Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:12](#[N:16])[CH2:13][C:14]#[N:15].C(N(CC)CC)C>C(O)C>[N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[C:13]([C:12]#[N:16])[C:14]#[N:15])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: N#CCC#N
Solvent: CCN(CC)CC
Solvent: CCO
Product: N#CC(C#N)=Cc1ccc([N+](=O)[O-])cc1

Procedure:
3.45 Grams(22.83 mmol) of 4-nitrobenzaldehyde and 1.52 grams(23.03 mmol) of malononitrile were dissolved in 200 milliliters of anhydrous ethanol. To this was added 0.35 milliliter of triethylamine, and the mixture was stirred and refluxed, under nitrogen, for 2 hours. The solvent was removed using a rotary evaporator and the crude reaction product was crystallized from ethanol. 2.33 Grams(51.5%) of the product was obtained. IR (in nujol) analysis showed bands at 3100, 3025, 2950-2850, 2220 (CN), 1595, 1570, 1510, 1450, 1410, 1365, 1340, 1315, 1300, 1210, 935, 850, 835, 780, 745, 680 and 620 cm-1NMR (CDCl3) analysis showed signals at 8.40(d, 2H, J=9 Hz), 8.08(d, 2H, J=9 Hz) and 7.89(s, 1H) ppm.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[C@H:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([Cl:17])[CH:11]=2)[O:8][CH2:7][CH2:6][N:5]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:4]1.C(N(CC)CC)C.[C:32](Cl)(=[O:34])[CH3:33]>C1COCC1>[C:32]([NH:1][CH2:2][C@H:3]1[C@H:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([Cl:17])[CH:11]=2)[O:8][CH2:7][CH2:6][N:5]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:4]1)(=[O:34])[CH3:33]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(Cl)c2)[C@H](CN)C1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)NC[C@@H]1CN(C(=O)OC(C)(C)C)CCO[C@H]1c1ccc(Cl)c(Cl)c1
Yield: 97.1 %

Procedure:
To a solution of tert-butyl (6R,7R)-6-(aminomethyl)-7-(3,4-dichlorophenyl)-1,4-oxazepane-4-carboxylate (150 mg) in THF (2 ml) were added triethylamine (0.084 mL) and acetyl chloride (47 mg), and the mixture was stirred at under ice-cooling for 2 hr. The solvent was evaporated under reduced pressure, distilled water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The combined organic layers were washed with brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (162 mg).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([NH:16][C:17](=[O:19])[CH3:18])=[N:13][C:14]=2[CH3:15])[CH:5]=[CH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].[CH3:26][N:27]1[CH:31]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:29]=[N:28]1>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:15][C:14]1[N:13]=[C:12]([NH:16][C:17](=[O:19])[CH3:18])[CH:11]=[CH:10][C:9]=1[O:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([C:30]2[CH:29]=[N:28][N:27]([CH3:26])[CH:31]=2)[CH:7]=1
Reactant: CC(=O)Nc1ccc(Oc2ccnc(Cl)c2)c(C)n1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)Nc1ccc(Oc2ccnc(-c3cnn(C)c3)c2)c(C)n1
Temperature: 80 °C
Yield: 87 %

