Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[C:2]1([CH3:16])[C:10]2[C:5](=[C:6]([N+:11]([O-])=O)[CH:7]=[CH:8][CH:9]=2)[C:4](=[O:14])[N:3]1[CH3:15].[H][H]>[Pd].CC(O)=O>[NH2:11][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[C:4](=[O:14])[N:3]([CH3:15])[CH:2]2[CH3:16]
Reactant: CN1C(=O)c2c([N+](=O)[O-])cccc2C1(C)O
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: CC1c2cccc(N)c2C(=O)N1C
Yield: 50.4 %

Procedure:
A mixture of 3-hydroxy-2,3-dimethyl-7-nitro-2,3-dihydro-1H-isoindol-1-one (Compound 157B, 500 mg), AcOH (12 mL), and 5% Pd/C (60 mg) was hydrogenated for 14 h under 1 atm hydrogen atmosphere. The catalyst was filtered off and the filtrate was concentrated, residue was purified by column chromatography to afford 200 mg of the title compound (yield: 50%). 1H NMR (CDCl3, 300 MHz): δ=1.43 (d, J=6.8 Hz, 3H), 3.04 (s, 3H), 4.33 (q, J=6.3 Hz, 1H), 5.20 (s, br, 2H), 6.55 (d, J=8.1 Hz, 1H), 7.21-7.26 (m, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1[CH:16]=[CH:15][C:14](CO)=[CH:13][CH:12]=1)=[CH2:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:19]([O:26]C(C1C=CC=C(CO)C=1)=C)C1C=CC=CC=1>>[CH3:19][O:26][C:5]1[CH:4]=[CH:3][C:2]([CH2:1][O:8][C:9]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[CH2:10])=[CH:7][CH:6]=1
Reactant: C=C(OCc1ccccc1)c1ccc(CO)cc1
Reactant: C=C(OCc1ccccc1)c1cccc(CO)c1
Product: C=C(OCc1ccc(OC)cc1)c1ccccc1

Procedure:
α-Benzyloxy[4-(hydroxymethyl)styrene] and α-Benzyloxy[3-(hydroxymethyl)styrene]
Reaction SMILES: C(OC(C)(C)C)(=O)[CH2:2][C:3]([CH3:5])=[O:4].[C:12]([CH2:14][CH2:15][C:16](Cl)=[O:17])#[N:13]>CCOCC>[O:17]=[C:16]([CH2:2][C:3](=[O:4])[CH3:5])[CH2:15][CH2:14][C:12]#[N:13]
Reactant: N#CCCC(=O)Cl
Reactant: CC(=O)CC(=O)OC(C)(C)C
Solvent: CCOCC
Product: CC(=O)CC(=O)CCC#N

