Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[N+:12]([O-])=O)=[O:3].[CH:15]([Mg]Br)=[CH2:16]>C1COCC1>[F:11][C:8]1[CH:9]=[CH:10][C:5]([NH:4][C:2](=[O:3])[CH3:1])=[C:6]2[C:7]=1[CH:15]=[CH:16][NH:12]2
Reactant: CC(=O)Nc1ccc(F)cc1[N+](=O)[O-]
Reactant: C=C[Mg]Br
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(F)c2cc[nH]c12
Temperature: -78 °C
Reaction time: 2 h

Procedure:
4-Fluoro-2-nitroacetanilide (1 eq.) was dissolved in dry THF. After the solution was cooled down to −78° C., an excess of vinyl magnesium bromide (3-4 eq.) was added. Then, the reaction was kept below −40° C. for two hours before quenched with 20% NH4Cl. The aqueous phase was extracted with EtOAc. The combined organic layer was dried over MgSO4. After filtration and concentration, the crude product was purified by silica gel column chromatography to afford N-(4-fluoro-1H-indol-7-yl)acetamide. MS m/z: (M+H)+ calc'd for C10H10FN2O: 193.08. Found 193.09. HPLC retention time: 1.29 minutes (column E, solvent system II).
Reaction SMILES: S(=O)(=O)(O)[OH:2].[NH2:6][C:7]1[N:11]([C:12]2[C:17]([Cl:18])=[CH:16][C:15]([C:19]([F:22])([F:21])[F:20])=[CH:14][C:13]=2[Cl:23])[N:10]=[C:9]([C:24]([F:27])([F:26])[F:25])[C:8]=1[C:28]#[N:29]>>[NH2:6][C:7]1[N:11]([C:12]2[C:17]([Cl:18])=[CH:16][C:15]([C:19]([F:20])([F:21])[F:22])=[CH:14][C:13]=2[Cl:23])[N:10]=[C:9]([C:24]([F:27])([F:26])[F:25])[C:8]=1[C:28](=[O:2])[NH2:29]
Reactant: O=S(=O)(O)O
Reactant: N#Cc1c(C(F)(F)F)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Product: NC(=O)c1c(C(F)(F)F)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Reaction time: 1 h

Procedure:
To stirred 80% sulphuric acid (22 ml) was added 5-amino-4-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-3-trifluoromethylpyrazole (3.98 g) at 80° C. After 1 hour, the cooled solution was poured onto ice and extracted with dichloromethane (3×). The combined extracts were washed with water, dried over anhydrous magnesium sulphate, filtered, and evaporated in vacuo to give a white solid. This solid was recrystallized from ethyl acetate-petroleum ether to give 5-amino-4-carbamoyl-1-(2,6-dichloro-4-trifluoromethylphenyl)-3-trifluoromethylpyrazole (3.5 g), m.p. 169°-171° C. in the form of white crystals.
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6](=[O:35])[CH2:7][C:8]1[C:17]([CH3:18])=[C:16]([C:19]2[CH:24]=[CH:23][C:22]([S:25]([N:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)(=[O:27])=[O:26])=[CH:21][CH:20]=2)[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([F:34])[CH:14]=2)[CH:9]=1.C1COCC1.O>CCCCCC>[F:34][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH2:7][C:6]([OH:35])=[O:5])[C:17]([CH3:18])=[C:16]2[C:19]1[CH:20]=[CH:21][C:22]([S:25]([N:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)(=[O:26])=[O:27])=[CH:23][CH:24]=1
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(-c2ccc(S(=O)(=O)N3CCCCC3)cc2)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(CC(=O)O)cc2ccc(F)cc2c1-c1ccc(S(=O)(=O)N2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.7 %

