Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][CH3:3].F[C:5]1[CH:19]=[CH:18][C:8]([C:9]([C:11]2[S:15][C:14](=[O:16])[NH:13][C:12]=2[CH3:17])=[O:10])=[CH:7][CH:6]=1>C(O)C>[CH3:1][N:2]([CH3:3])[C:5]1[CH:19]=[CH:18][C:8]([C:9]([C:11]2[S:15][C:14](=[O:16])[NH:13][C:12]=2[CH3:17])=[O:10])=[CH:7][CH:6]=1
Reactant: CNC
Reactant: Cc1[nH]c(=O)sc1C(=O)c1ccc(F)cc1
Solvent: CCO
Product: Cc1[nH]c(=O)sc1C(=O)c1ccc(N(C)C)cc1
Temperature: 120 °C
Reaction time: 16 h

Procedure:
Dimethylamine (100 ml, 40% solution) was added to a solution of 5-(4-fluorobenzoyl)-4-methyl-2(3H)-thiazolone (4.7 g) in ethanol (200 ml). The mixture was stirred in a sealed stainless steel vessel at 120° C. for 16 hours. After cooling to ambient temperature the solvent and excess dimethylamino was evaporated. The residue was recrystallized twice from ethanol to give the title compound, mp. 224°-226° C.
Reaction SMILES: [C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@H:8]2[N:12]([C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])[C:11](=[O:19])[CH2:10][CH2:9]2)=[CH:3][CH:2]=1.[CH3:26][Si]([N-][Si](C)(C)C)(C)C.[K+].S(OC)(OC)(=O)=O>C1(C)C=CC=CC=1>[C:1]1([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:2]=[CH:3][C:4]([CH2:7][C@H:8]2[N:12]([C:13](=[O:18])[C:14]([CH3:16])([CH3:17])[CH3:15])[C:11](=[O:19])[C@H:10]([CH3:26])[CH2:9]2)=[CH:5][CH:6]=1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CC(C)(C)C(=O)N1C(=O)CC[C@H]1Cc1ccc(-c2ccccc2)cc1
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: Cc1ccccc1
Product: C[C@@H]1C[C@@H](Cc2ccc(-c3ccccc3)cc2)N(C(=O)C(C)(C)C)C1=O
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
10 g of (S)-5-biphenyl-4-ylmethyl-1-(2,2-dimethylpropionyl)pyrrolidin-2-one (1-a, R1=pivaloyl) were dissolved in 150 ml toluene. The mixture was cooled to about 0° C. and 71.5 ml potassium bis(trimethylsilyl)amide solution (0.5 M in toluene) were added. After 15 min, 11 ml dimethyl sulphate were added and the mixture was stirred for a further hour. The reaction was quenched with ammonium chloride solution and extracted with ethyl acetate. The combined organic phases were concentrated to dryness to obtain 15.3 g of crude (3R,5S)-5-biphenyl-4-ylmethyl-1-(2,2-dimethylpropionyl)-3-methylpyrrolidin-2-one. According to HNMR analysis, on the crude, the ratio of diastereoisomers is 83:17 [(3R,5S):(3S,5S)]. Spectroscopic data for (2-a, R1=Pivaloyl) is reported in Example 5-1, Method 1. Spectroscopic data for (2-b, R1=Pivaloyl) is reported in Example 5-2.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[CH2:12][C:13]1[C:22]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[O:29][CH3:30])=[CH:21][CH:20]=[C:19]2[C:14]=1[C:15]([CH3:33])=[CH:16][C:17]([CH3:32])([CH3:31])[NH:18]2.C(OCC)(=O)C>O1CCCC1>[CH2:3]([O:10][CH2:12][C:13]1[C:22]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[O:29][CH3:30])=[CH:21][CH:20]=[C:19]2[C:14]=1[C:15]([CH3:33])=[CH:16][C:17]([CH3:32])([CH3:31])[NH:18]2)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COc1ccccc1-c1ccc2c(c1CCl)C(C)=CC(C)(C)N2
Reactant: OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccccc1-c1ccc2c(c1COCc1ccccc1)C(C)=CC(C)(C)N2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 6.7 %

