Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([F:18])[CH:16]=3)[CH2:11][CH2:10]2)[C:5]([N+:19]([O-:21])=[O:20])=[CH:4][CH:3]=1.[NH2:22][C:23]1[CH:27]=[C:26]([CH3:28])[NH:25][N:24]=1.C(N(CC)C(C)C)(C)C>CS(C)=O>[F:18][C:15]1[CH:16]=[C:17]2[C:12]([CH2:11][CH2:10][CH:9]2[NH:8][C:6]2[C:5]([N+:19]([O-:21])=[O:20])=[CH:4][CH:3]=[C:2]([NH:22][C:23]3[NH:24][N:25]=[C:26]([CH3:28])[CH:27]=3)[N:7]=2)=[CH:13][CH:14]=1
Reactant: Cc1cc(N)n[nH]1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1NC1CCc2ccc(F)cc21
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(Nc2ccc([N+](=O)[O-])c(NC3CCc4ccc(F)cc43)n2)[nH]n1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 55.8 %

Procedure:
Combine 6-chloro-N-(6-fluoro-2,3-dihydro-1H-inden-1-yl)-3-nitropyridin-2-amine (9.00 g, 29.34 mmol) and 3-amino-5-methylpyrazole (4.56 g, 46.95 mmol) in dimethylsulfoxide (60 mL). Add N,N-diisopropylethylamine (8.18 mL, 46.95 mmol) and heat the reaction under nitrogen at 120° C. for 90 minutes. Pour the reaction into ice water (200 mL) and stir 20 minutes, then filter. Suspend the solid obtained in a mixture of dichloromethane and methanol and stir at 40° C. for 20 minutes. Filter the mixture to give the title compound as a yellow solid (6.03 g, 56%). MS (ES) m/z=369 [M+1].
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([C:6](=[O:26])[CH2:7][CH2:8][NH:9][C:10]2[C:18]3[C:13](=[CH:14][C:15]([Cl:20])=[CH:16][C:17]=3[Cl:19])[NH:12][C:11]=2[C:21]([O:23]CC)=[O:22])=[CH:4][CH:3]=1.[OH-].[Li+].O1CCCC1.O>C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6](=[O:26])[CH2:7][CH2:8][NH:9][C:10]2[C:18]3[C:13](=[CH:14][C:15]([Cl:20])=[CH:16][C:17]=3[Cl:19])[NH:12][C:11]=2[C:21]([OH:23])=[O:22])=[CH:27][CH:28]=1
Reactant: CCOC(=O)c1[nH]c2cc(Cl)cc(Cl)c2c1NCCC(=O)c1ccc(Cl)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(CCNc1c(C(=O)O)[nH]c2cc(Cl)cc(Cl)c12)c1ccc(Cl)cc1

Procedure:
Mix 3-[(p-chlorophenacyl)methylamino]-2-carbethoxy-4,6-dichloroindole (1.3 g, 3.1 mmol), excess lithium hydroxide, tetrahydrofuran and water and stirovernight. Dilute with ethyl acetate and separate the layers. Dry the organic phase over magnesium sulfate, filter and concentrate in vacuo to yield the title compound; mp 279°-283° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7](Br)[CH:6]=[CH:5]2.[F:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[C:18]([F:21])[C:19]=1[F:20].C([O-])([O-])=O.[K+].[K+]>[N+](CCCC)(CCCC)(CCCC)CCCC.[Br-].C1(C)C=CC=CC=1>[F:13][C:14]1[CH:15]=[C:16]([C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][CH:6]=2)[CH:3]=[C:2]([OH:1])[CH:11]=[CH:10]3)[CH:17]=[C:18]([F:21])[C:19]=1[F:20]
Reactant: Oc1ccc2cc(Br)ccc2c1
Reactant: OB(O)c1cc(F)c(F)c(F)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: Cc1ccccc1
Product: Oc1ccc2cc(-c3cc(F)c(F)c(F)c3)ccc2c1
Temperature: 85 °C