Procedure:
Lithium hydroxide monohydrate (0.06 g, 1.6 mmol) was added to a stirred solution of {6-fluoro-3-methyl-4-[4-(piperidine-1-sulfonyl)-phenyl]-naphthalen-2-yl}-acetic acid methyl ester (0.186 g, 0.39 mmol) in a 3:1 mixture of THF—H2O mixture (16 mL). The reaction mixture was stirred for 16 hours at room temperature. The reaction mixture was concentrated to remove THF, and the crude material was diluted with water, acidified [pH˜2] with a 6 N aqueous solution of hydrochloric acid. The mixture was extracted twice with ethyl acetate. The collected organic layers were washed with water and brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product. Trituration with hexane afforded {6-fluoro-3-methyl-4-[4-(piperidine-1-sulfonyl)-phenyl]-naphthalen-2-yl}-acetic acid (0.17 g, 94%) as a solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.39-12.68 (br. s, 1 H), 8.02 (dd, J=8.80, 6.20 Hz, 1 H), 7.88-7.92 (m, 3 H), 7.52 (d, J=8.31 Hz, 2 H), 7.39 (td, J=8.80, 2.40 Hz, 1 H), 6.71 (dd, J=11.00, 2.00 Hz, 1 H), 3.85 (s, 2 H), 3.01 (m, 4 H), 2.07 (s, 3 H), 1.54-1.64 (m, 4 H), 1.39-1.47 (m, 2 H). MS calcd. for C24H23FNO4S [(M−H)−] 440, obsd. 440.3.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([CH2:11][S:12][C:13]2[NH:14][CH:15]=[CH:16][N:17]=2)=[C:9](Br)[N:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:7]=1)=[O:5])[CH3:2].CN(C)CC(O)=O.C([O-])([O-])=O.[K+].[K+]>CS(C)=O.C(Cl)Cl>[C:19]1([N:8]2[C:9]3[N:17]4[CH:16]=[CH:15][N:14]=[C:13]4[S:12][CH2:11][C:10]=3[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[N:7]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCOC(=O)c1nn(-c2ccccc2)c(Br)c1CSc1ncc[nH]1
Agent: CN(C)CC(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CS(C)=O
Product: CCOC(=O)c1nn(-c2ccccc2)c2c1CSc1nccn1-2
Temperature: 180 °C

Procedure:
Ethyl-5-bromo-4-[(1H-imidazol-2ylthio) methyl]-1-phenyl-1H-pyrazole-3-carboxylate (0.3 g, 0.74 mmol, 1 eq), Cul (14 mg, 0.074 mmol, 0.1 eq), N,N-dimethylglycine (15 mg, 0.147 mmol, 0.2 eq), K2CO3 (0.2 g, 1.47 mmol, 2 eq) are taken in DMSO (6 mL) heated at 180° C. for 0.5 h under microwave irradiation. The reaction mixture is diluted with DCM and filtered through a pad of celite. The filtrate is partitioned between DCM and water. The organic layer is washed with brine, dried over Na2SO4 and concentrated. The crude is purified by flash chromatography to afford the title compound. 1H NMR (DMSO-d6, 400 MHz): δ 7.67-7.59 (m, 5H), 6.93 (d, J=1.5 Hz, 1H), 6.48 (d, J=1.4 Hz, 1H), 4.40 (s, 2H), 4.34 (q, J=7.7 Hz, 2H), 1.31 (t, J=7.7 Hz, 3H). MS (ESI+): 313.2. HPLC (max plot) 97.73%; Rt 2.73 min.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1.[CH3:12][O:13]C(Cl)Cl>[Ti](Cl)(Cl)(Cl)Cl.C(Cl)Cl>[CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[CH:12]=[O:13]
Reactant: COC(Cl)Cl
Reactant: Cc1ccc2ccccc2c1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: Cc1ccc2ccccc2c1C=O

Procedure:
By the method of Preparation 1, except that a reaction time of 1 hour at 0° C. was employed, 2-methylnaphthalene (10 g., 0.070 mole) in 200 ml. of methylene chloride was reacted with titanium tetrachloride (52.6 g., 30.5 ml., 0.28 mole) and 1,1-dichloromethyl methyl ether (24.1 g., 0.21 mole). The crude product, obtained as an oil, was distilled, yielding 12.2 g. of distillate b.p. 155°-160° C./2.3-3.0 mm. On standing, crystalline product separated from the distillate. Filtration gave purified 2-methyl-1-naphthaldehyde (0.53 g., m.p. 48°-50° C.).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH:4]([N:6]1[C:19]2[CH:18]=[C:17]([C:20]#[N:21])[CH:16]=[CH:15][C:14]=2[S:13][C:12]2[C:7]1=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH3:5].C(=O)([O-])O.[Na+].Br[CH2:28][CH2:29][OH:30]>CN(C)C=O>[CH3:1][N:2]([CH2:3][CH:4]([N:6]1[C:19]2[CH:18]=[C:17]([C:20]#[N:21])[CH:16]=[CH:15][C:14]=2[S:13][C:12]2[C:7]1=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH3:5])[CH2:28][CH2:29][OH:30]
Reactant: OCCBr
Reactant: CNCC(C)N1c2ccccc2Sc2ccc(C#N)cc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(CN(C)CCO)N1c2ccccc2Sc2ccc(C#N)cc21

