Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1([Si](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC([C:14]3[CH:15]=[CH:16][C:17]4[NH:18][C:19]5[C:24]([C:25]=4[CH:26]=3)=[CH:23][C:22](C3C=CC([Si](C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)=CC=3)=[CH:21][CH:20]=5)=CC=2)C=CC=CC=1.[OH:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][O:73][C:74]1[CH:79]=[CH:78][C:77](I)=[CH:76][CH:75]=1.C(=O)([O-])[O-].[K+].[K+].[N+](C1C=CC=CC=1)([O-])=O>[Cu]>[OH:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][O:73][C:74]1[CH:79]=[CH:78][CH:77]=[CH:76][C:75]=1[C:26]1[C:25]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[NH:18][C:17]=2[CH:16]=[CH:15][CH:14]=1
Reactant: OCCCCCCCCOc1ccc(I)cc1
Reactant: c1ccc([Si](c2ccccc2)(c2ccccc2)c2ccc(-c3ccc4[nH]c5ccc(-c6ccc([Si](c7ccccc7)(c7ccccc7)c7ccccc7)cc6)cc5c4c3)cc2)cc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=[N+]([O-])c1ccccc1
Product: OCCCCCCCCOc1ccccc1-c1cccc2[nH]c3ccccc3c12

Procedure:
The 3,6-bis(4-triphenylsilylphenyl)carbazole (1.30 g), 4-(8-hydroxyoctyloxy)iodobenzene (0.65 g), potassium carbonate (0.54 g), copper powder (0.4 g) and nitrobenzene (5 mL) were stirred under nitrogen flow at 195° C. for 16 hours. The resultant mixture was filtrated through CELITE and the solvent was evaporated. The residue was treated through silica gel column chromatography (eluent: 10% ethyl acetate/toluene solution), to thereby obtain 1.50 g (89.8%) of 3,6-bis(4-triphenylsilylphenyl)-N-[4-(8-hydroxyoctyloxyphenyl]carbazole as colorless needle crystals.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([CH:7]([CH2:9][C:10]#[CH:11])O)=[CH:4][CH:3]=1.[OH-:12].[Na+].Cl.[Cl-].[Na+]>O>[CH2:3]([C:4]1[C:5](=[O:6])[CH2:7][CH:9]([OH:12])[C:10]=1[CH3:11])[C:2]#[CH:1]
Reactant: C#CCC(O)c1ccc(C)o1
Reactant: [OH-]
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: C#CCC1=C(C)C(O)CC1=O
Reaction time: 4 h

Procedure:
In a reaction vessel, water (200 ml) and 5-methyl-2-furylpropargylcarbinol (5 g) were charged, and the pH value was adjusted to 4 with an aqueous 1/3N NaOH solution and an aqueous 1/3N HCl solution. The temperature was elevated to 100° C. to reflux, and the mixture was stirred under reflux for 16 hours while maintaining the pH value of 3.8 to 4.1 by the addition of an aqueous 1/3N NaOH solution and an aqueous 1/3N HCl solution. Then, the pH value was adjusted to 8.0 with an aqueous 1/3N NaOH solution, and stirring under reflux was continued for 4 hours while maintaining the pH value of 7.5 to 8.0 by the addition of an aqueous 1/3N NaOH solution and an aqueous 1/3N HCl solution. After cooling, sodium chloride (70 g) was added, and the mixture was extracted with toluene (100 ml) four times. The extract was concentrated at 60° C. under reduced pressure to remove toluene, whereby an oily substance (4.7 g) was obtained. The crude product was purified by column chromatography with silica gel (60 g) (developing solvent, ethyl acetate-n-hexane (1:2 by volume)) to obtain 2-propargyl-3-methyl-4-hydroxy-2-cyclopentenone (3.4 g). Yield, 68%.
Reaction SMILES: Cl.[CH3:2][CH:3]1[C:8](=[O:9])[CH2:7][CH2:6][NH:5][CH2:4]1.[CH3:10][S:11](Cl)(=[O:13])=[O:12]>>[CH3:10][S:11]([N:5]1[CH2:6][CH2:7][C:8](=[O:9])[CH:3]([CH3:2])[CH2:4]1)(=[O:13])=[O:12]
Reactant: CC1CNCCC1=O
Reactant: CS(=O)(=O)Cl
Agent: Cl
Product: CC1CN(S(C)(=O)=O)CCC1=O