Procedure:
A flame dried 500 ml round-bottomed flask with a magnetic stir bar, was charged with 6-hydroxy-2-bromonaphthalene (8.0 g, 35.89 mMol), 3,4,5-trifluorophenyl boronic acid (6.9 g, 39.5 mMol), 75 mL toluene, 2M K2CO3 (80 mL), Bu4NBr (50 mg) and the mixture flushed with argon for 10 min. [Pd(PPh3)4] (0.5 g) was added and the mixture heated under argon at ˜85° C. overnight, with vigorous stirring. After cooling to room temperature, 50 mL water was added, extracted with 3×25 mL ethyl acetate, the organic extracts dried over MgSO4, and the crude product was then crystallized from a mixture of hexane and few drops of methanol. Yield: 8 g (87%).
Reaction SMILES: F[C:2]1[N:7]=[C:6]([F:8])[C:5]([F:9])=[C:4]([F:10])[C:3]=1[F:11].[CH2:12]([O:19][C:20]([C:22]1[CH:28]=[CH:27][C:25]([O-:26])=[CH:24][CH:23]=1)=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[K+].[K]>CN(C)C=O>[CH2:12]([O:19][C:20]([C:22]1[CH:23]=[CH:24][C:25]([O:26][C:2]2[C:3]([F:11])=[C:4]([F:10])[C:5]([F:9])=[C:6]([F:8])[N:7]=2)=[CH:27][CH:28]=1)=[O:21])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: Fc1nc(F)c(F)c(F)c1F
Reactant: O=C(OCc1ccccc1)c1ccc([O-])cc1
Agent: [K+]
Agent: [K]
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)c1ccc(Oc2nc(F)c(F)c(F)c2F)cc1
Reaction time: 24 h
Yield: 91 %

Procedure:
33.8 g of pentafluoropyridine (0.2 mol) are dissolved in 500 ml of dimethylformamide, the solution is cooled to OC by means of a cryostat, and a solution of 53.3 g of potassium 4-benzyloxycarbonylphenoxide (0.2 mol) in 400 ml of dimethylformamide is then added dropwise over the course of 2 hours. After 24 hours at 0° C., the potassium salt has reacted. The dimethylformamide is then removed in a rotary evaporator, the residue is taken up in a little tetrahydrofuran, and the solution is filtered through a silica-gel column. The clear solution obtained is evaporated in a rotary evaporator until the reaction product precipitates out. The reaction product is then stirred in n-hexane, filtered off via a fluted filter and then dried for 48 hours under nitrogen at 40° C./10 mbar in a vacuum drying cabinet (yield: 91%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\NC1C=CC(N2C[C@H](C)N[C@H](C)C2)=C(C(F)(F)F)C=1.BrC1C=C2C(=CC=1)[C:41](=[O:45])NC(=O)C2=CNC1C=CC(N2CC(C)NC(C)C2)=CC=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]/[O:45][CH3:41]
Reactant: CC1CN(c2ccc(NC=C3C(=O)NC(=O)c4ccc(Br)cc43)cc2)CC(C)N1
Reactant: C[C@@H]1CN(c2ccc(N/C=C3\C(=O)NC(=O)c4ccc(Br)cc43)cc2C(F)(F)F)C[C@H](C)N1
Product: CO/C=C1/C(=O)NC(=O)c2ccc(Br)cc21