Procedure:
A suspension of 10-[(2RS)-1-methylamino-2-propyl]-2-phenothiazinecarbonitrile (3.7 g), sodium hydrogen carbonate (1.6 g) and 2-bromoethanol (0.9 cc) in dimethylformamide (60 c ) is heated under reflux for 6 hours 15 minutes. After cooling, the mixture is concentrated to dryness under reduced pressure (5 mm Hg; 0.68 kPa) at 40° C. The residue is taken up with ethyl acetate (100 cc), washed successively with distilled water (2×50 cc) and with saturated aqueous sodium chloride solution (50 cc), dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. The residual orange oil (4.4 g) is purified by chromatography on a column (height: 35 cm; diameter: 2.6 cm) of silica gel (0.2-0.063 mm), eluting with a mixture (70:30 by volume) (1.25 liters) of ethyl acetate and cyclohexane and collecting 50-cc fractions. The combined fractions 9 to 22 are concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. 10-{(2RS)-1-[N-methyl-N-(2-hydroxyethyl)amino]-2-propyl}-2-phenothiazinecarbonitrile (3.1 g) is thereby obtained in the form of a yellow oil.
Reaction SMILES: Cl.[CH2:2]([N:9]1[CH2:14][CH2:13][O:12][CH:11]([C:15]([OH:17])=O)[CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.O.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.O[N:61]=[C:62]([NH2:69])[C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1>CN(C)C=O.O>[CH2:2]([N:9]1[CH2:14][CH2:13][O:12][CH:11]([C:15]2[O:17][N:69]=[C:62]([C:63]3[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=3)[N:61]=2)[CH2:10]1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: NC(=NO)c1ccccc1
Reactant: O=C(O)C1CN(Cc2ccccc2)CCO1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: c1ccc(CN2CCOC(c3nc(-c4ccccc4)no3)C2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77 %