Procedure:
Racemic 1-methanesulfonyl-3-methyl-piperidin-4-one was prepared in the same manner from racemic 3-methyl-piperidin-4-one hydrochloride and methanesulfonyl chloride.
Reaction SMILES: [CH2:1]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14](Cl)=[N:15][OH:16])=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH3:4].[C:18]([C:20]1[C:21]([NH2:26])=[N:22][CH:23]=[CH:24][CH:25]=1)#[CH:19].C(N(CC)CC)C>O1CCCC1>[CH2:1]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]2[CH:19]=[C:18]([C:20]3[C:21]([NH2:26])=[N:22][CH:23]=[CH:24][CH:25]=3)[O:16][N:15]=2)=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCc1ccc(CC(Cl)=NO)cc1
Reactant: C#Cc1cccnc1N
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCOCc1ccc(Cc2cc(-c3cccnc3N)on2)cc1
Temperature: 25 °C
Reaction time: 1.17 h
Yield: 6.2 %

Procedure:
To a solution of 4-butoxymethyl-phenyl-acetohydroximoyl chloride (28 mg, 0.11 mmol) described in Manufacturing Example 4-1-4 and 3-ethynyl-pyridin-2-ylamine (13 mg, 0.11 mmol) described in Manufacturing Example 1-2-3 in tetrahydrofuran (1 mL) was added triethylamine (31 μL, 0.22 mmol) at room temperature, which was stirred for 70 minutes at room temperature. The reaction solution was partitioned into water and ethyl acetate at room temperature. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=2:1) and then further purified by reverse-phase high performance liquid chromatography (using an acetonitrile-water mobile phase containing 0.1% trifluoroacetic acid) to obtain the title compound (2.3 mg, 5%) as a trifluoroacetic acid salt.
Reaction SMILES: BrC1C=CC(O)=C([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:18]4[N:22]([CH:23]5[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]5)[C:21]5[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=5[N:19]=4)[CH:14]=3)[N:9]=2)C=1.[Cl:37][C:38]1[CH:39]=[C:40]([C:45]2[CH:49]=[C:48](C(=O)C)[O:47][N:46]=2)[CH:41]=[CH:42][C:43]=1[Cl:44].[OH-].[K+]>C(O)C>[CH:23]1([N:22]2[C:21]3[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=3[N:19]=[C:18]2[C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][CH:12]=2)[N:9]=[C:8]([C:48]2[O:47][N:46]=[C:45]([C:40]4[CH:41]=[CH:42][C:43]([Cl:44])=[C:38]([Cl:37])[CH:39]=4)[CH:49]=2)[CH:17]=[CH:16]3)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: CC(=O)c1cc(-c2ccc(Cl)c(Cl)c2)no1
Reactant: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc(Br)ccc4O)ccc3c1)n2C1CCCCC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc(-c5ccc(Cl)c(Cl)c5)no4)ccc3c1)n2C1CCCCC1
Yield: 15 %

Procedure:
Following the procedure and workup for Compound 354, Compound 354e (100 mg, 0.256 mmol) was reacted with 1-[3-(3,4-dichloro-phenyl)-isoxazol-5-yl]-ethanone (0.256 mmol) in ethanol (2 mL) using 10% w/v KOH in ethanol (506 μL, 0.64 mmol) to produce the title compound (21 mg, 15% yield). MS: 583.16 (M+H+); HPLC Procedure B, retention time=8.77 min.
Reaction SMILES: Cl.[F:2][CH:3]([F:32])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH:15]3[CH2:20][CH2:19][N:18]([CH:21]([CH3:23])[CH3:22])[CH2:17][CH2:16]3)=[CH:11][CH:12]=2)[CH:7]=[C:6]1[C:24]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)=[O:25].[F:33][C:34]([F:41])([F:40])[CH2:35][S:36](Cl)(=[O:38])=[O:37]>>[F:32][CH:3]([F:2])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH:15]3[CH2:20][CH2:19][N:18]([CH:21]([CH3:23])[CH3:22])[CH2:17][CH2:16]3)=[CH:11][CH:12]=2)[CH:7]=[C:6]1[C:24]([N:26]1[CH2:27][CH2:28][N:29]([S:36]([CH2:35][C:34]([F:41])([F:40])[F:33])(=[O:38])=[O:37])[CH2:30][CH2:31]1)=[O:25]
Reactant: O=S(=O)(Cl)CC(F)(F)F
Reactant: CC(C)N1CCC(Oc2ccc3c(c2)cc(C(=O)N2CCNCC2)n3CC(F)F)CC1
Agent: Cl
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc(C(=O)N2CCN(S(=O)(=O)CC(F)(F)F)CC2)n3CC(F)F)CC1