Procedure:
Using the procedure described for the preparation of 4Z)-6-bromo-4-({[4-(3,5-dimethylpiperazin-1-yl)phenyl]amino}methylene)isoquinoline-1,3(2H,4H)-dione, \2.28 g (62% yield) of yellow solid is obtained from 2.0 g (7.0 mmol) of (4E)-6-bromo-4-(methoxymethylene)isoquinoline 1,3(2H,4H)-dione, and 2.13 g (7.7 mmol) of 4-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-3-(trifluoromethyl)phenyl]amine; mp: 224-225° C.; MS (ESI) m/z 523.1 (M+H)+1
Reaction SMILES: [CH:1]1[N:5]([CH:6]2[O:10][CH:9]([CH2:11][OH:12])[CH:8]([OH:13])[CH:7]2[OH:14])[C:4]2[N:15]=[C:16]([Cl:20])[N:17]=[C:18]([NH2:19])[C:3]=2[C:2]=1[C:21]#[N:22].[OH:23]O>[OH-].[NH4+]>[NH2:19][C:18]1[C:3]2[C:2]([C:21]([NH2:22])=[O:23])=[CH:1][N:5]([C@@H:6]3[O:10][C@H:9]([CH2:11][OH:12])[C@@H:8]([OH:13])[C@H:7]3[OH:14])[C:4]=2[N:15]=[C:16]([Cl:20])[N:17]=1
Reactant: N#Cc1cn(C2OC(CO)C(O)C2O)c2nc(Cl)nc(N)c12
Reactant: OO
Agent: [NH4+]
Agent: [OH-]
Product: NC(=O)c1cn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c2nc(Cl)nc(N)c12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-Chlorotoyocamycin (6, 200 mg) was suspended in 40 ml of conc. ammonium hydroxide and 4 ml of 30% hydrogen peroxide were added. The mixture was stirred at room temperature for 2 hr and 2 more ml of 30% hydrogen peroxide were added. Stirring at room temperature was continued for 2 more hours and 2 more ml of 30% hydrogen peroxide were added and the solution was stirred at room temperature for an additional 12 hr. One more ml of hydrogen peroxide was added and stirring at room temperature was continued for an additional hour and the solution was evaporated to dryness in vacuo. The residue was coevaporated first with 40 ml of ethanol and then 40 ml of acetone. The residue was suspended in 50 ml of chloroform, the solid was collected by filtration, washed with 25 ml of chloroform and air dried. The product was then crystallized from 10 ml of absolute ethanol to yield, after drying the sample in an Abderhalden apparatus for 2 hr in vacuo at 110°, 100 mg (47%) of 8, mp 175° dec.
Reaction SMILES: N1(C(Cl)=O)CCOCC1.[N:10]1([C:16]([N:18]=[C:19]=[S:20])=[O:17])[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1.[Cl:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][C:28]=1[O:29][C:30]1[C:39]2[C:34](=[CH:35][C:36]([O:42][CH3:43])=[C:37]([O:40][CH3:41])[CH:38]=2)[N:33]=[CH:32][CH:31]=1)[NH2:25].C1(C)C=CC=CC=1>C(O)C>[N:10]1([C:16]([N:18]=[C:19]=[S:20])=[O:17])[CH2:11][CH2:12][O:13][CH2:14][CH2:15]1.[Cl:21][C:22]1[CH:23]=[C:24]([NH:25][C:19]([NH:18][C:16]([N:10]2[CH2:11][CH2:12][O:13][CH2:14][CH2:15]2)=[O:17])=[S:20])[CH:26]=[CH:27][C:28]=1[O:29][C:30]1[C:39]2[C:34](=[CH:35][C:36]([O:42][CH3:43])=[C:37]([O:40][CH3:41])[CH:38]=2)[N:33]=[CH:32][CH:31]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3Cl)c2cc1OC
Agent: O=C(Cl)N1CCOCC1
Agent: O=C(N=C=S)N1CCOCC1
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)N4CCOCC4)cc3Cl)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 52 %

Procedure:
4-Morpholinecarbonyl isothiocyanate was prepared using commercially available 4-morpholinecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 4-Morpholinecarbonyl isothiocyanate was dissolved in ethanol (1 ml) to prepare a solution. 3-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (40 mg, yield 52%).
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:5]=[C:6]([O:10][C:11]2[N:16]=[CH:15][C:14]([NH:17][C:18](=[O:22])[C@@H:19]([CH3:21])[NH2:20])=[CH:13][N:12]=2)[CH:7]=[CH:8][CH:9]=1)[CH3:3].Cl[C:24](Cl)([O:26]C(=O)OC(Cl)(Cl)Cl)Cl.C(N(CC)CC)C.O>ClCCl>[CH3:21][C@H:19]1[NH:20][C:24](=[O:26])[N:17]([C:14]2[CH:13]=[N:12][C:11]([O:10][C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([CH:2]([CH3:1])[CH3:3])[CH:5]=3)=[N:16][CH:15]=2)[C:18]1=[O:22]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)c1cccc(Oc2ncc(NC(=O)[C@@H](C)N)cn2)c1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)c1cccc(Oc2ncc(N3C(=O)N[C@H](C)C3=O)cn2)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 230.4 %