Procedure:
60% Sodium hydride (30 mg, 0.75 mmol) was suspended in anhydrous tetrahydrofuran (1 mL), and benzylalcohol (78 μL, 0.75 mmol) was added thereto under argon atmosphere at 0° C. After the reaction mixture was stirred at room temperature for 30 minutes, a solution of 5-chloromethyl-6-(2-methoxyphenyl)-2,2,4-trimethyl-1,2-dihydroquinoline (Reference Compound 5-1, 50 mg, 0.15 mmol) in anhydrous tetrahydrofuran solution (1.5 mL) was added thereto. The reaction mixture was stirred at 50° C. for 7 hours. After cooling down, ethyl acetate (50 mL) was added thereto. The whole was washed with water (50 mL) and saturated brine (30 mL) successively, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled compound (4.0 mg) as a colorless solid. (Yield 7%)
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]([N:9]2[C:13]([CH3:14])=[C:12]([C:15]([N:17]3[CH2:22][CH2:21][CH:20]([N:23]4[CH2:27][CH2:26][CH2:25][CH2:24]4)[CH2:19][CH2:18]3)=[O:16])[C:11]([CH3:28])=[N:10]2)[CH:6]=[CH:7][CH:8]=1.[Cl:29][C:30]1[CH:38]=[CH:37][C:33]([C:34](Cl)=[O:35])=[CH:32][CH:31]=1>>[Cl:29][C:30]1[CH:38]=[CH:37][C:33]([C:34]([NH:2][C:3]2[CH:8]=[CH:7][CH:6]=[C:5]([N:9]3[C:13]([CH3:14])=[C:12]([C:15]([N:17]4[CH2:22][CH2:21][CH:20]([N:23]5[CH2:24][CH2:25][CH2:26][CH2:27]5)[CH2:19][CH2:18]4)=[O:16])[C:11]([CH3:28])=[N:10]3)[CH:4]=2)=[O:35])=[CH:32][CH:31]=1
Reactant: Cc1nn(-c2cccc(N)c2)c(C)c1C(=O)N1CCC(N2CCCC2)CC1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: Cl
Product: Cc1nn(-c2cccc(NC(=O)c3ccc(Cl)cc3)c2)c(C)c1C(=O)N1CCC(N2CCCC2)CC1
Yield: 62 %

Procedure:
In analogy to the procedure described in Example 38E], [1-(3-amino-phenyl)-3,5-dimethyl-1H-pyrazol-4-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone hydrochloride (Example 38D]) and 4-chlorobenzoyl chloride gave the title compound in 62% yield as yellow oil. MS: 506.3 (MH+, 1 Cl).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[CH2:5][NH2:6].F[C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][N:21]=1)[C:17]#[N:18]>>[CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[CH2:5][NH:6][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][N:21]=1)[C:17]#[N:18]
Reactant: COc1ccc(CN)c(OC)c1
Reactant: N#Cc1ccnc(F)c1
Product: COc1ccc(CNc2cc(C#N)ccn2)c(OC)c1

Procedure:
The title compound was prepared according to the method described for Preparation 20 using 2,4-dimethoxybenzylamine and 2-fluoroisonicotinonitrile.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][C:8]([CH3:14])([CH3:13])[CH:7]1[O:15][CH:6]21)#[N:2].[OH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1.[OH-].C([N+](C)(C)C)C1C=CC=CC=1.O>O1CCOCC1>[C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][C:8]([CH3:14])([CH3:13])[C@@H:7]([OH:15])[C@@H:6]2[N:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]1=[O:16])#[N:2]
Reactant: Oc1ccccn1
Reactant: CC1(C)Oc2ccc(C#N)cc2C2OC21
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC1(C)Oc2ccc(C#N)cc2[C@@H](n2ccccc2=O)[C@@H]1O