Procedure:
The title compound was prepared in analogy to example 51, from [1-(2,2-difluoro-ethyl)-5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-piperazin-1-yl-methanone hydrochloride and 2,2,2-trifluoro-ethanesulfonyl chloride. Light-yellow solid. MS (m/z): 581.3 (M+H)+.
Reaction SMILES: C1(C)C=CC=CC=1.N1CCCCC1.[CH3:14][N:15]1[C:24]2[C:19](=[CH:20][C:21]([CH3:38])=[C:22]([C:25]3[CH:26]=[C:27]([CH:30]=[CH:31][C:32]=3[O:33][C:34]([F:37])([F:36])[F:35])[CH:28]=O)[CH:23]=2)[C:18]([CH3:40])([CH3:39])[CH2:17][C:16]1=[O:41].[CH3:42][N:43]1[C:47](=[O:48])[CH2:46][S:45][C:44]1=[O:49]>C(OCC)(=O)C.C(O)(=O)C>[CH3:42][N:43]1[C:47](=[O:48])[C:46](=[CH:28][C:27]2[CH:30]=[CH:31][C:32]([O:33][C:34]([F:37])([F:36])[F:35])=[C:25]([C:22]3[CH:23]=[C:24]4[C:19]([C:18]([CH3:39])([CH3:40])[CH2:17][C:16](=[O:41])[N:15]4[CH3:14])=[CH:20][C:21]=3[CH3:38])[CH:26]=2)[S:45][C:44]1=[O:49]
Reactant: CN1C(=O)CSC1=O
Reactant: Cc1cc2c(cc1-c1cc(C=O)ccc1OC(F)(F)F)N(C)C(=O)CC2(C)C
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: C1CCNCC1
Product: Cc1cc2c(cc1-c1cc(C=C3SC(=O)N(C)C3=O)ccc1OC(F)(F)F)N(C)C(=O)CC2(C)C
Temperature: 25 °C

Procedure:
A mixture of toluene (80 mL), piperidine (380 μL), acetic acid (380 μL), 3-(1,4,4,6-Tetramethyl-2-oxo-1,2,3,4-tetrahydro-quinolin-7-yl)-4-trifluoromethoxy-benzaldehyde (7.5 g, 19.16 mmol) and a 3-alkyl—thiazolidine-2,4-dione such as 3-Methyl-thiazolidine-2,4-dione (19.16 mmol) is heated at reflux overnight. The reaction mixture is cooled to room temperature, diluted with ethyl acetate and is washed with water and brine, dried over MgSO4. The residue is recrystallized to afford 3-methyl-5-[3-(1,4,4,6-tetramethyl-2-oxo-1,2,3,4-tetrahydro-quinolin-7-yl)-4-trifluoromethoxy-benzylidene]-thiazolidine-2,4-dione.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[CH3:8][C:9]1([CH3:24])[S:13][CH:12]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[NH:11][C@H:10]1[C:21]([OH:23])=[O:22]>O>[C:1]([N:11]1[C@@H:10]([C:21]([OH:23])=[O:22])[C:9]([CH3:24])([CH3:8])[S:13][C@H:12]1[C:14]1[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=1)(=[O:3])[CH3:2]
Reactant: CC1(C)SC(c2ccc(F)cc2)N[C@H]1C(=O)O
Reactant: CC(=O)OC(C)=O
Solvent: O
Product: CC(=O)N1[C@@H](C(=O)O)C(C)(C)S[C@H]1c1ccc(F)cc1
Temperature: 100 °C