Procedure:
The magnesium complex of t-butyl acetoacetate (135 gm; 635 mmole) is suspended in 250 ml of anhydrous ether in a three-neck one liter round bottom flask and beta-cyano propionyl chloride (78.05 gm: 664 mmole) added dropwise over fifteen minutes while the mixture is stirred from overhead. The dropping funnel is removed and the mixture refluxed for thirty minutes. The mixture is cooled and 250 ml of 2N aqueous sulfuric acid is slowly added. The mixture is transferred to a one liter separatory funnel and the layers separated. The aqueous layer is extracted with ether (2×150 ml) and the combined ether extracts washed with water (4×100 ml). The ether is evaporated and to the residual red oil is added 800 mg of toluene sulfonic acid monohydrate. The mixture is heated in an oil bath (with reflux condenser) to 175 degrees until evolution of gas has ceased. The mixture is cooled and taken up in 500 ml of ether. The ether is extracted with ice-cold 2M aqueous sodium hydroxide (175, 90, 50 , and 35 ml). The extracts were run from the separatory funnel directly into 250 ml of ice-cold 1.8M aqueous sulfuric acid. The acidic suspension is extracted with methylene chloride (3×150 ml) and the combined organic extracts washed with 5% aqueous sodium bicarbonate (2×100 ml) and brine (100 ml). The residue after evaporation of the methylene chloride may be purified by silica gel flash column chromatography using ethyl acetate: hexane 1:4 as eluant.
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[C:8]([C:12]3[N:16]4[CH:17]=[CH:18][C:19]([C:21]5[CH:22]=[N:23][CH:24]=[C:25]([CH:28]=5)[C:26]#[N:27])=[CH:20][C:15]4=[N:14][CH:13]=3)[CH:9]=[CH:10][CH:11]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.[OH-:29].[K+]>CC(O)(C)C>[N:1]1([C:6]2[CH:7]=[C:8]([C:12]3[N:16]4[CH:17]=[CH:18][C:19]([C:21]5[CH:22]=[N:23][CH:24]=[C:25]([CH:28]=5)[C:26]([NH2:27])=[O:29])=[CH:20][C:15]4=[N:14][CH:13]=3)[CH:9]=[CH:10][CH:11]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: [OH-]
Reactant: N#Cc1cncc(-c2ccn3c(-c4cccc(-n5cccn5)c4)cnc3c2)c1
Agent: [K+]
Solvent: CC(C)(C)O
Product: NC(=O)c1cncc(-c2ccn3c(-c4cccc(-n5cccn5)c4)cnc3c2)c1
Temperature: 85 °C

Procedure:
5-[3-(3-pyrazol-1-yl-phenyl)-imidazo-[1,2-a]-pyridin-7-yl]-nicotinonitrile (Ex. 1.8) (1 eq, 0.099 mmol, 40 mg) and potassium hydroxide (10 eq, 0.99 mmol, 64.8 mg) are dissolved in tBuOH (2 ml) and the reaction mixture is heated at 85° C. for 1.5 h. At the completion of this time the solvent is removed in vacuo and the reaction mixture is diluted with NaHCO3. The aqueous phase is extracted with EtOAc. The organic layer is washed with brine, dried over MgSO4, filtered and evaporated to dryness. The reaction mixture is purified by flash chromatography on silica eluting with DCM/MeOH 9/1 to yield 5-[3-(3-pyrazol-1-yl-phenyl)-imidazo-[1,2-a]pyridin-7-yl]-nicotinamide as a yellow solid; [M+H]+=381
Reaction SMILES: Br[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([Cl:11])=[CH:4][N:3]=1.[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[OH:19].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:11][C:5]1[CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]([O:19][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[F:12])=[N:3][CH:4]=1
Reactant: Oc1ccccc1F
Reactant: O=[N+]([O-])c1cc(Cl)cnc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(Cl)cnc1Oc1ccccc1F

Procedure:
This compound was prepared according to general procedure A using 2-bromo-5-chloro-3-nitro-pyridine (750 mg, 3.17 mmol), 2-fluorophenol (463 mmol, 4.13 mmol), K2CO3 (437 mg, 4.75 mmol) and DMF (5 mL). MS m/z: 269.0 (M+H).
Reaction SMILES: Cl.C[O:3][C:4]1[C:15]2[CH2:14][CH:13]3[CH2:16][CH:9]([CH2:10][NH:11][CH2:12]3)[C:8]=2[CH:7]=[CH:6][CH:5]=1.[OH-].[Na+]>>[CH:9]12[CH2:16][CH:13]([CH2:12][NH:11][CH2:10]1)[CH2:14][C:15]1[C:4]([OH:3])=[CH:5][CH:6]=[CH:7][C:8]2=1
Reactant: COc1cccc2c1CC1CNCC2C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Oc1cccc2c1CC1CNCC2C1