Procedure:
1 g of 6-cyano-2,2-dimethyl-3,4-epoxychromane is refluxed for 40 hours with I g of 2-hydroxypyridine in 10 ml of dioxane, in the presence of 0.20 ml of a methanolic solution containing 35% of benzyltrimethylammonium hydroxide. The mixture is taken up with 30 ml of water and the precipitate obtained is-filtered off, washed with isopropyl ether and then recrystallized from 20 ml of absolute ethyl alcohol to give 0.9 g of the expected product.
Reaction SMILES: [S:1]1[CH:5]=[C:4]([CH2:6][CH2:7][CH2:8][OH:9])[N:3]=[CH:2]1.CCN(C(C)C)C(C)C.[CH3:19][C:20]([Si:23](Cl)([CH3:25])[CH3:24])([CH3:22])[CH3:21]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Si:23]([O:9][CH2:8][CH2:7][CH2:6][C:4]1[N:3]=[CH:2][S:1][CH:5]=1)([C:20]([CH3:22])([CH3:21])[CH3:19])([CH3:25])[CH3:24]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCCCc1cscn1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCCCc1cscn1
Yield: 90.8 %

Procedure:
A sol. of 3-thiazol-4-yl-propan-1-ol (610 mg, 4.26 mmol), DIPEA (1.82 mL, 10.7 mmol), DMAP (catalytic amount) and TBDMS-Cl (964 mg, 6.40 mmol) in CH2Cl2 (12 mL) was stirred at rt for 1 h. The mixture was diluted with more CH2Cl2, and washed with aq. 1M HCl, aq. sat. NaHCO3, and brine. The org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (EtOAc/heptane 1:9→2:8→1:1) yielded the title compound (996 mg, 91%). LC-MS: tR=1.06, ES+: 258.18.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][OH:26]>CN(C=O)C>[N:5]1[CH:6]=[CH:7][C:2]([O:1][CH:25]([OH:26])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH3:15])=[CH:3][CH:4]=1
Reactant: OCCCCCCCCCCCBr
Reactant: Oc1ccncc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCC(O)Oc1ccncc1
Temperature: 90 °C
Yield: 21.9 %

Procedure:
The compound 4-pyridyloxyundecan-1-ol was prepared as follows: To a solution of 4-hydroxy-pyridine (5.71 g, 60 mmol) in DMF (150 cm3) was added cesium carbonate (19.56 g, 60 mmol). The mixture was heated to 90° C. for 5 mins then 11-bromoundecanol (12.56 g, 50 mmol) was added and the mixture heated to reflux temperature (125° C.) for 15 hours. After cooling, the contents of the flask were poured into rapidly stirring distilled water (800 cm3). A pale yellow precipitate formed which was filtered and dried (in air). Recrystallization from hexane gave white crystals of 4-pyridyloxyundecan-1-ol (2.9 g, 22%).
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][C:6]([Cl:14])=[CH:7][CH:8]=2)[N:3]=1.C1C=C[NH+]=CC=1.C1C=C[NH+]=CC=1.[O-:27][Cr](O[Cr]([O-])(=O)=O)(=O)=O.CN(C=O)C>O>[Cl:1][C:2]1[C:11]([C:12]([OH:27])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][C:6]([Cl:14])=[CH:7][CH:8]=2)[N:3]=1
Reactant: O=Cc1cc2ccc(Cl)cc2nc1Cl
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)c1cc2ccc(Cl)cc2nc1Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 84.3 %