Procedure:
A solution of Example A3 (3.83 g, 13.79 mmol) in dioxane (50 mL) was sparged with argon, treated with a solution of K2CO3 (3.81 g, 27.6 mmol) in H2O (10 mL), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (3.44 g, 16.55 mmol) and Pd(PPh3)4 (0.637 g, 0.552 mmol) and heated at 80° C. for 16 h. The mixture was cooled to RT, treated with H2O, extracted with EtOAc (2×) and the combined organics washed with H2O, then brine, dried over Na2SO4 and concentrated to dryness. The material was suspended in 3:2 EtOAc/Hex, sonicated and the resulting solid collected via filtration and dried. The filtrate was concentrated to dryness, purified via silica gel chromatography (MeOH/DCM) and combined with the isolated solid to afford N-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)acetamide (3.88 g, 87%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 10.60 (s, 1 H), 8.34 (d, J=5.7 Hz, 1 H), 8.25 (s, 1 H), 8.01 (d, J=8.8 Hz, 1 H), 7.95 (s, 1 H), 7.57 (d, J=8.8 Hz, 1 H), 7.17 (d, J=2.4 Hz, 1 H), 6.58 (dd, J=5.7, 2.4 Hz, 1 H), 3.84 (s, 3 H), 2.25 (s, 3 H), 2.08 (s, 3 H); MS (ESI) m/z: 324.1 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1([O:13][CH3:14])[CH2:8][NH:7][CH:6]([C:9]([O:11][CH3:12])=[O:10])[CH2:5][CH2:4]1.[CH3:15][C:16]1[S:17][C:18]([C:27](O)=[O:28])=[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:20]=1>>[CH3:1][O:2][C:3]1([O:13][CH3:14])[CH2:8][N:7]([C:27]([C:18]2[S:17][C:16]([CH3:15])=[N:20][C:19]=2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:28])[CH:6]([C:9]([O:11][CH3:12])=[O:10])[CH2:5][CH2:4]1
Reactant: COC(=O)C1CCC(OC)(OC)CN1
Reactant: Cc1nc(-c2ccccc2)c(C(=O)O)s1
Product: COC(=O)C1CCC(OC)(OC)CN1C(=O)c1sc(C)nc1-c1ccccc1

Procedure:
Methyl 5,5-dimethoxy-1-(2-methyl-4-phenylthiazole-5-carbonyl)piperidine-2-carboxylate was prepared according to general procedure A using methyl 5,5-dimethoxypiperidine-2-carboxylate and 2-methyl-4-phenylthiazole-5-carboxylic acid.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]=O.[CH3:13][N:14]([CH3:19])[CH2:15][CH2:16][CH2:17][NH2:18]>C1C=CC=CC=1>[CH3:13][N:14]([CH3:19])[CH2:15][CH2:16][CH2:17][N:18]=[CH:11][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1
Reactant: CN(C)CCCN
Reactant: O=Cc1ccc2ccccc2c1
Solvent: c1ccccc1
Product: CN(C)CCCN=Cc1ccc2ccccc2c1
Yield: 93.4 %

Procedure:
Interaction of 15.6 g of 2-naphthaldehyde and 10.2 g of 3-dimethylaminopropylamine in 80 ml. of benzene following the procedure described in Example 1 yields 22.4 g of oily product; boiling point 146°-149° C. at 0.1-0.2 mm. of Hg. The material solidifies when stored in the cold, melting point 29°-31° C.
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:13]#[N:14])[CH:10]=2)[NH:5]1.Cl[C:16]1[N:21]=[CH:20][C:19]([S:22]([N:25]2[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]2)(=[O:24])=[O:23])=[CH:18][CH:17]=1>CN(C)C=O>[OH:3][C:4]1[NH:5][C:6]2[C:11]([C:12]=1[C:16]1[CH:17]=[CH:18][C:19]([S:22]([N:25]3[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]3)(=[O:24])=[O:23])=[CH:20][N:21]=1)=[CH:10][C:9]([C:13]#[N:14])=[CH:8][CH:7]=2
Reactant: CN1CCN(S(=O)(=O)c2ccc(Cl)nc2)CC1
Reactant: N#Cc1ccc2c(c1)CC(=O)N2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCN(S(=O)(=O)c2ccc(-c3c(O)[nH]c4ccc(C#N)cc34)nc2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 9.8 %