Procedure:
6-Methoxy-11-aza-tricyclo[7.3.1.02,7]trideca-2(7),3,5-triene hydrochloride (55 mg, 0.23 mmol) was brought to reflux in 48% aq. hydrobronic acid (HBr) (5 mL). After 1 hour the solution was cooled and poured into 1N aq. NaOH soln. adjusted to pH 10 and product was extracted with EtOAc (3×40 mL). The organic layer was washed with brine (50 mL), dried (MgSO4) and concentrated to a white solid, which was recrystallized from EtOAc/hexanes (20 mg, 46%). 1H NMR (CDCl3) δ6.95 (t, J=8.0 Hz, 1H), 6.68 (d, J=8.0 Hz, 1H), 6.53 (d, J=8.0 Hz, 1H), 3.27 (m, 1H), 3.11 (m, 2H), 3.02 (m, 2H), 2.77 (m, 1H), 2.57 (m, 1H), 2.33 (br s, 1H), 1.90 (m, 2H). mp 106-108° C.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[C:7](=[O:30])[C:8]4[CH:20]=[C:19]([O:21][CH2:22][C@H:23]5[CH2:27][O:26][C:25]([CH3:29])([CH3:28])[O:24]5)[CH:18]=[CH:17][C:9]=4[C:10]([CH3:16])([CH3:15])[C:11]=3[NH:12]2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:33]C(N(C)C)=O.CI>O>[Br:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[C:7](=[O:30])[C:8]4[CH:20]=[C:19]([O:21][CH2:22][C@H:23]5[CH2:27][O:26][C:25]([CH3:29])([CH3:28])[O:24]5)[CH:18]=[CH:17][C:9]=4[C:10]([CH3:16])([CH3:15])[C:11]=3[N:12]2[CH3:33])=[CH:4][CH:3]=1
Reactant: CC1(C)OC[C@H](COc2ccc3c(c2)C(=O)c2c([nH]c4cc(Br)ccc24)C3(C)C)O1
Reactant: CC(=O)N(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: Cn1c2c(c3ccc(Br)cc31)C(=O)c1cc(OC[C@H]3COC(C)(C)O3)ccc1C2(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
To the mixture of 3-bromo-9-((S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one (Compound JJ3-1, 33.2 mg, 0.0706 mmol) and sodium hydride (60% in oil, 6.4 mg, 2.3 eq.), DMA (0.55 mL) and methyl iodide (0.015 mL, 3.4 eq.) were added under nitrogen atmosphere at 0° C., and the mixture was stirred at room temperature overnight. The reaction solution was added with water and extracted with ethyl acetate. The organic layer was washed with brine and dried over magnesium sulfate. After filtration and the concentration under reduced pressure, the resulting solid was washed with MTBE to obtain the title compound (white solid, 31.2 mg, 91%).
Reaction SMILES: C([N+](CCCC)(CCCC)CCCC)CCC.[P:18]([O:22][CH2:23][C@@H:24]1[C@@H:28]([O:29][P:30]([O:33][CH2:34][C@@H:35]2[C@@H:39]([OH:40])[C@@H:38]([OH:41])[C@H:37]([N:42]3[CH:50]=[N:49][C:48]4[C:43]3=[N:44][CH:45]=[N:46][C:47]=4[NH2:51])[O:36]2)([OH:32])=[O:31])[CH2:27][C@H:26]([N:52]2[CH:57]=[CH:56][C:55]([NH2:58])=[N:54][C:53]2=[O:59])[O:25]1)([OH:21])([OH:20])=[O:19].[N:60]([C:63]1[CH:103]=[CH:102][C:66]([CH2:67][O:68][C:69]([NH:71][C@@H:72]([CH2:95][S:96][S:97][C:98]([CH3:101])([CH3:100])[CH3:99])[C:73]([NH:75][CH2:76][CH2:77][CH2:78][CH2:79][C@H:80]([NH:87][C:88]([O:90][C:91]([CH3:94])([CH3:93])[CH3:92])=[O:89])[C:81](OCC#N)=[O:82])=[O:74])=[O:70])=[CH:65][CH:64]=1)=[N+:61]=[N-:62]>O.O1CCCC1>[N:60]([C:63]1[CH:64]=[CH:65][C:66]([CH2:67][O:68][C:69]([NH:71][C@@H:72]([CH2:95][S:96][S:97][C:98]([CH3:101])([CH3:100])[CH3:99])[C:73]([NH:75][CH2:76][CH2:77][CH2:78][CH2:79][C@@H:80]([NH:87][C:88]([O:90][C:91]([CH3:92])([CH3:93])[CH3:94])=[O:89])[C:81]([O:40][C@H:39]2[C@@H:38]([OH:41])[C@H:37]([N:42]3[CH:50]=[N:49][C:48]4[C:43]3=[N:44][CH:45]=[N:46][C:47]=4[NH2:51])[O:36][C@H:35]2[CH2:34][O:33][P:30]([O:29][C@H:28]2[CH2:27][C@H:26]([N:52]3[CH:57]=[CH:56][C:55]([NH2:58])=[N:54][C:53]3=[O:59])[O:25][C@@H:24]2[CH2:23][O:22][P:18]([OH:21])([OH:20])=[O:19])([OH:32])=[O:31])=[O:82])=[O:74])=[O:70])=[CH:102][CH:103]=1)=[N+:61]=[N-:62]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)[C@H](CSSC(C)(C)C)NC(=O)OCc1ccc(N=[N+]=[N-])cc1)C(=O)OCC#N
Reactant: Nc1ccn([C@H]2C[C@H](OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](COP(=O)(O)O)O2)c(=O)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H](CCCCNC(=O)[C@H](CSSC(C)(C)C)NC(=O)OCc1ccc(N=[N+]=[N-])cc1)C(=O)O[C@H]1[C@@H](O)[C@H](n2cnc3c(N)ncnc32)O[C@H]1COP(=O)(O)O[C@H]1C[C@H](n2ccc(N)nc2=O)O[C@@H]1COP(=O)(O)O
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 11.3 %