Procedure:
11.2 ml of acetic anhydride are portion-wise added to a suspension containing 5.1 g (20 mmoles) of 5,5-dimethyl-2-(4-fluorophenyl)-thiazolidine-4(S)-carboxylic acid in 11.2 ml of hot water. The mixture is heated at 100° C. for 5 minutes, then cooled down. The crystals are filtered out to give the title compound in a yield of 5.83 g (98%) which is recrystallized from the mixture of ethanol and ether, m.p.: 193.5° C., [α]D22 =-96.8° (c=0.62, methanol).
Reaction SMILES: O[C:2]1([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[C:4](=O)[O:3]1.[NH2:21][NH2:22]>CO>[N+:18]([C:14]1[CH:13]=[C:12]([C:2]2[C:6]3[N:7]=[CH:8][CH:9]=[CH:10][C:5]=3[C:4](=[O:3])[NH:22][N:21]=2)[CH:17]=[CH:16][CH:15]=1)([O-:20])=[O:19]
Reactant: NN
Reactant: O=C1OC(O)(c2cccc([N+](=O)[O-])c2)c2ncccc21
Solvent: CO
Product: O=c1[nH]nc(-c2cccc([N+](=O)[O-])c2)c2ncccc12
Reaction time: 17 h

Procedure:
7-Hydroxy-7-(3-nitrophenyl)-7H-furo[3,4-b]pyridin-5-one (38.65 g, 142 mmoles) was mixed with 800 mL of methanol. To this mixture was added 35 mL of anhydrous hydrazine. The resulting solution was then heated under reflux for 5 hours. After 17 hours of aging at room temperature the product was isolated by filtration. The crystalline mass was washed twice with methanol (250 mL) and dried, yielding 25.6 g of 8-(3-nitrophenyl)- pyrido[2,3-d]pyridazin-5-one.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[CH2:3][CH2:4][C:5](=O)[C:6]([OH:8])=[O:7].CC1[N:18]=CC(COP(O)(O)=O)=C(C=O)C=1O>P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[F:1][C:2]([F:11])([F:10])[CH2:3][CH2:4][C@@H:5]([NH2:18])[C:6]([OH:8])=[O:7]
Reactant: O=C(O)C(=O)CCC(F)(F)F
Reactant: Cc1ncc(COP(=O)(O)O)c(C=O)c1O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: N[C@H](CCC(F)(F)F)C(=O)O

Procedure:
A solution containing 5,5,5-trifluoro-2-oxopentanoic acid (100 mg, 0.588 mmoles), R,S-alanine (200 mg, 2.244 mmoles), and 0.02 mM pyridoxal phosphate, in 0.1 M potassium phosphate buffer, pH 7.5, was incubated with R-transaminase AT-103 from Biocatalytics (5 mg, 44 units) or cloned R-transaminase from Bacillus thuringiensis SC16569 (0.5 mL, 10 units, BMS transaminase) at 30° C. in a total volume of 5 mL in 15 mL tubes for 44 h. Reaction yields of (R)-5,5,5-trifluoro-2-aminopentanoic acid of 49% and 48% were obtained with AT-103 and BMS transaminases, respectively. Ee was 100% in both cases.
Reaction SMILES: [CH3:1][C@@:2]12[C@:10]3([C:16]([CH2:18][OH:19])=[O:17])[O:11][C:12]([CH3:15])([CH3:14])[O:13][C@@H:9]3[CH2:8][C@H:7]1[C@@H:6]1[CH2:20][CH2:21][C:22]3[C@@:28]([CH3:29])([C@@:5]1(F)[C@@H:4]([OH:31])[CH2:3]2)[CH:27]=[CH:26][C:24](=[O:25])[CH:23]=3.C[C@@]12[C@@](O)(C(CO)=O)[C@H](O)C[C@H]1[C@@H]1CCC3[C@@](C)([C@@]1([F:58])[C@@H](O)C2)C=CC(=O)C=3>>[CH3:29][C@@:28]12[C@H:5]3[C@@H:4]([OH:31])[CH2:3][C@:2]4([CH3:1])[C@:10]5([C:16]([CH2:18][OH:19])=[O:17])[O:11][C:12]([CH3:15])([CH3:14])[O:13][C@@H:9]5[CH2:8][C@H:7]4[C@@H:6]3[CH2:20][C@H:21]([F:58])[C:22]1=[CH:23][C:24](=[O:25])[CH2:26][CH2:27]2
Reactant: C[C@]12C=CC(=O)C=C1CC[C@H]1[C@@H]3C[C@@H](O)[C@](O)(C(=O)CO)[C@@]3(C)C[C@H](O)[C@@]12F
Reactant: CC1(C)O[C@@H]2C[C@H]3[C@@H]4CCC5=CC(=O)C=C[C@]5(C)[C@@]4(F)[C@@H](O)C[C@]3(C)[C@]2(C(=O)CO)O1
Product: CC1(C)O[C@@H]2C[C@H]3[C@@H]4C[C@H](F)C5=CC(=O)CC[C@]5(C)[C@H]4[C@@H](O)C[C@]3(C)[C@]2(C(=O)CO)O1