Procedure:
A mixture of sodium hydride (0.157 g, 3.9 mmol, 60% dispersion in oil, pre-washed with hexane) in N,N-dimethylformamide (2 mL) was added to 2-oxoindoline-5-carbonitrile (0.464 g, 2.9 mmol) in N,N-dimethylformamide (5 mL). The formed brown mixture was stirred at room temperature for 10 min and 1-[(6-chloropyridin-3-yl)sulfonyl]-4-methylpiperazine (0.255 g, 0.92 mmol; described in: Thunus L. Annuale Pharmacetiques Francisies, 1977, 35, 197-203) in N,N-dimethylformamide (3 mL) was added. The obtained red solution was heated at 150° C. for 10 min and was then allowed to reach room temperature overnight. The solvent was removed in vacuo and the residue was partitioned between an aqueous HCl solution (2 M) and ethyl acetate. The aqueous mixture was alkalized to pH 8 by adding sodium hydrogen carbonate (s), and extracted with ethyl acetate (3×10 mL). The combined extracts were dried (Na2SO4), and the solvent was removed in vacuo. The residue was purified on a silica gel column using chloroform/methanol/conc. NH3 (aq), (84:14:2), as an eluent to afford 0.050 g. Further purification was done by preparative HPLC (Xterra column (19×300 mm) with 0.05 M NH4OAc buffer/acetonitrile, (90:10-30:70), as a eluent). Fractions containing product were collected, evaporated in vacuo, and dried at 25° C. in vacuo over night to afford 0.036 g (10% yield) of the title compound: 1H NMR (D2O, 400 MHz) δ 8.12 (s, 1H), 7.60 (d, J=10 Hz, 1H), 7.13 (s, 1H), 7.00 (dd, J=8, 2 Hz, 1H), 6.93 (d, J=9 Hz, 1H), 6.73 (dd, J=8, 2 Hz, 1H), 3.91 (d, J=13 Hz, 2H), 3.60 (d, J=11 Hz, 2H), 3.24 (app. t, J=11 Hz, 2H), 3.02 (app. t, J=12 Hz, 2H), 2.89 (s, 3H); MS (TSP) m/z 398 (M++1).
Reaction SMILES: [CH2:1]([N:8]1[C:17](=[O:18])[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>CO>[CH2:1]([N:8]1[CH:17]([OH:18])[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1Cc2ccccc2C(=O)N1Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: O=C1c2ccccc2CC(O)N1Cc1ccccc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a well-stirred ice-bath-chilled solution of 2-benzyl-4H-isoquinoline-1,3-dione (5.0 g, 20 mmol) in methanol (40 ml), sodium borohydride (3.0 g, 80 mmol) was added portionwise over 20 minutes. The reaction mixture was stirred at ambient temperature for 48 hours. TLC inspection of a reaction aliquot confirmed substantial formation of product, with some starting material remaining. TLC Rf of the title compound (silica gel plates; u.v. detection; elution with ethyl acetate/hexane=3.7 in volume): 0.24. The ice-bath-chilled reaction mixture was cautiously quenched with water (3 ml). Anhydrous sodium sulfate was added to dry the mixture, which was then filtered. The filtrate was concentrated in vacuo to a dark green oil (3.5 g). Flash chromatography (silica gel, 40 micron mesh; elution with ethyl acetate hexane=3.7 volume) afforded the title compound as a colorless amorphous solid (1.35 g). The labile material was used immediately in the next step.
Reaction SMILES: N1C=CC=CC=1.[C:7](Cl)([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:8].[C:15]([O:18][CH2:19][CH2:20][N:21]1[CH:25]=[CH:24][CH:23]=[CH:22]1)(=[O:17])[CH3:16]>ClCCl>[C:15]([O:18][CH2:19][CH2:20][N:21]1[CH:22]=[CH:23][CH:24]=[C:25]1[C:7](=[O:8])[C:9]([O:11][CH2:12][CH3:13])=[O:10])(=[O:17])[CH3:16]
Reactant: CC(=O)OCCn1cccc1
Reactant: CCOC(=O)C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)C(=O)c1cccn1CCOC(C)=O