Procedure:
A solution of ((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-3-(((((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy) (hydroxy)phosphoryl)oxy)tetrahydrofuran-2-yl)methyl dihydrogenphosphate (Compound 1h) (30.3 mg, 0.048 mmol) in water (0.3 mL) and a solution of (S)-cyanomethyl 6-((R)-2-((((4-azidobenzyl)oxy)carbonyl)amino)-3-(tert-butyldisulfanyl)propanamido)-2-((tert-butoxycarbonyl)amino)hexanoate (Compound tk24) (93 mg, 0.143 mmol) in tetrahydrofuran (0.3 mL) were added to buffer A (9 mL), and the mixture was stirred at room temperature for 4.5 hours. Following lyophilization, the resulting residue was purified by reverse-phase silica gel column chromatography (0.05% aqueous trifluoroacetic acid solution/0.05% trifluoroacetic acid-acetonitrile solution) to afford (2S)-(2R,3S,4R,5R)-2-((((((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-2-((phosphonooxy)methyl)tetrahydrofuran-3-yl)oxy)(hydroxy)phosphoryl)oxy)methyl)-5-(6-amino-9H-purin-9-yl)-4-hydroxytetrahydrofuran-3-yl 6-((R)-2-((((4-azidobenzyl)oxy)carbonyl)amino)-3-(tert-butyldisulfanyl)propanamido)-2-((tert-butoxycarbonyl)amino)hexanoate (Compound tk25) (6.7 mg, 11%).
Reaction SMILES: [Br:1][CH2:2][CH2:3]Br.[OH:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[CH:8][C:7]=1[O:14][CH3:15].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Br:1][CH2:2][CH2:3][O:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[CH:8][C:7]=1[O:14][CH3:15]
Reactant: COc1cc(C=O)ccc1O
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C=O)ccc1OCCBr
Temperature: 25 °C
Reaction time: 16 h
Yield: 95.3 %