Procedure:
A dry reaction flask equipped with a magnetic stirring bar and a rubber septum was charged with 2,7-dichloro-3-formylquinoline 3 (1.1 g, 5 mmol), PDC (3.76 g, 10 mmol) and dry DMF (5 mL) and stirred at room temperature for 24 h. The reaction mixture was diluted with water (500 mL), filtered, the filtrate was saturated with NaCl and the resulting aqueous solution was extracted with EtOAc (3×200 mL). The EtOAc extract was dried over anhydrous Na2SO4 and solvent was removed to give 1.02 g (85%) of the desired 2,7-dichloroquinoline-3-carboxylic acid 4. TLC Rf: 0.12 (20% MeOH/EtOAc); 1H NMR (acetone d6): 8.96 (s, 1H); 8.22 (d, 1H, J=9.0 Hz), 8.04 (d, 1H, J=1.8 Hz), 7.97 (bs, 1H), 7.74 (dd, 1H, J=1.8 and 8.7 Hz); LCMS (ret. time): 25.15 min.; MS (m/z): 241 (MH+).
Reaction SMILES: CC(C)([O-])C.[K+].C([NH:10][OH:11])(=O)C.[F:12][CH:13]([F:24])[O:14][C:15]1[CH:22]=[CH:21][CH:20]=[C:19](F)[C:16]=1[C:17]#[N:18]>CN(C)C=O>[NH2:18][C:17]1[C:16]2[C:15]([O:14][CH:13]([F:24])[F:12])=[CH:22][CH:21]=[CH:20][C:19]=2[O:11][N:10]=1
Reactant: CC(=O)NO
Reactant: N#Cc1c(F)cccc1OC(F)F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1noc2cccc(OC(F)F)c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
8.00 g (71.29 mmol) of potassium tert-butoxide and 5.20 g (69.27 mmol) of acetohydroxamic acid are dissolved in 50 ml of dry dimethylformamide and stirred at room temperature for 1 hour. After the addition of 4.40 g (23.51 mmol) of 2-(difluoromethoxy)-6-fluorobenzonitrile, the mixture is stirred first at room temperature for 3 hours and then at 60° C. for 16 hours. The mixture is concentrated under reduced pressure, the residue is stirred with water and the pale olive-coloured precipitate is filtered off with suction. This gives 4.4 g of product, which, according to LC-MS, is about 89% pure.
Reaction SMILES: [CH3:1][C:2]1([OH:39])[CH:25]=[C:24]2[C@:19]([CH3:37])([CH2:20][CH2:21][C@H:22]([O:26][Si:27]([CH:34]([CH3:36])[CH3:35])([CH:31]([CH3:33])[CH3:32])[CH:28]([CH3:30])[CH3:29])[CH2:23]2)[C@@H:18]2[C@@H:3]1[C@H:4]1[C@:15]([CH3:38])([CH2:16][CH2:17]2)[C@@H:7]([C@H:8]([CH3:14])[CH2:9][CH2:10][C:11]([OH:13])=[O:12])[CH2:6][CH2:5]1.[CH3:40][Si](C=[N+]=[N-])(C)C.N#N>C1(C)C=CC=CC=1.CO>[OH:39][C:2]1([CH3:1])[CH:25]=[C:24]2[C@:19]([CH3:37])([CH2:20][CH2:21][C@H:22]([O:26][Si:27]([CH:28]([CH3:30])[CH3:29])([CH:31]([CH3:32])[CH3:33])[CH:34]([CH3:36])[CH3:35])[CH2:23]2)[C@@H:18]2[C@@H:3]1[C@H:4]1[C@:15]([CH3:38])([CH2:16][CH2:17]2)[C@@H:7]([C@H:8]([CH3:14])[CH2:9][CH2:10][C:11]([O:13][CH3:40])=[O:12])[CH2:6][CH2:5]1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CC(C)[Si](O[C@H]1CC[C@@]2(C)C(=CC(C)(O)[C@H]3[C@@H]4CC[C@H]([C@H](C)CCC(=O)O)[C@@]4(C)CC[C@@H]32)C1)(C(C)C)C(C)C
Agent: N#N
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@H]3[C@H](CC[C@]12C)[C@@]1(C)CC[C@H](O[Si](C(C)C)(C(C)C)C(C)C)CC1=CC3(C)O

Procedure:
To a solution of 7-hydroxy-7-methyl-3β-triisopropylsilyl-oxychol-5-en-24-oic acid (5) (5.38 g, 9.68 mmoles) in toluene (70 ml) and methanol (20 ml) was added dropwise at room temperature trimethylsilyldiazomethane (2.0N in hexane, ~5 ml). After 30 minutes N2 evolution ceased, and the reaction mixture was a pale yellow. The solvent was removed in vacuo to give 4.67 g of crude 6 as a brown syrup. NMR (CDCl3) indicated a mixture of 7-isomers: δ0.69 (two peaks, 18-Me); 3.63 (s, CO2Me); 5.12 & 5.18 (6-H). The mixture was used directly in the next reaction (Example 6).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4](Cl)[N:3]=1.[CH2:17]([NH2:20])[CH2:18][CH3:19]>C(N(CC)CC)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([NH:20][CH2:17][CH2:18][CH3:19])[N:3]=1
Reactant: Clc1nc(Cl)c2ncn(C3CCCC3)c2n1
Reactant: CCCN
Solvent: CCN(CC)CC
Product: CCCNc1nc(Cl)nc2c1ncn2C1CCCC1