Procedure:
Triamcinolone acetonide 0.1% (Kenalog®, Aristocort® A ointment)
Reaction SMILES: [CH2:1]([C:3]1[C:7]([CH:8]=[O:9])=[CH:6][N:5]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=2)[N:4]=1)[CH3:2].[CH:18]1([Mg]Br)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>O1CCCC1>[CH:18]1([CH:8]([C:7]2[C:3]([CH2:1][CH3:2])=[N:4][N:5]([C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=3)[CH:6]=2)[OH:9])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: CCc1nn(-c2cccc(OC)c2)cc1C=O
Reactant: Br[Mg]C1CCCCC1
Solvent: C1CCOC1
Product: CCc1nn(-c2cccc(OC)c2)cc1C(O)C1CCCCC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution (20 mL) of 3-ethyl-1-(3-methoxyphenyl)-1H-pyrazole-4-carbaldehyde (1.9 g) synthesized in the above-mentioned (2) in tetrahydrofuran was added dropwise under ice-cooling cyclohexylmagnesium bromide (12.0 mL, 1M tetrahydrofuran solution). After the completion of the dropwise addition, the ice bath was removed, and the mixture was stirred at room temperature for 15 min. To the reaction mixture was added aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure to give a crude product (2.6 g, quantitative) of the title object compound as a pale-yellow oil.
Reaction SMILES: FC(F)(F)C1C=CC(CBr)=CC=1.Br[CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:24]=1[N:23]=[CH:22][CH:21]=[CH:20]2.[CH3:25][C:26]1[N:27]=[C:28]([N:36]2[CH2:40][CH2:39][NH:38][C:37]2=[O:41])[S:29][C:30]=1[C:31]([O:33][CH2:34][CH3:35])=[O:32]>>[CH3:25][C:26]1[N:27]=[C:28]([N:36]2[CH2:40][CH2:39][N:38]([CH2:14][C:15]3[CH:16]=[CH:17][CH:18]=[C:19]4[C:24]=3[N:23]=[CH:22][CH:21]=[CH:20]4)[C:37]2=[O:41])[S:29][C:30]=1[C:31]([O:33][CH2:34][CH3:35])=[O:32]
Reactant: CCOC(=O)c1sc(N2CCNC2=O)nc1C
Reactant: BrCc1cccc2cccnc12
Agent: FC(F)(F)c1ccc(CBr)cc1
Product: CCOC(=O)c1sc(N2CCN(Cc3cccc4cccnc34)C2=O)nc1C
Yield: 82 %

Procedure:
Following the procedure as described in Example 13, making variations as required to replace 4-(trifluoromethyl)benzyl bromide with 8-(bromomethyl)quinoline to react with ethyl 4-methyl-2-(2-oxoimidazolidin-1-yl)thiazole-5-carboxylate, the title compound was obtained as a colorless solid in 82% yield: MS (ES+) m/z 397.3 (M+1)
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([F:11])[CH:3]=1.S(Cl)(Cl)=O.C(=O)([O-])O.[Na+].[CH2:21](O)[CH3:22]>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH2:21][CH3:22])=[O:7])=[C:4]([F:11])[CH:3]=1
Reactant: CCO
Reactant: O=C(O)c1ccc(Br)cc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1ccc(Br)cc1F
Temperature: 70 °C
Reaction time: 8 h

Procedure:
To a solution of 4-bromo-2-fluorobenzoic acid (3.0 g) in ethanol (20 mL) was added thionyl chloride (2.0 mL) at 0° C., and the mixture was stirred overnight at 70° C. To the reaction mixture was added saturated aqueous sodium hydrogencarbonate solution, the mixture was concentrated under reduced pressure, and the residue was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (3.30 g).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:31])=[C:5]([C:21]([O:23][CH2:24][C:25]2(OCC[O:27]2)[CH3:26])=[O:22])[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:7]=1[C:8]([O:10][CH3:11])=[O:9].Cl>C(O)C>[CH3:1][C:2]1[NH:3][C:4]([CH3:31])=[C:5]([C:21]([O:23][CH2:24][C:25](=[O:27])[CH3:26])=[O:22])[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OCC2(C)OCCO2)C1c1cccc([N+](=O)[O-])c1
Agent: Cl
Solvent: CCO
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCC(C)=O)C1c1cccc([N+](=O)[O-])c1
Yield: 65.2 %