Procedure:
To a solution of N-(2-{[3-(1-methylethyl)phenyl]oxy}-5-pyrimidinyl)-D-alaninamide (Intermediate 87, 100 mg) in dichloromethane (30 mL) were added triphosgene (40 mg, 0.133 mmol) and triethylamine (51 mg, 0.5 mmol). The resulting mixture was stirred at 0° C. for 30 minutes and water (30 mL) was added. It was extracted with dichloromethane (3 times 30 mL) and the combined organic layer was dried over sodium sulphate and evaporated to afford the title compound (100 mg). 1HNMR (400 MHz, CDCl3): δ ppm 8.62 (2H, s), 7.26-7.30 (1H, t), 7.08-7.05 (2H, m), 6.99-6.92 (2H, m), 4.22-4.20 (1H, d), 2.88-2.84 (1H, m), 1.47-1.45 (3H, d), 1.19-1.18 (6H, d); MS—2 (ESI): 326 [M+H]+.
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10](=[O:15])[NH:11][CH:12]([CH3:14])[CH3:13])[CH2:6][C:5]1=[O:16])[CH:2]=[CH2:3].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[C:27](OCC)(=[O:33])[C:28](OCC)=[O:29]>CN(C=O)C.C1COCC1>[OH:33][C:27]1[C:28](=[O:29])[N:11]([CH:12]([CH3:14])[CH3:13])[C:10](=[O:15])[N:7]2[CH2:8][CH2:9][N:4]([CH2:1][CH:2]=[CH2:3])[C:5](=[O:16])[C:6]=12
Reactant: CCOC(=O)C(=O)OCC
Reactant: C=CCN1CCN(C(=O)NC(C)C)CC1=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: C=CCN1CCn2c(c(O)c(=O)n(C(C)C)c2=O)C1=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 1-(2-propenyl)-4-(N-2-propylcarbamoyl)-2-piperazinone (8.0 g, 35 mmol) in DMF (80 mL) at 0° C. was added lithium bis(trimethylsily)amide (40 mL of a 1.0 M solution in THF, 40 mmol). Diethyl oxalate (5.84 g, 40 mmol) was added and the mixture was stirred for 1 h at 0° C. More lithium bis(trimethylsily)amide was added (35 mL of a 1.0 M solution in THF, 35 mmol) and the mixture was stirred for 1 h at 0° C., and then at ambient temperature for 18 h. The reaction was quenched by the addition of 0.5 N aqueous HCl to pH 3 and the solvents were removed in vacuo. The residue was vigorously stirred in methanol-water, and the precipitate was collected by filtration and dried in vacuo to give the title compound. HPLC RT=2.72 min (Method A); ES MS (M+H)=280; 1H NMR (400 MHz, DMSO-d6) δ 11.79 (s, 1H), 5.80 (ddt, 1H), 5.29 (d, J=17 Hz, 1H), 5.22 (d, J=10 Hz, 1H), 5.05 (septet, J=7 Hz, 1H), 4.10 (d, J=7 Hz, 2H), 3.94 (t, J=7 Hz), 3.58 (t, J=7 Hz, 2H), 1.38 (d, J=7 Hz, 6H).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][CH:13]([C:17]([OH:19])=O)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:23])=O>CN(C)C=O.C(Cl)Cl>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][CH:13]([C:17]([Cl:23])=[O:19])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)C1CCCN(C(=O)OCc2ccccc2)C1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)C1CCCN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C

Procedure:
To an ice cooled methylene chloride solution of 1-[(Benzyloxy)carbonyl]piperidine-3-carboxylic acid (512 mg, 1.95 mmol) under nitrogen was added oxalyl chloride (0.185 mL, 1.95 mmol) and a few drops N,N-dimethylformamide. The reaction flask was warmed slowly to room temperature and after 2 hours the solvent was removed in vacuo. Toluene was added and removed in vacuo (2×) to give the title compound.
Reaction SMILES: [CH2:1]1[C:6]2([CH2:11][CH:10]([C:12]([O:14][CH3:15])=[O:13])[NH:9][CH2:8][CH2:7]2)[CH2:5][CH2:4][NH:3][CH2:2]1.Cl[C:17]1[CH:22]=[C:21]([O:23][C@H:24]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:30]=2[N:36]2[CH:40]=[CH:39][C:38]([CH3:41])=[N:37]2)[C:25]([F:28])([F:27])[F:26])[N:20]=[C:19]([NH2:42])[N:18]=1>O1CCOCC1>[NH2:42][C:19]1[N:18]=[C:17]([N:3]2[CH2:4][CH2:5][C:6]3([CH2:11][CH:10]([C:12]([O:14][CH3:15])=[O:13])[NH:9][CH2:8][CH2:7]3)[CH2:1][CH2:2]2)[CH:22]=[C:21]([O:23][C@H:24]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:30]=2[N:36]2[CH:40]=[CH:39][C:38]([CH3:41])=[N:37]2)[C:25]([F:27])([F:26])[F:28])[N:20]=1
Reactant: COC(=O)C1CC2(CCNCC2)CCN1
Reactant: Cc1ccn(-c2cc(Cl)ccc2[C@@H](Oc2cc(Cl)nc(N)n2)C(F)(F)F)n1
Solvent: C1COCCO1
Product: COC(=O)C1CC2(CCN1)CCN(c1cc(O[C@H](c3ccc(Cl)cc3-n3ccc(C)n3)C(F)(F)F)nc(N)n1)CC2
Temperature: 100 °C