Procedure:
To a stirred solution of 4-benzyl-2-morpholinecarboxylic acid hydrochloride (intermediate 20, 1.5 g, 5.82 mmol) in N,N-dimethylformamide (10 ml) was added 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluroniumtetrafluoroborate (2.2 g, 6.98 mmol), 1-hydroxybenzotriazole hydrate (236 mg, 1.74 mmol) and N,N-diisopropylethylamine (5.1 ml, 29.1 mmol), and the reaction mixture was stirred at room temperature for 30 minutes. After the addition of N′-hydroxybenzamidine (792 mg, 5.82 mmol), the reaction mixture was stirred at room temperature for one hour, and then heated to 110° C. When the reaction was complete (checked by thin layer chromatography), excess reagent was decomposed by the addition of water and the aqueous layer was extracted with ethyl acetate. The extract was washed with water and brine, dried over magnesium sulfate, and concentrated in vacuo. The resulting residue was purified by column chromatography on silica gel, (eluent; 25% ethyl acetate in hexane) to afford 4-benzyl-2-(3-phenyl-1,2,4-oxadiazol-5-yl)morpholine (intermediate 21, 1.44 g, 77%) as a colorless oil.
Reaction SMILES: [CH2:1]([CH:3]1[CH:20]([OH:21])[CH:19]([CH3:22])[CH:18]=[C:17]([CH3:23])[CH:16]=[C:15]([O:24][CH3:25])[C:14](=[O:26])[O:13][CH:12]([CH:27]([CH:29]([OH:48])[CH:30]([CH3:47])/[C:31](=[N:41]\[O:42][CH2:43][C:44](O)=[O:45])/[CH:32]=[CH:33]/[CH:34]([CH3:40])[CH:35]([OH:39])/[CH:36]=[CH:37]/[CH3:38])[CH3:28])[CH:11]([O:49][CH3:50])[CH:10]=[CH:9][CH:8]=[C:7]([CH3:51])[CH2:6][CH:5]([CH3:52])[CH:4]1[OH:53])[CH3:2].C1C=CC2N(O)N=NC=2C=1.[N:64]1([CH:70]2[CH2:75][CH2:74][NH:73][CH2:72][CH2:71]2)[CH2:69][CH2:68][CH2:67][CH2:66][CH2:65]1.O>ClCCl>[N:64]1([CH:70]2[CH2:75][CH2:74][N:73]([C:44](=[O:45])[CH2:43][O:42]/[N:41]=[C:31](/[CH:32]=[CH:33]/[CH:34]([CH3:40])[CH:35]([OH:39])/[CH:36]=[CH:37]/[CH3:38])\[CH:30]([CH3:47])[CH:29]([OH:48])[CH:27]([CH:12]3[O:13][C:14](=[O:26])[C:15]([O:24][CH3:25])=[CH:16][C:17]([CH3:23])=[CH:18][CH:19]([CH3:22])[CH:20]([OH:21])[CH:3]([CH2:1][CH3:2])[CH:4]([OH:53])[CH:5]([CH3:52])[CH2:6][C:7]([CH3:51])=[CH:8][CH:9]=[CH:10][CH:11]3[O:49][CH3:50])[CH3:28])[CH2:72][CH2:71]2)[CH2:69][CH2:68][CH2:67][CH2:66][CH2:65]1
Reactant: C1CCN(C2CCNCC2)CC1
Reactant: C/C=C/C(O)C(C)/C=C/C(=N/OCC(=O)O)C(C)C(O)C(C)C1OC(=O)C(OC)=CC(C)=CC(C)C(O)C(CC)C(O)C(C)CC(C)=CC=CC1OC
Agent: C/C=C/C(O)C(C)/C=C/C(=N/OCC(=O)N1CCC(N2CCCCC2)CC1)C(C)C(O)C(C)C1OC(=O)/C(OC)=C/C(C)=C/C(C)C(O)C(CC)C(O)C(C)C/C(C)=C/C=C/C1OC
Agent: C/C=C/C(O)C(C)/C=C/C(=N/OCC(=O)O)C(C)C(O)C(C)C1OC(=O)/C(OC)=C/C(C)=C/C(C)C(O)C(CC)C(O)C(C)C/C(C)=C/C=C/C1OC
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: C/C=C/C(O)C(C)/C=C/C(=N/OCC(=O)N1CCC(N2CCCCC2)CC1)C(C)C(O)C(C)C1OC(=O)C(OC)=CC(C)=CC(C)C(O)C(CC)C(O)C(C)CC(C)=CC=CC1OC
Reaction time: 0.33 h

Procedure:
To a solution of compound of example 10 (10 mg) in dichloromethane (2 mL) dicyclohexylcarbodiimide (3 mg), and HOBT (2 mg) were added. After 20 min, 4-piperidino-piperidine 2.5 mg) was added. The reaction mixture was stirred for 18 h under nitrogen atmosphere. Cold water was added to the reaction mixture, the organic layer was separated; Reaction mixture was extracted with dichloromethane (3×5 mL). The combined organic layer was washed with water (2×5 mL). The organic layer was dried over sodium sulphate, and was concentrated. The crude product was purified by preparative HPLC [Eurospere-100, C18 column (250 mm×8 mm), mobile phase: acetonitrile-water (1:1 isocratic)] to obtain the title compound.
Reaction SMILES: O=[C:2]1[O:7][CH:6]=[C:5]([C:8]([O:10]C)=[O:9])[CH:4]=[CH:3]1.[CH3:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH:15]([NH2:19])[CH2:14]1.CO.[Li+].[OH-]>C1COCC1>[CH3:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH:15]([N:19]2[C:2](=[O:7])[CH:3]=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[CH:6]2)[CH2:14]1
Reactant: CC1CCCC(N)C1
Reactant: COC(=O)c1ccc(=O)oc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC1CCCC(n2cc(C(=O)O)ccc2=O)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 21.3 %