Procedure:
In the next step, a solution of pyridine in anhydrous dichloromethane is added to a stirred and cooled solution of ethoxalyl chloride in anhydrous dichloromethane so that the reaction temperature remains at about -20° to -25° C. Upon completion of this addition an approximately equimolar amount of 1-(2-acetoxyethyl)pyrrole of Formula (III) in anhydrous dichloromethane is added while the temperature is maintained at temperatures of about 0° to -20° C. Washing with water, drying, removal of the solvent and purification gives ethyl 1-(2-acetoxyethyl)pyrrole-2-glyoxylate.
Reaction SMILES: C[Si]([O:5][C:6]1[C:11]([Cl:12])=[CH:10][C:9](I)=[CH:8][C:7]=1[Cl:14])(C)C.[O:15]1[CH:19]=[CH:18][CH:17]=[CH:16]1>>[Cl:14][C:7]1[CH:8]=[C:9]([C:16]2[O:15][CH:19]=[CH:18][CH:17]=2)[CH:10]=[C:11]([Cl:12])[C:6]=1[OH:5]
Reactant: C[Si](C)(C)Oc1c(Cl)cc(I)cc1Cl
Reactant: c1ccoc1
Product: Oc1c(Cl)cc(-c2ccco2)cc1Cl
Yield: 52 %

Procedure:
2,6-Dichloro-4-(2-furanyl)phenol [IV; R1 =2-Cl, R2 =6-Cl, Het=2-furanyl] was prepared from 2,6-dichloro-4-iodophenyl trimethylsilyl ether and furan according to the procedure of Example 1(b), and was obtained in 52% yield as a light brown solid, m.p. 68-70° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[C:7]([C:12]#[N:13])([CH2:10][CH3:11])[CH2:8][CH3:9])([CH3:4])([CH3:3])[CH3:2].N>C(O)C.[Ni]>[C:1]([O:5][C:6](=[O:14])[C:7]([CH2:12][NH2:13])([CH2:10][CH3:11])[CH2:8][CH3:9])([CH3:2])([CH3:4])[CH3:3]
Reactant: CCC(C#N)(CC)C(=O)OC(C)(C)C
Agent: [Ni]
Agent: N
Solvent: CCO
Product: CCC(CC)(CN)C(=O)OC(C)(C)C

Procedure:
29.21 g of 2-cyano-2-ethylbutyric acid tert-butyl ester, dissolved in 300 ml of ethanol, which contains 4% ammonia, are hydrogenated under normal pressure at 40° in the presence of 6 g of Raney nickel. After separating off from the catalyst, the batch is concentrated by evaporation in vacuo and the liquid that remains is distilled in vacuo to yield 2-aminomethyl-2-ethylbutyric acid tert-butyl ester, boiling point 65° at 0.6 mbar.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:24])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18]3[N:19]=[CH:20][N:21]([CH3:23])[CH:22]=3)[S:17][C:10]=12.FC1C=C(NC(NC(=O)CC2C=CC=CC=2)=S)C=CC=1OC1C=CN=C2C=C(C3C=CC(S(C)(=O)=O)=CC=3)SC=12.[F:65][C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][C:67]=1[CH2:72][C:73]([N:75]=[C:76]=[S:77])=[O:74]>>[F:1][C:2]1[CH:3]=[C:4]([NH:24][C:76]([NH:75][C:73](=[O:74])[CH2:72][C:67]2[CH:68]=[CH:69][CH:70]=[CH:71][C:66]=2[F:65])=[S:77])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18]3[N:19]=[CH:20][N:21]([CH3:23])[CH:22]=3)[S:17][C:10]=12
Reactant: Cn1cnc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)c1
Reactant: O=C(Cc1ccccc1F)N=C=S
Agent: CS(=O)(=O)c1ccc(-c2cc3nccc(Oc4ccc(NC(=S)NC(=O)Cc5ccccc5)cc4F)c3s2)cc1
Product: Cn1cnc(-c2cc3nccc(Oc4ccc(NC(=S)NC(=O)Cc5ccccc5F)cc4F)c3s2)c1
Yield: 24 %

