yield).
Reaction SMILES: [C:1](#[N:4])[CH2:2][OH:3].[S:5]1[CH:9]=[CH:8][CH:7]=[C:6]1[S:10](Cl)(=[O:12])=[O:11]>C(OCC)C>[S:5]1[CH:9]=[CH:8][CH:7]=[C:6]1[S:10]([O:3][CH2:2][C:1]#[N:4])(=[O:12])=[O:11]
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: N#CCO
Solvent: CCOCC
Product: N#CCOS(=O)(=O)c1cccs1
Reaction time: 3 h

Procedure:
Method of preparation: Glycolonitrile is reacted with 2-thiophenesulfonyl chloride using the procedure as described in the previous example, with 2 hours of reaction at 0° C., followed by three hours at room temperature. The reaction mixture separates into two layers; the bottom dark layer is isolated and dissolved in diethyl ether, the solution washed with weak caustic solution and cold water, and the solvent is stripped off under reduced pressure to give the product (in 79% conversion), a green oily liquid, nD24.5 1.535.
Reaction SMILES: [C:1]([C:3]1[N:4]=[C:5]([C:16]([OH:18])=O)[N:6]([CH2:8][O:9][CH2:10][CH2:11][Si:12]([CH3:15])([CH3:14])[CH3:13])[CH:7]=1)#[N:2].[K+].C(C1N=C(C([O-])=O)N(COCC[Si](C)(C)C)C=1)#N.CCN(C(C)C)C(C)C.[C:47]1([C:53]2[CH:58]=[C:57]([CH:59]3[CH2:64][CH2:63][N:62]([O:65][CH3:66])[CH2:61][CH2:60]3)[CH:56]=[CH:55][C:54]=2[NH2:67])[CH2:52][CH2:51][CH2:50][CH2:49][CH:48]=1.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[C:47]1([C:53]2[CH:58]=[C:57]([CH:59]3[CH2:64][CH2:63][N:62]([O:65][CH3:66])[CH2:61][CH2:60]3)[CH:56]=[CH:55][C:54]=2[NH:67][C:16]([C:5]2[N:6]([CH2:8][O:9][CH2:10][CH2:11][Si:12]([CH3:13])([CH3:14])[CH3:15])[CH:7]=[C:3]([C:1]#[N:2])[N:4]=2)=[O:18])[CH2:52][CH2:51][CH2:50][CH2:49][CH:48]=1
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)O
Reactant: CON1CCC(c2ccc(N)c(C3=CCCCC3)c2)CC1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)[O-]
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CON1CCC(c2ccc(NC(=O)c3nc(C#N)cn3COCC[Si](C)(C)C)c(C3=CCCCC3)c2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 48 %

Procedure:
A mixture of 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid, potassium salt (as prepared in Example 3, step (d), 35.6 mg, 0.100 mmol), DIEA (0.34 μL, 0.20 mmol), 2-cyclohex-1-enyl-4-(1-methoxy-piperidin-4-yl)-phenylamine (as prepared in previous step, 28.6 mg, 0.1 mmol) and PyBroP (69.9 mg, 0.150 mmol) in DCM (2 mL) was stirred at RT for 12 h. The reaction mixture was diluted with DCM (10 mL) and washed with saturated aqueous NaHCO3 (10 mL) and water (10 mL). The organic layer was separated, dried (Na2SO4) and concentrated in vacuo. The product was chromatographed on silica (20-40% EtOAc/hexane) to obtain the title compound (26 mg, 48%). Mass spectrum (ESI, m/z): Calcd. for C29H41N5O3Si, 536.3 (M+H), found 536.2.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][NH2:8].[CH:14]1[C:23]2[C:18](=[C:19]([CH:24]([CH3:28])[C:25](O)=[O:26])[CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][N:15]=1.C1C2C(=C(CC(O)=O)C=CC=2)C=CN=1>>[CH:14]1[C:23]2[C:18](=[C:19]([CH:24]([CH3:28])[C:25]([NH:8][CH2:7][C:6]3[CH:9]=[CH:10][CH:11]=[C:4]([O:3][C:2]([F:12])([F:13])[F:1])[CH:5]=3)=[O:26])[CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][N:15]=1
Reactant: NCc1cccc(OC(F)(F)F)c1
Reactant: CC(C(=O)O)c1cccc2cnccc12
Agent: O=C(O)Cc1cccc2cnccc12
Product: CC(C(=O)NCc1cccc(OC(F)(F)F)c1)c1cccc2cnccc12

Procedure:
The title compound was prepared using the procedure described in Example 222B using 3-(trifluoromethoxy)benzylamine and 2-(5-isoquinolinyl)propanoic acid instead of 4-(trifluoromethoxy)benzylamine and 5-isoquinolinylacetic acid. MS (ESI+) m/z 375 (M+H)+; MS (ESI−) m/z 373 (M−H)−; 1H NMR (DMSO, 300 MHz) δ 1.54 (d, J 7.1, 3H), 4.28 (d, J 6.1, 2H), 4.50 (q, J 7.1, 1H), 7.05 (s, 1H), 7.20 (m, 2H), 7.40 (m, 1H), 7.81 (t, J 7.8, 1H), 7.96 (d, J 7.2, 1H), 8.21 (d, J 8.1, 1H), 8.32 (d, J 6.2, 1H), 8.61 (d, J 6.8, 1H), 8.70 (t, J 5.8, 1H), 9.57 (s, 1H).