Procedure:
1,2-Dibromoethane (57 mL, 0.66 moles) was added to a mixture of 4-hydroxy-3-methoxybenzaldehyde (10 g, 66 mmoles) and potassium carbonate (45 g, 0.33 moles) in DMF (130 ml) and the resulting mixture was stirred vigorously at room temperature for 16 hours. The mixture was poured into water (1.2 L) and extracted with ethyl acetate (500+4×300 mL). The combined organic phases were washed with saturated sodium chloride (500 mL), dried over MgSO4 and evaporated in vacuo to afford 16.3 g (95%) of 4-(2-bromoethoxy)-3-methoxybenzaldehyde. M.p. 61-64° C.
Reaction SMILES: Br[CH2:2][C:3]1[S:4][C:5](=[S:10])[S:6][C:7]=1[CH2:8]Br.[C:11]1(=[O:18])[CH:16]=[CH:15][C:14](=[O:17])[CH:13]=[CH:12]1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>[I-].C([N+](CC)(CC)CC)C.C(#N)C>[S:10]=[C:5]1[S:4][C:3]2[CH:2]=[C:12]3[C:13](=[CH:8][C:7]=2[S:6]1)[C:14](=[O:17])[CH:15]=[CH:16][C:11]3=[O:18]
Reactant: O=C1C=CC(=O)C=C1
Reactant: S=c1sc(CBr)c(CBr)s1
Agent: CC[N+](CC)(CC)CC
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: [I-]
Solvent: CC#N
Product: O=C1C=CC(=O)c2cc3sc(=S)sc3cc21
Yield: 78 %

Procedure:
In a vessel, the 4,5-bis(bromomethyl)-1,3-dithiol-2-thione: 1-3 (1.10 g), tetraethylammonium iodide (0.38 g), p-benzoquinone (2.77 g), and acetonitrile (60 mL) were charged, and then refluxed for 1 hour. Thereafter, dichloro dicyano benzoquinone (1.62 g) was added in the resultant mixture, and then refluxed for 7 hours. After completion of the reflux, the solvent was distilled away, and methanol was added in the vessel, and then the precipitate was recovered through filtration. The precipitate was washed with methanol, distilled water, and ether in this order, the obtained residue was dissolved in chloroform, and then filtered. The obtained filtrate was recrystallized, to thereby obtain 2-thioxonaphth[2,3-d] [1,3]dithiol-5,8-dione: 1-4 in a yield of 78%. The target compound was identified through NMR analysis: 1H-NMR (CDCl3, TMS) σ: 7.04 (s, 2H), 8.15 (s, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:14][C:15]([OH:17])=O)[CH2:10][C:11]([OH:13])=[O:12])[CH:5]=[C:6]([F:8])[CH:7]=1>CO.ClCCl>[F:8][C:6]1[CH:7]=[C:2]([F:1])[CH:3]=[C:4]2[C:5]=1[C:15](=[O:17])[CH2:14][CH:9]2[CH2:10][C:11]([OH:13])=[O:12]
Reactant: O=C(O)CC(CC(=O)O)c1cc(F)cc(F)c1
Solvent: ClCCl
Solvent: CO
Product: O=C(O)CC1CC(=O)c2c(F)cc(F)cc21
Yield: 23.1 %

Procedure:
This compound was prepared in an analogous manner to that of Example 25d with the replacement of 3-(3-fluorophenyl)glutaric acid with 3-(3,5-difluorophenyl)glutaric acid (9.02 g, 36.9 mmol) and an increase of the heating time from 10 min to 30 min. Chromatography of the collected product on a column of Silica Gel 60 (51×450 mm) with methanol: dichloromethane (4:96) gave a material which was recrystallized from water to give 1.93 g (23%) of 2-(4,6-difluoro-3-oxo-1-indanyl)acetic acid: m.p., 170°-172° C.;
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][CH2:6][S:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1.C(N(CC)CC)C.[C:21](Cl)(=[O:37])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]>C(Cl)Cl>[C:21]([NH:3][CH2:4][CH2:5][CH2:6][S:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)(=[O:37])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]
Reactant: NCCCSc1ccncc1
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCC(=O)NCCCSc1ccncc1
Yield: 73.8 %