Procedure:
Starting from the amine 177, following the procedure described above for the synthesis of compound 50 (scheme 10, example 55) but replacing 2-phenylacetyl isothiocyanate with 2-(2-fluorophenyl)acetyl isothiocyanate, title compound 178 was obtained in 24% yield. 1H NMR (400 MHz, DMSO-d6) δ ppm: 12.44 (s, 1H), 11.88 (s, 1H), 8.46 (d, 1H, J=5.5 Hz), 8.34 (dd, 1H, J=12.3/2.2 Hz), 7.87 (d, 1H, J=1.2 Hz), 7.72 (d, 1H, J=1.2 Hz), 7.69 (s, 1H), 7.57-7.49 (m, 2H), 7.43-7.31 (m, 2H), 7.23-7.15 (m, 2H), 6.59 (d, 1H, J=5.5 Hz), 3.94 (s, 2H), 3.73 (s, 3H). LRMS (M+1) 536.1 (100%).
Reaction SMILES: [Li+].[OH-].C[O:4][C:5](=[O:26])[CH:6]=[CH:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]([S:17]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)(=[O:19])=[O:18])[CH2:12][CH2:11]2>O1CCOCC1>[C:20]1([S:17]([N:13]2[C:14]3[C:10](=[CH:9][C:8]([CH:7]=[CH:6][C:5]([OH:26])=[O:4])=[CH:16][CH:15]=3)[CH2:11][CH2:12]2)(=[O:19])=[O:18])[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: COC(=O)C=Cc1ccc2c(c1)CCN2S(=O)(=O)c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)C=Cc1ccc2c(c1)CCN2S(=O)(=O)c1ccccc1
Temperature: 40 °C
Reaction time: 8 h
Yield: 83.8 %

Procedure:
1M LiOH aqueous solution (1.16 ml, 1.16 mmol) was added to a solution of 14 (0.20 g, 0.58 mmol) in dioxane (15 mL). The reaction mixture was stirred at 40° C. overnight before it was concentrated under reduced pressure. The residue was dissolved in water and concentrated HCl was added up to acidic pH to give the precipitation, which was dried by vacuum to afford 15 (0.16 g). 1H NMR (500 MHz, CD3OD): δ 2.92 (t, J=8.5 Hz, 2H), 3.96 (t, J=8.5 Hz, 2H), 6.33 (d, J=15.9 Hz, 1H), 7.38 (s, 1H), 7.41 (d, J=8.5 Hz, 1H), 7.50-7.53 (m, 2H), 7.55 (d, J=16.1 Hz, 1H), 7.58-7.64 (m, 2H), 7.82 (d, J=7.6 Hz, 2H).
Reaction SMILES: [C:1]([CH2:3][C:4]([NH:6][CH:7]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[CH:13][CH:12]=1)[CH2:8][CH2:9][CH3:10])=[O:5])#[N:2].NCCC(O)=O.O.[Br:32][C:33]1[N:38]=[C:37]([CH:39]=O)[CH:36]=[CH:35][CH:34]=1>C(O)C.C(OCC)(=O)C>[Br:32][C:33]1[N:38]=[C:37](/[CH:39]=[C:3](\[C:1]#[N:2])/[C:4]([NH:6][CH:7]([C:11]2[CH:12]=[CH:13][C:14]([O:17][CH2:18][CH2:19][N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[CH:15][CH:16]=2)[CH2:8][CH2:9][CH3:10])=[O:5])[CH:36]=[CH:35][CH:34]=1
Reactant: CCCC(NC(=O)CC#N)c1ccc(OCCN(CC)CC)cc1
Reactant: O=Cc1cccc(Br)n1
Agent: NCCC(=O)O
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: CCCC(NC(=O)/C(C#N)=C/c1cccc(Br)n1)c1ccc(OCCN(CC)CC)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 80.1 %