Procedure:
2-Chloro-6-(propylamino)-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, n-propylamine, and triethylamine essentially as described above in Example 1, Scheme A, step b.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-:13])=[O:12])[NH:4][N:3]=1.Cl.Cl[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]([CH3:25])[CH3:24])[N:18]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-:13])=[O:12])[N:4]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]([CH3:25])[CH3:24])[N:18]=2)[N:3]=1
Reactant: O=[N+]([O-])c1cccc2[nH]nc(Br)c12
Reactant: CC(C)c1cccc(CCl)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)c1cccc(Cn2nc(Br)c3c([N+](=O)[O-])cccc32)n1
Temperature: 35 °C
Reaction time: 0.33 h
Yield: 91.9 %

Procedure:
A flask was charged with 3-bromo-4-nitro-1H-indazole (64 g, 0.264 mol), 2-(chloromethyl)-6-isopropylpyridine hydrochloride (55 g, 0.264 mol), powdered potassium carbonate (91 g, 0.661 mol), and 500 mL of DMF. This mixture was warmed to 35° C. for 72 hours, then poured into 2 liters of cold water, upon which a tan solid precipitated. After stirring for 20 minutes, the solids were collected by filtration and dried under vacuum to give 91 g (92%) of 3-bromo-1-((6-isopropylpyridin-2-yl)methyl)-4-nitro-1H-indazole.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=2)[C:8]([NH:10][C:11]2[S:12][C:13]([C:16](O)=[O:17])=[CH:14][N:15]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.C[N:30]1CCOCC1.C(OC(Cl)=O)C(C)C.[OH-].[NH4+]>O1CCCC1.O>[CH:1]1([CH2:6][CH:7]([C:19]2[CH:20]=[CH:21][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:23][CH:24]=2)[C:8]([NH:10][C:11]2[S:12][C:13]([C:16]([NH2:30])=[O:17])=[CH:14][N:15]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN1CCOCC1
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2ncc(C(=O)O)s2)cc1
Agent: CC(C)COC(=O)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2ncc(C(N)=O)s2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.2 %

Procedure:
A solution of 2-[3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionylamino]-thiazole-5-carboxylic acid (100 mg, 0.24 mmol) in dry tetrahydrofuran (3 mL) under argon was treated with N-methylmorpholine (0.04 mL, 0.36 mmol) followed by iso-butylchloroformate (50 μL, 0.36 mmol). The reaction was stirred at 25° C. for 2 h, after which time, a concentrated aqueous ammonium hydroxide solution (0.2 mL) was added. The resulting reaction mixture was stirred at 25° C. for 2 h. The reaction mixture was then treated with water (5 mL), and the tetrahydrofuran was concentrated in vacuo. The product was then extracted with ethyl acetate (3×10 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70–230 mesh, 9/1 chloroform/methanol) afforded 2-[3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionylamino]-thiazole-5-carboxylic acid amide (68 mg, 67%) as a white solid: mp 155–160° C.; EI-HRMS m/e calcd for C19H23N3O4S2 (M+) 421.1130, found 421.1135.
Reaction SMILES: [C:1]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([N:16]2[CH2:21][CH2:20][O:19][CH:18]([C:22]3[N:23]=[C:24]([C:27]([F:30])([F:29])[F:28])[S:25][CH:26]=3)[CH2:17]2)[CH3:15])=[CH:9][CH:8]=1)([O:3]C)=[O:2].[OH-].[Na+].Cl>CO>[C:1]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([N:16]2[CH2:21][CH2:20][O:19][CH:18]([C:22]3[N:23]=[C:24]([C:27]([F:28])([F:29])[F:30])[S:25][CH:26]=3)[CH2:17]2)[CH3:15])=[CH:9][CH:8]=1)([OH:3])=[O:2]
Reactant: COC(=O)COc1ccc(CC(C)N2CCOC(c3csc(C(F)(F)F)n3)C2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(Cc1ccc(OCC(=O)O)cc1)N1CCOC(c2csc(C(F)(F)F)n2)C1