Procedure:
8.2 g of methyl 2,2-ethylenedioxypropyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate was refluxed in 35 ml of an ethanol solution containing 5 ml of 10% hydrochloric acid for 6 hours. The solvent was then distilled off and the residue was crystallized from diethyl ether. Recrystallization of the crystals from a mixture of ethyl acetate and hexane gave 4.8 g (65% yield) of methyl 2-oxopropyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate as yellow prisms having a melting point of 139° C.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH:4]([C:8]([O:10][CH3:11])=[O:9])[CH2:3]1.[CH2:12](O)[CH2:13][OH:14].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1.C1(C)C=CC=CC=1.O>[CH2:12]1[CH2:13][O:14][C:2]2([CH2:7][CH2:6][CH2:5][CH:4]([C:8]([O:10][CH3:11])=[O:9])[CH2:3]2)[O:1]1
Reactant: COC(=O)C1CCCC(=O)C1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)C1CCCC2(C1)OCCO2
Temperature: 95 °C

Procedure:
A solution composed of 30 g (192 mmol) of crude methyl 3-oxocyclohexanecarboxylate and 430 cm3 of toluene is introduced into a one-liter three-necked flask equipped with a Dean and Stark apparatus, and 14.3 g (230 mmol) of ethylene glycol are then added with 814 mg (4.3 mmol) of para-toluenesulfonic acid monohydrate. The mixture is heated to reflux, the toluene-water azeotrope forms instantaneously and, after 40 min, no further refluxing of azeotrope (95° C.) takes place. The mixture is maintained for 6 h under reflux of the toluene (110° C.). After cooling, sodium hydrogen carbonate solution is added and the solution is then washed with saturated sodium chloride solution and dried over sodium sulfate. After concentration, 39 g of a yellow oil are obtained, which product is either distilled or chromatographed on a column of 215 g of silica (eluant: cyclo-hexane/ether, 98:2).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][C:10]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])([CH2:12][OH:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:29][S:30](Cl)(=[O:32])=[O:31].C(O)(=O)C>C(Cl)Cl.O>[C:1]([O:5][C:6]([N:8]1[CH2:11][C:10]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])([CH2:12][O:13][S:30]([CH3:29])(=[O:32])=[O:31])[CH2:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)NC1(CO)CN(C(=O)OC(C)(C)C)C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)NC1(COS(C)(=O)=O)CN(C(=O)OC(C)(C)C)C1
Temperature: -5 °C
Reaction time: 0.58 h

Procedure:
3-tert-Butoxycarbonylamino-3-hydroxymethyl-azetidine-1-carboxylic acid tert-butyl ester (490 mg; 1.6 mmol) and triethylamine (1.7 ml; 19 mmol), dissolved in CH2Cl2 (3 ml), are cooled to −5° C. and treated with methanesulfonyl chloride (280 mg; 2.43 mmol). The reaction mixture is kept at 0° C. for 35 minutes, poured on 10% acetic acid in water and extracted with TBME. The combined organic phases are washed with 2N Na2CO3, dried over Na2SO4, filtered and evaporated to dryness, yielding the desired product as colorless crystals. 1H-NMR (400 MHz; DMSO-d6: 7.75 (bs, 1H); 4.40 (s, 2H); 3.81 (bs, 4H); 3.23 (s, 3H); 1.40 (s, 9H); 1.38 (s, 9H). MS (m/z) ES+: 381 (MH+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=1)[CH2:5][O:6][CH2:7][CH2:8][N:9]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]1=[O:19].[C:23]([C:25]([OH:32])([CH2:29][CH2:30][CH3:31])[CH2:26][CH2:27][CH3:28])#[CH:24]>>[OH:32][C:25]([CH2:29][CH2:30][CH3:31])([CH2:26][CH2:27][CH3:28])[C:23]#[C:24][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=1)[CH2:5][O:6][CH2:7][CH2:8][N:9]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]1=[O:19]
Reactant: C#CC(O)(CCC)CCC
Reactant: O=C1c2ccccc2C(=O)N1CCOCc1cccc(Br)c1
Product: CCCC(O)(C#Cc1cccc(COCCN2C(=O)c3ccccc3C2=O)c1)CCC