Procedure:
A solution of methyl 6-oxo-6H-pyran-3-carboxylate (620 mg, 4.0 mmol, Aldrich) and 3-methylcyclohexanamine (900 mg, 8.0 mmol, Pfaltz and Bauer) was heated in the Emry's optimizer microwave at 150° C. for 15 min. The resulting solution was transferred to a 50 mL round bottom flask with THF, then diluted with THF:MeOH to give approximately 40 mL of a 3:1 THF:MeOH solution. Add 1 M LiOH (6 mL, 6 mmol) and stir at RT overnight. The solution was concentrated in vacuo and the residue taken up in H2O. The aqueous solution was extracted with ether (30 mL). 2 N HCl was added to acidify the aqueous solution to pH 2. The aqueous solution was extracted with EtOAc (3×) and the combined EtOAc layers dried over MgSO4, and concentrated in vacuo to give 200 mg (21%) of the desired product as a light brown residue. MS m/z: 612.5 (M+1).
Reaction SMILES: [C:1]([N:20]1[CH:24]=[C:23]([CH:25]=[O:26])[N:22]=[CH:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[C:28]([O:31][CH2:32][CH3:33])(=[O:30])[CH3:29]>O1CCCC1>[OH:26][CH:25]([C:23]1[N:22]=[CH:21][N:20]([C:1]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:24]=1)[CH2:29][C:28]([O:31][CH2:32][CH3:33])=[O:30]
Reactant: O=Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: CCOC(C)=O
Agent: Cl
Solvent: C1CCOC1
Product: CCOC(=O)CC(O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reaction time: 0.42 h
Yield: 92 %

Procedure:
Under argon atmosphere, 5.6 mL (2.96 mmol, 1 equivalent) of the solution of ethyl bromozincacetate in tetrahydrofuran obtained in Example 43 was added dropwise to a solution of 1 g (2.96 mmol) of 1-trityl-1H-imidazol-4-carbaldehyde in 10 mL of THF at 3˜6° C. The mixture was stirred at 0˜5° C. for 1 hour and 25 minutes. 5.6 mL (2.96 mmol, 1 equivalent) of the solution of ethyl bromozincacetate in tetrahydrofuran obtained in Example 43 was added dropwise at 0˜3° C. The mixture was stirred at 2˜3° C. for 5 hours and 30 minutes. 5 mL of 1N hydrochloric acid was added dropwise at 20° C. or lower, followed by dilution with 30 mL of ethyl acetate. Then, the layers were separated. The organic layer was washed successively with 5 mL of 1N hydrochloric acid, 5 mL of water, 5 mL (×2) of an aqueous saturated sodium bicarbonate solution, and 5 mL (×2) of an aqueous saturated sodium chloride solution. After washing, the organic layer was dried with anhydrous magnesium sulfate. After concentration under reduced pressure, recrystallization with 3 mL of IPE afforded 1.16 g of the desired product (yield 92%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=[N:22][O:23][CH3:24])[CH2:10][N:11]1C(=O)C2=CC=CC=C2C1=O.O.NN.O>C(O)C>[CH3:24][O:23][N:22]=[C:9]([C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1])[CH2:10][NH2:11]
Reactant: CON=C(CN1C(=O)c2ccccc2C1=O)c1ccc(Cl)cc1Cl
Agent: NN
Solvent: O
Solvent: CCO
Product: CON=C(CN)c1ccc(Cl)cc1Cl
Temperature: 60 °C
Reaction time: 2 h
Yield: 83.8 %

