Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]#[C:18][C:19]4[CH:29]=[CH:28][C:22]([C:23]([O:25]CC)=[O:24])=[CH:21][CH:20]=4)[CH:15]=3)[S:10][C:9]([CH3:31])([CH3:30])[CH:8]=2)=[CH:4][CH:3]=1.[OH-].[Na+].Cl>C1COCC1.CCO>[CH3:1][C:2]1[S:6][C:5]([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]#[C:18][C:19]4[CH:20]=[CH:21][C:22]([C:23]([OH:25])=[O:24])=[CH:28][CH:29]=4)[CH:15]=3)[S:10][C:9]([CH3:31])([CH3:30])[CH:8]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ccc(C)s2)=CC(C)(C)S3)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1ccc(C2=CC(C)(C)Sc3ccc(C#Cc4ccc(C(=O)O)cc4)cc32)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
To a solution of ethyl 4-[[4-(5-methylthiophen-2-yl)-2,2-dimethyl-(2H)-thiochromen-6-yl]-ethynyl]-benzoate (Compound 230, 143.0 mg, 0.322 mmol) in 3.0 mL THF and 3.0 mL EtOH was added NaOH (160.0 mg, 4.0 mmol, 4.0 mL of a 1M aqueous solution). The resulting solution was stirred overnight at room temperature. The reaction mixture was acidified with 10% aqueous HCl and extracted with EtOAc. The combined organic layers were washed with H2O, saturated aqueous NaCl, and dried (Na2SO4) before removing the solvent under reduced pressure. The residual solid was recrystallized from CH3CN to give 110.0 mg (82%) of the title compound as a pale-yellow solid. 1H NMR (300 MHz, d6 -acetone) δ: 8.03 (2H, d, J=8.4 Hz), 7.63 (2H, d, J=8.3 Hz), 7.60 (1H, s), 7.44 (2H, s), 6.87 (1H, d, J=3.5 Hz), 6.79 (1H, m), 6.10 (1H, s), 2.49 (3H, s), 1.45 (6H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5](Cl)=[O:6].[F:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][C:14]=1[N+:20]([O-:22])=[O:21].C(N(CC)CC)C>C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([NH:17][C:16]1[CH:18]=[CH:19][C:13]([F:12])=[C:14]([N+:20]([O-:22])=[O:21])[CH:15]=1)=[O:6]
Reactant: Nc1ccc(F)c([N+](=O)[O-])c1
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(F)c([N+](=O)[O-])c1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3,4-Dichlorobenzoyl chloride (4.3 g, 20.5 mmol) was added all at once to 4-fluoro-3-nitroaniline (3.14 g, 20.1 mmol) and triethylamine (3 mL, 21.5 mmol) in ethyl acetate (200 mL) at room temperature. The reaction mixture was stirred overnight at room temperature then diluted to ˜500 mL with ethyl acetate. The ethyl acetate was washed successively with 1N HCl (100 mL), saturated sodium bicarbonate (100 mL), and brine (100 mL), then dried (magnesium sulfate), filtered, and stripped of solvent under reduced pressure. Trituration of the residue in hexanes (125 mL) and a few milliliters of ethyl acetate afforded the product by filtration (5.6 g); m.p. 202-204° C.