Procedure:
To the solution of 2-cyano-N-(1-(4-(2-(diethylamino)ethoxy)phenyl)butyl)acetamide (29; 116 mg, 0.35 mmol) in ethanol (2 mL) was added β-alanine (499 mg, 5.6 mmol) and water (2 mL). 6-Bromopicolinaldehyde (260 mg, 1.4 mmol) was added, and the resulting mixture was then stirred at room temperature for 18 hours. The reaction mixture was diluted with ethyl acetate, washed with sat. aqueous NaHCO3 (2×) and sat. brine, dried over sodium sulfate, and concentrated to a crude solid. Purification by flash silica gel column chromatography, eluting with 5:95 methanol/dichloromethane, afforded 33 (140 mg, 80%) as a thick yellow oil: MS (ES+) m/z=499.1 (M+H)+.
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:7]([N:32]2[N:41]=[CH:40][C:39]3[C:34](=[C:35]([F:46])[CH:36]=[C:37]([C:42]([CH3:45])([CH3:44])[CH3:43])[CH:38]=3)[C:33]2=[O:47])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:18][C:19]2[CH:29]=[C:22]3[CH2:23][O:24][C:25]([CH3:28])([CH3:27])[CH2:26][N:21]3[N:20]=2)[C:15](=[O:30])[N:14]([CH3:31])[CH:13]=1)(=O)C.[OH-].[Li+]>C(O)(C)C.C1COCC1.O>[C:42]([C:37]1[CH:38]=[C:39]2[C:34](=[C:35]([F:46])[CH:36]=1)[C:33](=[O:47])[N:32]([C:7]1[C:6]([CH2:5][OH:4])=[C:11]([C:12]3[CH:17]=[C:16]([NH:18][C:19]4[CH:29]=[C:22]5[CH2:23][O:24][C:25]([CH3:28])([CH3:27])[CH2:26][N:21]5[N:20]=4)[C:15](=[O:30])[N:14]([CH3:31])[CH:13]=3)[CH:10]=[CH:9][N:8]=1)[N:41]=[CH:40]2)([CH3:45])([CH3:43])[CH3:44]
Reactant: CC(=O)OCc1c(-c2cc(Nc3cc4n(n3)CC(C)(C)OC4)c(=O)n(C)c2)ccnc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC(C)O
Solvent: O
Product: Cn1cc(-c2ccnc(-n3ncc4cc(C(C)(C)C)cc(F)c4c3=O)c2CO)cc(Nc2cc3n(n2)CC(C)(C)OC3)c1=O
Temperature: 30 °C
Reaction time: 1 h
Yield: 40 %

Procedure:
A mixture of 139f (160 mg, 0.25 mmol) and lithium hydroxide (60 mg, 2.5 mmol) in i-propanol/THF (1:1, 4 mL) and water (1 mL) was stirred at 30° C. for 1 h. The mixture was evaporated under reduced pressure and the residue was diluted with water (5 mL). It was then extracted with ethyl acetate (3×10 mL). The combined ethyl acetate extract was concentrated under reduced pressure and the residue was purified by reverse-phase prep-HPLC to afford 139 (60 mg, 40%) as a light yellow solid. MS-ESI: [M+H]+ 599.8. 1H NMR (500 MHz, DMSO-d6) δ 8.57 (d, J=5.0 Hz, 1H), 8.54 (d, J=2.5 Hz, 1H), 8.34 (s, 1H), 8.08 (d, J=2.5 Hz, 1H), 7.90 (d, J=1.5 Hz, 1H), 7.79-7.76 (m, 1H), 7.51 (d, J=5.0 Hz, 1H), 7.39 (d, J=2.0 Hz, 1H), 5.95 (s, 1H), 4.92 (bs, 1H), 4.73 (s, 2H), 4.42 (s, 2H), 3.80 (s, 2H), 3.60 (s, 3H), 1.40 (s, 9H), 1.26 (s, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[CH2:18]([N:25]=[C:26]=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH2:18]([NH:25][C:26]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1)=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Reactant: O=C=NCc1ccccc1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)NCc4ccccc4)cc23)CC1
Yield: 39.6 %