Procedure:
To 316 mg of N-[2-(2,4-dichlorophenyl)-2-(methoxyimino)ethyl]phthalimide in 10 ml of ethanol, 108 mg of hydrazine monohydrate was added, and the mixture was stirred at 60° C. for 2 hours. After completion of the reaction, the reaction mixture was allowed to cool to room temperature, mixed with 30 ml of water and extracted with ethyl acetate (40 ml×1). The resulting organic layer was dried over saturated aqueous sodium chloride and then anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain 170 mg of the desired crude product as a colorless oil. The oil was used in the next step without further purification.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][C:8]=2[C:16]2[C:17]3[CH:26]=[CH:25][NH:24][C:18]=3[C:19](=[O:23])[N:20]([CH3:22])[CH:21]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.CN1C=C(C2C=C([N+]([O-])=O)C=CC=2OC2C=CC=CC=2)C2C=CNC=2C1=O>>[NH2:13][C:10]1[CH:11]=[CH:12][C:7]([O:6][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)=[C:8]([C:16]2[C:17]3[CH:26]=[CH:25][NH:24][C:18]=3[C:19](=[O:23])[N:20]([CH3:22])[CH:21]=2)[CH:9]=1
Reactant: Cn1cc(-c2cc([N+](=O)[O-])ccc2OC2CCCC2)c2cc[nH]c2c1=O
Agent: Cn1cc(-c2cc([N+](=O)[O-])ccc2Oc2ccccc2)c2cc[nH]c2c1=O
Product: Cn1cc(-c2cc(N)ccc2OC2CCCC2)c2cc[nH]c2c1=O

Procedure:
Example 58b was prepared according to the procedure used for the preparation of Example 3, substituting the product of Example 58a for the product of Example 2b, to provide the title compound.
Reaction SMILES: [NH2:1][C@:2]1([C:14]([O:16][CH3:17])=[O:15])[CH2:6][CH2:5][C@@H:4]([C:7]2[CH:12]=[CH:11][C:10](Br)=[CH:9][CH:8]=2)[CH2:3]1.C(O)(=O)[C@@H]([C@H](C(O)=O)O)O.N1CCCCC1.[CH2:34]([O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:35]#[CH:36].C1C=CC=CC=1>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[NH2:1][C@:2]1([C:14]([O:16][CH3:17])=[O:15])[CH2:6][CH2:5][C@@H:4]([C:7]2[CH:12]=[CH:11][C:10]([C:36]#[C:35][CH2:34][O:37][CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)=[CH:9][CH:8]=2)[CH2:3]1
Reactant: COC(=O)[C@@]1(N)CC[C@@H](c2ccc(Br)cc2)C1
Reactant: C#CCOCc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Solvent: C1CCNCC1
Solvent: C1CCOC1
Solvent: c1ccccc1
Product: COC(=O)[C@@]1(N)CC[C@@H](c2ccc(C#CCOCc3ccccc3)cc2)C1
Yield: 86 %

Procedure:
A round bottomed flask was charged with (1R,3R)-methyl 1-amino-3-(4-bromophenyl)cyclopentanecarboxylate, 0.5 L-tartaric acid 2 (30 g, 80 mmol), copper(I) iodide (0.153 g, 0.804 mmol), bis(triphenylphosphine)palladium(II) dichloride (2.82 g, 4.02 mmol) and THF (200 mL). The reaction mixture was purged with nitrogen. After about 15 minutes piperidine (35.8 mL, 362 mmol) and ((prop-2-ynyloxy)methyl)benzene (11.75 g, 80 mmol) were added and the reaction mixture was heated to about 65°. After about 2 hours additional (prop-2-ynyloxy)methyl)benzene (11.75 g, 80 mmol) was added. After about 8 hours the crude reaction mixture was partitioned between EtOAc and saturated NaHCO3. The organic layer was washed with brine, dried (Na2SO4) filtered, concentrated in vacuo and purified by flash chromatography on silica gel (eluting with EtOAC/Heptane followed by EtOAc/MeOH) to provide (1R,3R)-methyl 1-amino-3-(4-(3-(benzyloxy)prop-1-ynyl)phenyl)cyclopentanecarboxylate (25 g, 68.8 mmol, 86% yield) as a brown oil.
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[O:12][C@@H:13]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14]1.O[C@@H]1CCN(C(OC(C)(C)C)=O)C1.NN>CO>[NH2:3][O:12][C@@H:13]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14]1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](ON2C(=O)c3ccccc3C2=O)C1
Agent: CC(C)(C)OC(=O)N1CC[C@@H](O)C1
Agent: NN
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC[C@@H](ON)C1
Reaction time: 2 h
Yield: 78.3 %