Procedure:
To a solution of methyl 3,9-diazaspiro[5.5]undecane-10-carboxylate (30 mg, 0.14 mmol) in dioxane (2 mL)/1-PrOH (2 mL) was added 4-chloro-6-[(1R)-1-[4-chloro-2-(3-methylpyrazol-1-yl)phenyl]-2,2,2-trifluoro-ethoxy]pyrimidin-2-amine (92 mg, 0.22 mmol), and the reaction was heated at 100° C. under microwave for 3 h. The reaction was cooled to RT, and concentrated in vacuo. The residue was purified by reversed phase HPLC (MeOH/H2O/0.5% TFA) to provide methyl 9-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-3,9-diazaspiro[5.5]undecane-2-carboxylate as an off-white solid.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.[C:7]1([Mg]Br)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Cl>C(OCC)C>[C:7]1([C:2]2[S:3][CH:4]=[CH:5][CH:6]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Br[Mg]c1ccccc1
Reactant: Brc1cccs1
Agent: Cl
Solvent: CCOCC
Product: c1ccc(-c2cccs2)cc1
Temperature: 0 °C
Yield: 91.7 %

Procedure:
Under a nitrogen atmosphere, a mixture of 0.7 gram (catalyst) of bis(1,3-diphenylphosphine)propane-nickel(II) chloride in 200 mL of dry diethyl ether was stirred, and 40 grams (0.245 mole) of 2-bromothiophene was added. The mixture was cooled to 0° C., and 113 mL (0.328 mole) of phenylmagnesium bromide (3M in diethyl ether) was added during a 20 minute period. Upon complete addition the reaction mixture was allowed to warm to room temperature and then was heated at reflux for 16 hours. The reaction mixture was poured into 500 mL of an aqueous 10% hydrochloric acid solution and shaken. The organic layer was separated from the mixture and washed with distilled water. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residue. This residue was distilled under vacuum to yield 36 grams of 2-phenylthiophene, b.p. 140° C. 3 mm, which slowly solidified upon standing.
Reaction SMILES: [CH:1]1([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.Cl[CH2:25][C:26]([NH:28][CH:29]1[C:34]([CH3:36])([CH3:35])[CH:33]2[CH2:37][C:30]1([CH3:38])[CH2:31][CH2:32]2)=[O:27].O>O1CCCC1>[CH:8]1([N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:25][C:26]([NH:28][CH:29]2[C:34]([CH3:36])([CH3:35])[CH:33]3[CH2:37][C:30]2([CH3:38])[CH2:31][CH2:32]3)=[O:27])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: c1ccc(NC2CCCCC2)cc1
Reactant: CC12CCC(C1)C(C)(C)C2NC(=O)CCl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC12CCC(C1)C(C)(C)C2NC(=O)CN(c1ccccc1)C1CCCCC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of N-cyclohexylaniline (100 mg, 0.56 mmol) in tetrahydrofuran (4 ml) at −78° C. was added LiHMDS (1 ml of a 1M solution in tetrahydrofuran) dropwise. The solution was allowed to warm to 0° C., then recooled to −78° C., and a solution of 2-chloro-N-(1,3,3-trimethylbicyclo[2,2,1]hept-2-yl)acetamide (124 mg, 0.56 mmol) in tetrahydrofuran (1 ml) added dropwise. The mixture was allowed to warm to room temperature, and was stirred for 1 hour. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, and dried over magnesium sulfate. The ethyl acetate solution was absorbed onto silica gel, which was eluted with 3% methanol/methylene chloride, to yield 2-(cyclohexylphenylamino)-N-(1,3,3-trimethylbicyclo[2.2.1]hept-2-yl)acetamide.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[CH2:9]([NH:11][CH2:12][CH3:13])[CH3:10]>C(OCC)C>[CH3:1][N:2]1[CH2:7][CH2:6][C:5]([N:11]([CH2:12][CH3:13])[CH2:9][CH3:10])=[CH:4][CH2:3]1
Reactant: CN1CCC(=O)CC1
Reactant: CCNCC
Solvent: CCOCC
Product: CCN(CC)C1=CCN(C)CC1
Reaction time: 96 h
Yield: 59.9 %