Procedure:
Beginning with 15.0 mg (0.0655 mMol) 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 11.32 mg (0.0852 mMol) benzyl isocyanate, 9.4 mg of the title compound were recovered.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([O:9][C:10](N1C=CN=C1)=[O:11])[CH2:2]2.[F:17][C:18]1[CH:19]=[C:20]([CH:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[OH:25])[CH:21]=[CH:22][CH:23]=1>>[F:17][C:18]1[CH:19]=[C:20]([CH:24]([O:25][C:10](=[O:11])[O:9][C@@H:3]2[CH:4]3[CH2:5][CH2:6][N:1]([CH2:8][CH2:7]3)[CH2:2]2)[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:21]=[CH:22][CH:23]=1
Reactant: OC(c1ccccc1)c1cccc(F)c1
Reactant: O=C(O[C@H]1CN2CCC1CC2)n1ccnc1
Product: O=C(OC(c1ccccc1)c1cccc(F)c1)O[C@H]1CN2CCC1CC2

Procedure:
The desired product was prepared by reacting imidazole-1-carboxylic acid (R)-1-aza-bicyclo[2.2.2]oct-3-yl ester with (3-fluoro-phenyl)-phenyl-methanol.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=1[C:18](OC)=[O:19])(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:22][NH:23][CH3:24]>CO>[C:1]([NH:5][S:6]([C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=1[C:18]([N:23]([CH3:24])[CH3:22])=[O:19])(=[O:8])=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CNC
Reactant: COC(=O)c1ccc([N+](=O)[O-])cc1S(=O)(=O)NC(C)(C)C
Solvent: CO
Product: CN(C)C(=O)c1ccc([N+](=O)[O-])cc1S(=O)(=O)NC(C)(C)C
Temperature: 35 °C
Yield: 76.8 %

Procedure:
115 g of N-tert.-butyl-2-methoxycarbonyl-5-nitrobenzenesulfonamide (Example c) in 1500 ml of methanol are gassed with about 200 g of dimethylamine. The mixture is stirred at about 35° C. for one week. The solution is concentrated under reduced pressure, the residue is taken up in ethyl acetate and the mixture is washed successively with dilute hydrochloric acid, saturated NaHCO3 solution and saturated NaCl solution. After drying over MgSO4, the organic phase is concentrated. 92 g of N-tert.-butyl-2-dimethylaminocarbonyl-5-nitro-benzensulfonamide are obtained: m.p.: 138-141° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:26][C:13]3([CH3:27])[CH2:14][N:15]([CH3:25])[CH2:16][C:17]4[C:18]5[CH:19]=[C:20]([CH3:24])[CH:21]=[CH:22][C:23]=5[N:11]([C:12]=43)[CH2:10][CH:9]=2)=[CH:4][CH:3]=1>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:26][C:13]3([CH3:27])[CH2:14][N:15]([CH3:25])[CH2:16][C:17]4[C:18]5[CH:19]=[C:20]([CH3:24])[CH:21]=[CH:22][C:23]=5[N:11]([C:12]=43)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: Cc1ccc2c(c1)c1c3n2CC=C(c2ccc(F)cc2)CC3(C)CN(C)C1
Solvent: CO
Product: Cc1ccc2c(c1)c1c3n2CCC(c2ccc(F)cc2)CC3(C)CN(C)C1