Procedure:
Sonogashira coupling of 2-(2-(3-bromobenzyloxy)ethyl)isoindoline-1,3-dione and 4-ethynylheptan-4-ol following the method described in Example 12 gives 2-(2-(3-(3-hydroxy-3-propylhex-1-ynyl)benzyloxy)ethyl)isoindoline-1,3-dione.
Reaction SMILES: [CH3:1][C:2]([CH3:5])([O-:4])[CH3:3].[K+].C1COCC1.[CH:12]1([CH2:17][C:18](Cl)=[O:19])[CH2:16][CH2:15][CH2:14][CH2:13]1.[Cl-].[NH4+]>>[CH:12]1([CH2:17][C:18]([O:4][C:2]([CH3:5])([CH3:3])[CH3:1])=[O:19])[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: CC(C)(C)[O-]
Reactant: O=C(Cl)CC1CCCC1
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CC1CCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
136 ml of a 1 M solution of potassium tert-butoxide in THF (136 mmol) were cooled to 0° C., and 21.0 g (143.2 mmol) of cyclopentylacetic chloride were added dropwise. After the addition had ended, the suspension was warmed to RT and stirred overnight and then added to saturated aqueous ammonium chloride solution. The mixture was extracted three times with diethyl ether. The combined organic phases were dried over magnesium sulphate and concentrated under reduced pressure. The desired product was isolated from the residue by kugelrohr distillation (1.6 mbar/160-180° C.). This gave 17.58 g of the target compound (66.6% of theory).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.[N+:20]([O-])([OH:22])=[O:21]>>[Cl:1][C:2]1[C:10]([N+:20]([O-:22])=[O:21])=[CH:9][C:8]([C:11]([F:12])([F:13])[F:14])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1cc(C(F)(F)F)ccc1Cl
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=C(O)c1cc(C(F)(F)F)cc([N+](=O)[O-])c1Cl

Procedure:
After dissolving at room temperature 2-chloro-5-trifluoromethylbenzoic acid (2.25 g; 10 mmol) in fuming sulfuric acid comprising 20% oleum (6 ml), fuming nitric acid (1.7 ml) is added dropwise over 30 minutes, so as to maintain the temperature of the reaction medium below 60° C. After cooling, ice is added and the precipitate is separated out, washed with water and dried. After recrystallisation from water, 2.15 g of solid corresponding to 2-chloro-3-nitro-5-trifluoromethylbenzoic acid are obtained (m.p.=173° C.).
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[O:7][CH:8]=[CH:9][CH:10]=1)CCC.[C@@H:19]1([N:27]2[CH:31]=[C:30](I)[CH:29]=[C:28]2[N+:33]([O-:35])=[O:34])[O:24][C@H:23]([CH2:25][OH:26])[C@@H:21]([OH:22])[CH2:20]1>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.CN(C=O)C>[C@@H:19]1([N:27]2[CH:31]=[C:30]([C:6]3[O:7][CH:8]=[CH:9][CH:10]=3)[CH:29]=[C:28]2[N+:33]([O-:35])=[O:34])[O:24][C@H:23]([CH2:25][OH:26])[C@@H:21]([OH:22])[CH2:20]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccco1
Reactant: O=[N+]([O-])c1cc(I)cn1[C@H]1C[C@H](O)[C@@H](CO)O1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(-c2ccco2)cn1[C@H]1C[C@H](O)[C@@H](CO)O1
Yield: 76 %

Procedure:
2-(Tributylstannyl)furan (472 μL, 1.5 mmol) was added to a DMF (2.5 mL) solution containing 1-(2-deoxy-β-D-ribofuranosyl)-4-iodo-2-nitropyrrole (177 mg, 0.5 mmol) and bis(triphenylphosphine)palladium(II) dichloride (18 mg, 0.025 mmol). The mixture was reacted at 100° C. for 30 minutes in a microwave machine (standard mode). The reaction solution was separated between ethyl acetate (50 mL) and water (50 mL). The organic layer was concentrated and purified by HPLC to yield 1-(2-deoxy-β-D-ribofuranosyl)-4-(furan-2-yl)-2-nitropyrrole (111 mg, 0.38 mmol, 76%).