Procedure:
To (R)-tert-butyl 3-((1,3-dioxoisoindolin-2-yl)oxy)pyrrolidine-1-carboxylate (2.73 g, 8.21 mmol) prepared following a procedure analogous to Reference Example 7 from (R)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate in methanol (43 mL) was gradually added hydrazine.monohydrate (1.54 g), followed by stirring for 2 hours. The reaction solution was filtered, and the residue resulting from distilling off the filtrate under reduced pressure was subjected to silica gel column chromatography (hexane/ethyl acetate=4/1→0/1) to afford 1.30 g of the title compound (yield 78.3%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.O1CCOC[CH2:15]1>CO>[F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([O:12][CH3:15])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Reactant: C1COCCO1
Agent: Cl
Solvent: CO
Product: COC(=O)Cc1cc(F)cc(F)c1

Procedure:
A solution of 5.0 g (29.1 mmol) of 3,5-difluorophenylacetic acid and a solution of 20 mL (80 mmol) of HCl in dioxane (4M) in 60 mL of methanol was heated at reflux for 6 h. After cooling, the solution was concentrated and the residue poured into 200 mL of ether/ethyl acetate (1/1). The organic layer was washed with 20 mL of water, dried over Na2S04 and concentrated to afford the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:7]([O:8][C:9]2[C:10]([NH:22][C:23]3[S:27][N:26]=[C:25]([C@@:28]4([CH3:35])[CH2:32][O:31]C(C)(C)[O:29]4)[N:24]=3)=[N:11][CH:12]=[C:13]([S:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[CH:14]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[ClH:36]>CCO>[ClH:36].[CH3:1][C:2]1[C:7]([O:8][C:9]2[C:10]([NH:22][C:23]3[S:27][N:26]=[C:25]([C@@:28]([OH:29])([CH3:35])[CH2:32][OH:31])[N:24]=3)=[N:11][CH:12]=[C:13]([S:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[CH:14]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Cc1ncccc1Oc1cc(Sc2ccccn2)cnc1Nc1nc([C@@]2(C)COC(C)(C)O2)ns1
Agent: Cl
Solvent: CCO
Product: Cc1ncccc1Oc1cc(Sc2ccccn2)cnc1Nc1nc([C@](C)(O)CO)ns1
Temperature: 25 °C
Reaction time: 24 h
Yield: 63.9 %

Procedure:
(S)-N-(3-(2-methylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-yl)-3-(2,2,4-trimethyl-1,3-dioxolane-4-yl)-1,2,4-thiadiazol-5-amine (55 mg, 0.108 mmol) was dissolved in EtOH (3 mL). 1M HCl (0.3 mL) was added and the mixture was stirred at ambient temperature for 24 hours. Additional 1M HCl (0.3 mL) was added and the mixture was stirred overnight. The mixture was partitioned between saturated aqueous sodium bicarbonate and CH2Cl2, dried over sodium sulfate, filtered and concentrated. The residue was purified over silica gel (15% methanol in EtOAc) to afford (S)-2-(5-(3-(2-methylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)propane-1,2-diol hydrochloride (34.9 mg, 0.0691 mmol, 63.9% yield) as a white solid after HCl salt formation. Mass Spectrum (apci) m/z=451.1 (M+H−H2O−HCl) (100) and 469.1 (M+H−HCl) (30).
Reaction SMILES: C([NH2:8])C1C=CC=CC=1.[O:9]1[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:10]1>>[NH2:8][CH2:10][CH:11]([OH:9])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: NCc1ccccc1
Reactant: CCCCCCCCCCCCCCCCC1CO1
Product: CCCCCCCCCCCCCCCCC(O)CN
Temperature: 100 °C
Reaction time: 12 h
Yield: 83.1 %

Procedure:
A 500-ml flask equipped with a stirrer was charged with 160 g (1.5 mol) of benzylamine, to which 29 g (0.11 mol) of 1,2-epoxyoctadecane were added dropwise over 3 hours while stirring at 100° C. Stirring was conducted further for 12 hours at 100° C. Benzyl alcohol was distilled off under reduced pressure, and the residue was charged into a 500-ml autoclave, to which 300 ml of ethanol and 10 g of 5% Pd/C were added to conduct hydrogenolysis for 48 hours at room temperature under a hydrogen pressure of 5 atm. After the catalyst was separated by filtration, the filtrate was concentrated under reduced pressure, and the residue was recrystallized from hexane, thereby obtaining 26.1 g (yield: 83%) of the title compound (IIh-7).