Procedure:
5-(4-Fluoro-phenyl)-2,3a,10-trimethyl-1,2,3,3a,4,7-hexahydro-2,7a-diaza-cyclohepta[jk]fluorene (30 mg, 0.083 mmol) was dissolved in MeOH (4 mL) and the solution was purged with nitrogen. Palladium chloride (15 mg) was added and hydrogen gas was bubbled through the reaction mixture for 2 h. The reaction mixture was filtered through Celite bed and the Celite bed was rinsed with MeOH. The filtrate was concentrated under reduced pressure to obtain 5-(4-fluoro-phenyl)-2,3a,10-trimethyl-1,2,3,3a,4,5,6,7-octahydro-2,7a-diaza-cyclohepta[jk]fluorene. 1H NMR, (HCl, salt, CD3OD) δ (ppm): 7.30 (m, 3H), 7.18 (m, 1H), 7.05-6.95 (m, 3H), 4.70 (m, 2H), 4.30 (m, 2H), 4.10 (m, 1H), 3.58-3.40 (m, 2H), 3.15 (s, 3H), 2.42 (s, 3H), 2.30 (m, 2H), 1.90-1.80 (m, 2JH), 1.70 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7]O[C:9]2=[O:14])([O-:3])=[O:2].[O:15]1[C:20]2[CH:21]=[CH:22][C:23]([CH2:25][NH2:26])=[CH:24][C:19]=2[O:18][CH2:17][CH2:16]1.CO>>[O:15]1[C:20]2[CH:21]=[CH:22][C:23]([CH2:25][N:26]3[CH:7]=[CH:6][C:5]4[C:10](=[CH:11][CH:12]=[CH:13][C:4]=4[N+:1]([O-:3])=[O:2])[C:9]3=[O:14])=[CH:24][C:19]=2[O:18][CH2:17][CH2:16]1
Reactant: NCc1ccc2c(c1)OCCO2
Reactant: O=c1occc2c([N+](=O)[O-])cccc12
Solvent: CO
Product: O=c1c2cccc([N+](=O)[O-])c2ccn1Cc1ccc2c(c1)OCCO2

Procedure:
5-Nitro-isochromen-1-one (1.0 g, 0.0052 mol) and C-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-methylamine (1.0 g, 0.0060 mol) were refluxed in methanol (40 mL, 1 mol) for 2 hours. The solvent was removed and the residue was purified via flash chromatography (40 g of silica gel, 0-30% EtOAc/Hexanes) to give a yellow solid.
Reaction SMILES: CC([O-])(C)C.[K+].Cl.[NH2:8][OH:9].[CH3:10][C:11]1([CH3:28])[O:15][CH:14]([CH2:16][O:17][C:18]2[C:25]([CH3:26])=[CH:24][C:21]([C:22]#[N:23])=[CH:20][C:19]=2[CH3:27])[CH2:13][O:12]1>CO>[CH3:10][C:11]1([CH3:28])[O:15][CH:14]([CH2:16][O:17][C:18]2[C:25]([CH3:26])=[CH:24][C:21]([C:22]([NH:8][OH:9])=[NH:23])=[CH:20][C:19]=2[CH3:27])[CH2:13][O:12]1
Reactant: Cc1cc(C#N)cc(C)c1OCC1COC(C)(C)O1
Reactant: NO
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CO
Product: Cc1cc(C(=N)NO)cc(C)c1OCC1COC(C)(C)O1
Yield: 59.7 %

Procedure:
To a solution of potassium tert-butylate (6.18 g, 55.1 mmol) in MeOH (125 mL), hydroxylamine hydrochloride (5.74 g, 82.7 mmol) was added. To this solution, a solution of rac-4-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-3,5-dimethyl-benzonitrile (7.20 g, 27.6 mmol) in MeOH (40 mL) was added. The mixture was refluxed for 72 h before the solvent was removed in vacuo. The residue was purified by prep. HPLC (XBridge Prep C18, 30×75 mm, 5 μm, 2-95% acetonitrile in water containing 0.5% sat. aq. NH3) to give the title compound as a pale yellow solid (4.85 g). LC-MS: tR=0.67 min, [M+1]+=295.06; 1H NMR (CDCl3): δ1.43 (s, 3H), 1.48 (s, 3H), 2.29 (s, 6H), 3.76-3.81 (m, 1H), 3.83-3.88 (m, 1H), 3.93-3.99 (m, 1H), 4.17-4.23 (m, 1H), 4.47-4.54 (m, 1H), 5.02 (br s, 1H), 7.28 (s, 2H).