Procedure:
Prepared by analogy to Example 16 by reaction of N-[2-(4-carbomethoxymethoxyphenyl)-1-methylethyl]-2-(2-trifluoromethyl-thiazol-4-yl)morpholine (diastereomer B) in methanol with 1N sodium hydroxide solution. After the mixture has been neutralised with 1N hydrochloric acid it is extracted by shaking with methylene chloride, the extract is evaporated to dryness, and the remaining residue is triturated with petroleum ether and is filtered off with suction.
Reaction SMILES: [CH2:1]1[C@@H:5]([CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=O)[S:4][S:3][CH2:2]1.[CH3:13][S:14]([NH2:17])(=[O:16])=[O:15].[H-].[Na+]>CN(C)C=O>[S:3]1[CH2:2][CH2:1][C@@H:5]([CH2:6][CH2:7][CH2:8][CH2:9][C:10]([NH:17][S:14]([CH3:13])(=[O:16])=[O:15])=[O:12])[S:4]1
Reactant: O=C(O)CCCC[C@@H]1CCSS1
Reactant: CS(N)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)NC(=O)CCCC[C@@H]1CCSS1
Temperature: 25 °C
Reaction time: 4 h
Yield: 45 %

Procedure:
110 mg of (R)-α-lipoic acid were dissolved in 2 ml of anhydrous dimethylformamide, and 97 mg of N,N'-carbonyldiimidazole were added to the solution, whilst ice-cooling. The mixture was then stirred at room temperature for 4 hours. At the end of this time, 57 mg of methanesulfonamide and 26 mg of sodium hydride (as a 55% w/w dispersion in mineral oil) were added to the reaction mixture, whilst ice-cooling, and the mixture was stirred at room temperature for 5 hours and then left to stand overnight. The solvent was then removed from the reaction mixture by evaporation under reduced pressure, and water was added to the residue this obtained. The resulting mixture was neutralized by the addition of 2 N aqueous hydrochloric acid, after which it was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. The solvent was removed from the extraction solution by evaporation under reduced pressure. The residue thus obtained was purified by silica gel column chromatography, using 1:1 and 3:1 by volume mixtures of ethyl acetate and hexane as eluent, after which it was dissolved in dioxane and lyophilised, to obtain 68 mg of the title compound, melting at 71° C. to 73° C.
Reaction SMILES: [C:1]1([CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[Mg]Cl.[O:10]=[C:11]1[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12]1.[Cl-].[NH4+]>C1COCC1>[OH:10][C:11]1([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[CH3:9])[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12]1
Reactant: Cc1ccccc1[Mg]Cl
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1ccccc1C1(O)CN(C(=O)OC(C)(C)C)C1
Temperature: -78 °C
Reaction time: 1 h
Yield: 78.6 %