Procedure:
To a solution of 1.21 g (5.00 mmol) of 4-(3-aminopropylthio)pyridine dihydrochloride and 2.79 ml (20.0 mmol) of triethylamine in 50 ml of methylene chloride was added 1.65 ml (6.00 mmol) of palmitoyl chloride under ice-cooling with stirring and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was washed with an aqueous saturated sodium bicarbonate solution and water and dried. The solvent was distilled off. The residue was purified by column chromatography (eluent: ethyl acetate) to obtain the powder which was washed with hexane and dried to obtain 1.50 g of the desired compound (73.8%, colorless powder), mp: 84.0°-85.0° C.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH:12]1[CH2:17][CH2:16][C:15]([CH3:21])([C:18](O)=[O:19])[CH2:14][CH2:13]1.C(Cl)(=O)C([Cl:25])=O.CN(C=O)C>C(Cl)Cl>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH:12]1[CH2:17][CH2:16][C:15]([CH3:21])([C:18]([Cl:25])=[O:19])[CH2:14][CH2:13]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC1(C(=O)O)CCC(N2C(=O)c3ccccc3C2=O)CC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC1(C(=O)Cl)CCC(N2C(=O)c3ccccc3C2=O)CC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
4-(1,3-Dioxoisoindolin-2-yl)-1-methylcyclohexanecarboxylic acid (Intermediate 74, 220 mg, 0.786 mmol) was dissolved in DCM (5 mL), and oxalyl chloride (146 mg, 0.1 mL, 1.149 mmol) was added slowly, followed by addition of a drop of DMF. The mixture was stirred at room temperature for 20 min, then concentrated under vacuum to provide the product as a yellow solid that was used as is in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:30]=[C:29]([O:31][CH3:32])[C:28]([O:33][CH3:34])=[CH:27][C:13]=2[C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([S:23](F)(=[O:25])=[O:24])=[CH:19][CH:18]=2)=[O:15])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH:35]1[CH2:40][CH2:39][S:38][CH2:37][CH2:36]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:30]=[C:29]([O:31][CH3:32])[C:28]([O:33][CH3:34])=[CH:27][C:13]=2[C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([S:23]([N:35]3[CH2:40][CH2:39][S:38][CH2:37][CH2:36]3)(=[O:25])=[O:24])=[CH:19][CH:18]=2)=[O:15])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: COc1cc(NS(=O)(=O)c2ccc(Cl)cc2)c(C(=O)Nc2ccc(S(=O)(=O)F)cc2)cc1OC
Reactant: C1CSCCN1
Product: COc1cc(NS(=O)(=O)c2ccc(Cl)cc2)c(C(=O)Nc2ccc(S(=O)(=O)N3CCSCC3)cc2)cc1OC
Temperature: 90 °C

Procedure:
500 mg (0.95 mmol) of 4-((2-(4-chloro-phenylsulfonylamino)-4,5-dimethoxy-benzoyl)-amino)-benzenesulfonyl fluoride were dissolved in 1 ml of thiomorpholine and heated to 90° C. for 30 min. For working up the mixture was poured onto 50 ml of ice/1 N hydrochloric acid, the precipitate was filtered off with suction, dried in a vacuum-drying chamber over phosphorus pentoxide and recrystallized from hexane/ethyl acetate. 378 mg (65%) of the title compound having a melting point of 241° C. were obtained.
Reaction SMILES: [SH:1][C:2]1[N:6]([CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C:5]2[CH:15]=[CH:16][CH:17]=[CH:18][C:4]=2[N:3]=1.[CH2:19]([O:21][C:22](=[O:29])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]Br)[CH3:20].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[C:11]([O:10][C:8](=[O:9])[CH2:7][N:6]1[C:5]2[CH:15]=[CH:16][CH:17]=[CH:18][C:4]=2[N:3]=[C:2]1[S:1][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][C:22]([O:21][CH2:19][CH3:20])=[O:29])([CH3:13])([CH3:14])[CH3:12]
Reactant: CCOC(=O)CCCCCBr
Reactant: CC(C)(C)OC(=O)Cn1c(S)nc2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)CCCCCSc1nc2ccccc2n1CC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.6 %