Procedure:
The starting substance is prepared as follows: To 1000 g of Klinosorb-4 molecular sieve 1000 ml of dry diethyl ether, 226 g of 1-methyl-4-piperidone and 219 g of dry diethylamine are added. The reaction mixture is kept at room temperature for 4 days and then filtered off. The Klinosorb-4 is washed with ether, the filtrate and the washing are combined, the solvent is distilled off and the residue is purified by distillation in vacuo to give 1-methyl-4-diethylamino-1,2,5,6-tetrahydropyridine with a yield of 59.9%, bp.: 88°-106° C./1.5 kPa; nD20 =1.4825.
Reaction SMILES: [Br:1][C:2]1[N:7]2[N:8]=[C:9]([O:11][CH3:12])[CH:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.[N:13]([O-])=O.[Na+].C(O)C.O>C(O)(=O)C.[Zn]>[Br:1][C:2]1[N:7]2[N:8]=[C:9]([O:11][CH3:12])[C:10]([NH2:13])=[C:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: O=N[O-]
Reactant: COc1cc2cccc(Br)n2n1
Agent: [Na+]
Agent: [Zn]
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: COc1nn2c(Br)cccc2c1N
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 70.3 %

Procedure:
To a solution of 7-bromo-2-methoxypyrazolo[1,5-a]pyridine (1 g) dissolved in acetic acid (10 mL) was added an aqueous solution (5 mL) of sodium nitrite (334 mg), and the reaction mixture was stirred for 20 minutes at room temperature. After adding ethanol (60 mL) and water (30 mL) to the reaction mixture, zinc powder (1 g) was added and the reaction mixture was heated and stirred for 30 minutes at 60° C. The reaction mixture was filtered through celite to remove insoluble residue, water was added and extraction was performed with ethyl acetate. The organic extract was washed with brine, dried over anhydrous magnesium sulfate and filtered, the solvent was evaporated under reduced pressure, the residue was purified by silica gel column chromatography and the title compound (750 mg) was obtained as brown crystals from the n-hexane:ethyl acetate (3:1) fraction.
Reaction SMILES: C(N(CC)CC)C.[N+:8]([C:11]1[CH:12]=[C:13]([S:17](Cl)(=[O:19])=[O:18])[CH:14]=[CH:15][CH:16]=1)([O-:10])=[O:9].[C:21]([NH:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][NH2:34])([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22]>CC(C)=O.O>[C:24]([O:23][C:21](=[O:22])[NH:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][NH:34][S:17]([C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([N+:8]([O-:10])=[O:9])[CH:12]=1)(=[O:19])=[O:18])([CH3:27])([CH3:25])[CH3:26]
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Reactant: CC(C)(C)OC(=O)NCCCCCN
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)NCCCCCNS(=O)(=O)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4.2 ml (30.1 mmol) of triethylamine is added to a solution of 3.21 g (14.5 mmol) of 3-nitrobenzenesulfonyl chloride and 3.0 ml (14.4 mmol) of N-Boc-1,5-diaminopentane in 50 ml of acetone and 15 ml of water. The reaction mixture is stirred for one hour at room temperature. Then, the acetone is drawn off in a rotary evaporator. After water (20 ml) is added, it is extracted with ethyl acetate (2×). The combined organic phases are dried (Na2SO4), filtered and concentrated by evaporation. 5.00 g (12.9 mmol, corresponding to 90% of theory) of the product is obtained as a light yellow oil.
Reaction SMILES: Cl[C:2]1[S:6][C:5]([C:7](=[O:9])[CH3:8])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[Cl:13][C:14]1[CH:15]=[C:16]([SH:21])[CH:17]=[C:18]([Cl:20])[CH:19]=1>>[Cl:13][C:14]1[CH:15]=[C:16]([S:21][C:2]2[S:6][C:5]([C:7](=[O:9])[CH3:8])=[CH:4][C:3]=2[N+:10]([O-:12])=[O:11])[CH:17]=[C:18]([Cl:20])[CH:19]=1
Reactant: Sc1cc(Cl)cc(Cl)c1
Reactant: CC(=O)c1cc([N+](=O)[O-])c(Cl)s1
Product: CC(=O)c1cc([N+](=O)[O-])c(Sc2cc(Cl)cc(Cl)c2)s1