Procedure:
60 ml (60 mmol) of 1M ortho-tolylmagnesium chloride in THF are added dropwise to a solution of 7.4 g (43 mmol) of tert-butyl 3-oxoazetidine-1-carboxylate in 60 ml of tetrahydrofuran cooled to −78° C. After stirring for 1 h at ambient temperature, the mixture is hydrolysed with a saturated aqueous solution of ammonium chloride and then extracted with ethyl acetate. The organic phase is dried over sodium sulphate, filtered and concentrated. The beige solid obtained is purified by silica gel chromatography, elution being carried out with a 50/50 heptane/ethyl acetate mixture. 8.9 g of tert-butyl 3-hydroxy-3-o-tolylazetidine-1-carboxylate are obtained in the form of a white solid with a yield of 79%.
Reaction SMILES: C(O)(=O)C.[N:5]1[CH:10]=[CH:9][C:8]([CH:11]=O)=[CH:7][CH:6]=1.[C:13]([O:22][CH3:23])(=[O:21])[C:14]1[C:15](=[CH:17][CH:18]=[CH:19][CH:20]=1)[NH2:16].C([BH3-])#N.[Na+]>CO>[N:5]1[CH:6]=[CH:7][C:8]([CH2:11][NH:16][C:15]2[C:14](=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:13]([O:22][CH3:23])=[O:21])=[CH:9][CH:10]=1
Reactant: COC(=O)c1ccccc1N
Reactant: O=Cc1ccncc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)c1ccccc1NCc1ccncc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
3 mL Acetic acid and 8.6 g 4-pyridinecarbaldehyde are added to a solution of 7.5 g methyl anthranilate in 300 mL methanol. The mixture is stirred for 12 hours under nitrogen atmosphere at room temperature. 5.7 g Sodium cyanotrihydridoborate (85%) is added and the mixture is stirred for 3 hours at room temperature. Additional 1.14 g sodium cyanotrihydridoborate (85%) is added and the mixture is stirred for 12 hours at room temperature. The solvent is evaporated and the residue dissolved in ethyl acetate and washed with saturated NaHCO3 solution and saturated sodium chloride solution. The organic extract is concentrated and purified with hexane/ethyl acetate (1:1) on silica gel to yield methyl N-(4-pyridylmethyl)-anthranilate with m.p. 86° C.
Reaction SMILES: C([O-])(=[O:3])C.[Na+].[CH3:6][C:7]1[CH2:12][CH2:11][CH2:10][C:9]([CH3:14])([CH3:13])[C:8]=1[CH:15]([OH:19])[CH:16]=[CH:17][CH3:18].C(Cl)Cl>O>[CH3:6][C:7]12[O:3][C:8]1([CH:15]([OH:19])/[CH:16]=[CH:17]/[CH3:18])[C:9]([CH3:13])([CH3:14])[CH2:10][CH2:11][CH2:12]2
Reactant: CC(=O)[O-]
Reactant: CC=CC(O)C1=C(C)CCCC1(C)C
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: C/C=C/C(O)C12OC1(C)CCCC2(C)C

Procedure:
21 g. of 40 % percetic acid and 0.6 g. of sodium acetate were added under nitrogen to a suspension of 2,6,6-trimethyl-1-[1-hydroxy-2-butenyl]-1-cyclohexene (19.4 g.) and 12 g. of sodium acetate in 35 ml. of CH2Cl2 at 20°. The reaction mixture was left 2 more hours with stirring and it was then poured into 250 ml. of water.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:6]([CH:7]=O)[C:5]([OH:10])=[CH:4][CH:3]=1.[CH3:11][O:12][C:13]1[CH:26]=[CH:25][C:16]([NH:17][S:18]([CH2:21][C:22](O)=[O:23])(=[O:20])=[O:19])=[CH:15][CH:14]=1>C(O)(=O)C>[Br:1][C:2]1[CH:9]=[C:6]2[C:5](=[CH:4][CH:3]=1)[O:10][C:22](=[O:23])[C:21]([S:18]([NH:17][C:16]1[CH:25]=[CH:26][C:13]([O:12][CH3:11])=[CH:14][CH:15]=1)(=[O:20])=[O:19])=[CH:7]2
Reactant: COc1ccc(NS(=O)(=O)CC(=O)O)cc1
Reactant: O=Cc1cc(Br)ccc1O
Solvent: CC(=O)O
Product: COc1ccc(NS(=O)(=O)c2cc3cc(Br)ccc3oc2=O)cc1

Procedure:
A solution of 5-bromosalicylaldehyde (1 mmol) and 4-methoxyanilinosulfonyl acetic acid (1 mmol) in acetic acid (10 mL) was subjected to the General Procedure 1, Method A to yield the title compound; m.p. 182-184° C.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[C:10](OC(=O)C)(=[O:12])[CH3:11]>N1C=CC=CC=1>[C:10]([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)(=[O:12])[CH3:11]
Reactant: O=Cc1ccc(O)cc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc(C=O)cc1

Procedure:
4-Hydroxybenzaldehyde was acetylated with pyridine and acetic anhydride as in Example 12 to give 4-acetoxybenzaldehyde which was subjected to dehydration condensation with ethylene glycol to give 2-(4-acetoxyphenyl)-1,3-dioxolan. To a solution of 2-4-acetoxyphenyl)-1,3-dioxolan (13 g) in dichloromethane, bis(trimethylsilyl)-5-fluorouracil prepared as in Example 1 from 5-fluorouracil (10 g) was added followed by treating as in Example 10 to give 4.5 g of crystalline 1-[α-(2-hydroxyethoxy)-4-acetoxybenzyl]-5-fluorouracil.