Procedure:
A mixture of tert-butyl (2-mercapto-benzoimidazol-1-yl)-acetate (Intermediate 3-I, 52 mg, 0.2 mmol), 6-bromo-hexanoic acid ethyl ester (49 mg, 39 μl, 0.22 mmol) and K2CO3 (55 mg, 0.4 mmol) is refluxed in acetone (2 ml) for 5 h and stirred at rt overnight. Evaporation of the solvent in vacuo affords a residue that is purified by flash-chromatography on silica-gel (AcOEt/heptane, 25:75), yielding the title compound (55 mg) in 68% as a colourless oil: tR=7.24 min (LC-1), ESI-MS (pos.): m/z 407.23 [M+H]+, ESI-MS (neg.) 405.22 [M−H]+; 1H-NMR (CDCl3): δ (ppm) 1.25 (t, 3H CH3), 1.44 (s, 9H, tBu), 1.48 (m, 2H), 1.66 (quint., 2H), 1.79 (quint., 2H), 2.30 (t, 2H, CH2C═O), 3.38 (t, 2H, SCH2), 4.10 (q, 2H, OCH2), 4.73 (s, 2H, CH2CO2), 7.17-7.25 (m, 3Harom), 7.69 (m, 1Harom).
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[C:9](/[CH:13]=[N:14]/[C:15]3[CH:16]=[CH:17][C:18]([C:21]#[N:22])=[N:19][CH:20]=3)[CH:10]=[CH:11][CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH2:23]=[C:24]([CH3:26])[CH3:25].FC(F)(F)S([O-])(=O)=O.[Yb+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O>C(#N)C.C(OCC)(=O)C>[CH3:23][C:24]1([CH3:26])[C:20]2[N:19]=[C:18]([C:21]#[N:22])[CH:17]=[CH:16][C:15]=2[NH:14][CH:13]([C:9]2[CH:10]=[CH:11][CH:12]=[C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)[CH:8]=2)[CH2:25]1
Reactant: N#Cc1ccc(/N=C/c2cccc(N3CCOCC3)c2)cn1
Reactant: C=C(C)C
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC1(C)CC(c2cccc(N3CCOCC3)c2)Nc2ccc(C#N)nc21
Temperature: 90 °C
Reaction time: 18 h
Yield: 12.1 %

Procedure:
To a stirred solution of 5-{[1-(3-morpholin-4-yl-phenyl)-meth-(E)-ylidene]amino}-pyridine-2-carbonitrile (22.9 g, 78.4 mmol) in acetonitrile (150 mL) were added isobutene (21.0 mL, 313.5 mmol) and ytterbium(III) trifluoromethanesulfonate (Yb(OTf)3) (5.8 g, 9.5 mmol). The resulting mixture was stirred at 90° C. for 18 h in sealed tube. The mixture was diluted with ethyl acetate (300 mL) and washed with water (100 mL×2) and brine (100 mL×2) and then dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue was purified by ISCO combi-flash chromatography (gradient elution, 10-50% ethyl acetate in petroleum ether) to afford 8,8-dimethyl-6-(3-morpholin-4-yl-phenyl)-5,6,7,8-tetrahydro-[1,5]naphthyridine-2-carbonitrile (3.3 g, 12.1%) as a light yellow solid: MS (ESI) M+1=349.1.
Reaction SMILES: Cl.[C:2]1([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[Cl:16][C:17]1[N:18]([CH2:25][C@:26]2([CH3:29])[CH2:28][O:27]2)[CH:19]=[C:20]([N+:22]([O-:24])=[O:23])[N:21]=1.CN(C=O)C>O>[Cl:16][C:17]1[N:18]([CH2:25][C@@:26]([CH3:29])([OH:27])[CH2:28][N:11]2[CH2:10][CH2:9][CH:8]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:13][CH2:12]2)[CH:19]=[C:20]([N+:22]([O-:24])=[O:23])[N:21]=1
Reactant: C[C@@]1(Cn2cc([N+](=O)[O-])nc2Cl)CO1
Reactant: c1ccc(C2CCNCC2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: C[C@](O)(CN1CCC(c2ccccc2)CC1)Cn1cc([N+](=O)[O-])nc1Cl
Temperature: 70 °C
Reaction time: 5 h
Yield: 81 %