Procedure:
Prepared according to the procedure described as in Step B for example 1 from 1-(5-Chloro-4-nitro-2-thienyl)ethanone (0.502 g, 2.45 mmol) and 3,5-dichlorobenzenethiol (0.438 g, 2.45 mmol). The title compound was obtained as a yellow solid (0.403 g, 47.5% yield). 1H NMR (300 MHz, CDCl3) δ: 8.08 (1H, s), 7.57 (3H, m), 2.51 (3H, s).
Reaction SMILES: [NH2:1][C:2]1[C:7](I)=[CH:6][C:5]([N:9]2[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]2)=[CH:4][C:3]=1[CH3:15].[C-:16]#[N:17].[K+].CC(C)=O>O>[NH2:1][C:2]1[C:7]([C:16]#[N:17])=[CH:6][C:5]([N:9]2[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]2)=[CH:4][C:3]=1[CH3:15]
Reactant: [C-]#N
Reactant: Cc1cn(-c2cc(C)c(N)c(I)c2)cn1
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: Cc1cn(-c2cc(C)c(N)c(C#N)c2)cn1
Reaction time: 72 h
Yield: 66 %

Procedure:
A mixture of 2-amino-3-iodo-5-(4-methylimidazol-1-yl)toluene (391 mg), potassium cyanide (130 mg), PD(OCA) (catalytic amount) and dimethylformaldehyde (4.01 ml) was heated under stirring under nitrogen atmosphere for 3 days. Solvent was removed to give a residue. To the residue was added water and the solution was extracted with chloroform. The extract was dried with MgSO and solvent was removed to give 175 mg (66%) of the title compound.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:14]([OH:16])=O.CN(C)C=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[Cl:34][C:35]1[CH:42]=[CH:41][C:38]([CH2:39][NH2:40])=[CH:37][CH:36]=1>O>[Cl:34][C:35]1[CH:42]=[CH:41][C:38]([CH2:39][NH:40][C:14]([C:3]2[CH:4]=[N:5][C:6]3[C:11]([C:2]=2[OH:1])=[CH:10][CH:9]=[CH:8][C:7]=3[O:12][CH3:13])=[O:16])=[CH:37][CH:36]=1
Reactant: COc1cccc2c(O)c(C(=O)O)cnc12
Reactant: NCc1ccc(Cl)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CN(C)C=O
Product: COc1cccc2c(O)c(C(=O)NCc3ccc(Cl)cc3)cnc12
Temperature: 37 °C
Reaction time: 20 h

Procedure:
To a mixture of 0.50 g of 4-hydroxy-8-methoxy-3-quinolinecarboxylic acid (J. Amer. Chem. Soc., 68, 1268 (1946)) and 10 mL of dimethylformamide is added 0.41 g of carbonyldiimidazole. The mixture is stirred 20 h at 37° C. and then it is cooled to ° C. The mixture is treated with 0.25 mL of distilled water and stirred for 5 min. To the resulting solution is added 0.31 mL of 4-chlorobenzylamine. After stirring for 18 hours the mixture is warmed to 40° C. and stirred an additional 24 h. The solution is then cooled to 25° C. and it is diluted with 10 mL of distilled water. After minutes the precipitate is collected by filtration and it is washed with two successive 5 mL portions of 10% aqueous acetic acid. It is dried for 18 h in a stream of air at 25° C. This procedure yields the title compound as 485 mg of a tan solid.