Procedure:
4-Phenylpiperidine hydrochloride (0.522 g, 2.64 mmol) was added to a sodium hydroxide solution, and extracted with methylene chloride. The organic phase was dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure. To the residue, (R)-2-chloro-1-(2-methyloxiran-2-ylmethyl)-4-nitroimidazole prepared in Example 12 (0.5 g, 2.29 mmol) and DMF (5 ml) were added followed by stirring at 70° C. for 5 hours. The reaction mixture was poured into water and extracted with ethyl acetate twice. The organic phases were combined, washed with water and a saturated saline solution, dried over sodium sulfate and then filtered. The resulting filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=2/1) to afford (S)-1-(2-chloro-4-nitroimidazol-1-yl) -2-methyl-3-(4-phenylpiperidin-1-yl)propan-2-ol (0.703 g, yield 81%) as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[O:9][CH:8]=[CH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[O:11]1C2C=CC=CC=2C=[C:12]1C=O>>[CH3:1][C:2]1[C:10]2[O:9][C:8]([CH:12]=[O:11])=[CH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc2ccoc12
Reactant: O=Cc1cc2ccccc2o1
Product: Cc1cccc2cc(C=O)oc12

Procedure:
c. 7 -Methyl-benzofuran-2-aldehyde was prepared by formylating 7-methyl-benzofuran according to the same method as used for the preparation of benzofuran-2-aldehyde. The product thus obtained has the following ion peaks in its mass spectrum: 160 (100%), 159 (62%) and 131 (33%).
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH2:6][CH2:5]1.[F:20][C:21]1[CH:22]=[C:23]2[C:29]3([CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)[CH2:28][N:27]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[C:24]2=[CH:25][CH:26]=1>CCO>[F:20][C:21]1[CH:22]=[C:23]2[C:29]3([CH2:34][CH2:33][N:32]([CH2:3][CH:2]([OH:1])[CH:4]4[CH2:9][CH2:8][N:7]([C:10]([O:12][CH2:13][C:14]5[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=5)=[O:11])[CH2:6][CH2:5]4)[CH2:31][CH2:30]3)[CH2:28][N:27]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[C:24]2=[CH:25][CH:26]=1
Reactant: CC(C)(C)OC(=O)N1CC2(CCNCC2)c2cc(F)ccc21
Reactant: O=C(OCc1ccccc1)N1CCC(C2CO2)CC1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CC2(CCN(CC(O)C3CCN(C(=O)OCc4ccccc4)CC3)CC2)c2cc(F)ccc21
Temperature: 95 °C
Reaction time: 8 h

Procedure:
Phenylmethyl 4-(2-oxiranyl)-1-piperidinecarboxylate (990 mg) was added to a solution of 1,1-dimethylethyl 5-fluorospiro[indole-3,4′-piperidine]-1(2H)-carboxylate (1.16 g) in EtOH (20 mL). The reaction was heated to 95° C. for 7 h and then stirred at room temperature overnight. The solvent was removed and the title compound was obtained as crude oil. MS (ES) m/e 568 [M+H]+.