Reaction SMILES: [OH:1][C:2]([CH3:21])([CH3:20])[CH2:3][CH2:4][CH2:5][C@H:6]([C@H:8]1[CH2:17][CH2:16][CH2:15][C@@H:14]2[C@:9]1([CH3:19])[CH2:10][CH2:11][CH2:12][C@@H:13]2[OH:18])[CH3:7].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.C(OCC)C>C(Cl)Cl>[OH:1][C:2]([CH3:20])([CH3:21])[CH2:3][CH2:4][CH2:5][C@H:6]([C@H:8]1[CH2:17][CH2:16][CH2:15][C@@H:14]2[C@:9]1([CH3:19])[CH2:10][CH2:11][CH2:12][C:13]2=[O:18])[CH3:7]
Reactant: C[C@H](CCCC(C)(C)O)[C@H]1CCC[C@H]2[C@@H](O)CCC[C@]12C
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: C[C@H](CCCC(C)(C)O)[C@H]1CCC[C@H]2C(=O)CCC[C@]12C
Reaction time: 4 h
Yield: 85.4 %

Procedure:
To a solution of 104 mg (0.35 mMol) of (1S,4aR,5R,8aR)-5-[(R)-5-Hydroxy-1,5-dimethyl-hexyl]-4a-methyl-decahydro-naphtalen-1-ol in 2 ml of CH2Cl2 are added under stirring 91.5 mg (0.42 mMol) of pyridiniumchlorochromate. The reaction mixture is kept stirring for 4 hours, diethylether is added and the slurry is filtered through Florisil using diethylether as eluant. The residue obtained after evaporation in vacuo is chromatographed over 5 g of silicagel with CH2Cl2 /ethylacetate 9/1 to yield 88 mg (85.5%) of oily pure (4aR,5R,8aR)-5-[(R)-5-Hydroxy-1,5-dimethyl-hexyl]-4a-methyl-octahydro-naphtalen-1-one.
Reaction SMILES: [C:1]([C:3]1[C:4]([N:9]([CH3:14])[S:10]([CH3:13])(=[O:12])=[O:11])=[N:5][CH:6]=[CH:7][CH:8]=1)#[N:2].[H][H]>[Pd].N.CO>[NH2:2][CH2:1][C:3]1[C:4]([N:9]([CH3:14])[S:10]([CH3:13])(=[O:12])=[O:11])=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: [H][H]
Reactant: CN(c1ncccc1C#N)S(C)(=O)=O
Agent: [Pd]
Agent: N
Solvent: CO
Product: CN(c1ncccc1CN)S(C)(=O)=O

Procedure:
N-(3-Aminomethyl-pyridin-2-yl)-N-methyl-methanesulfonamide was prepared from N-(3-cyano-pyridin-2-yl)-N-methyl-methanesulfonamide (3.35 g, 15.8 mmol) (prepared as described in J. Heterocyclic Chemistry, 1979, 16, 1361-1363) via hydrogenation using a Paar apparatus with 10% palladium on carbon (50% Wet) (5:45:50, Palladium:carbon black:Water, 5.71 g, 2.68 mmol) and hydrogen (50 psi) in 7M ammonia in methanol (100 mL). The mixture was shaken on a Paar apparatus until adsorption of hydrogen ceased. The mixture was degassed, backflushed with nitrogen, filtered through a plug of diatomaceous earth and rinsed with dichloromethane. The filtrate was evaporated under reduced pressure. Product isolated as pale yellow oil (3.20, 93%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.37 (dd, J=4.6, 1.7 Hz, 1H), 7.92 (dd, J=7.7, 1.7 Hz, 1H), 7.32 (dd, J=7.7, 4.8 Hz, 1H), 4.04 (s, 2H), 3.26 (s, 3H), 3.08 (s, 3H). MS=216 (MH)+.
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].F[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][N:12]=2)=[CH:7][C:6]=1[N+:19]([O-:21])=[O:20].O>C(O)C>[CH2:1]([NH:3][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][N:12]=2)=[CH:7][C:6]=1[N+:19]([O-:21])=[O:20])[CH3:2]
Reactant: COc1ccnc(-c2ccc(F)c([N+](=O)[O-])c2)c1
Reactant: CCN
Solvent: O
Solvent: CCO
Product: CCNc1ccc(-c2cc(OC)ccn2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of ethylamine in ethanol (20% w/w, 2 ml) was added 1-fluoro-4-(4-methoxypyridin-2-yl)-2-nitrobenzene (200 mg). The mixture was stirred at ambient temperature for 4 hours and poured into water. The precipitate was collected by filtration and dried to give 1-ethylamino-4-(4-methoxypyridin-2-yl)-2-nitrobenzene (206 mg).
Reaction SMILES: [CH2:1]([N:3]([CH2:30][CH3:31])[C:4]([NH:6][C@H:7]1[CH2:21][C@H:20]2[C@@H:10]([CH2:11][C:12]3[C:22]4[C:15](=[CH:16][C:17]([CH:23]5SCCS5)=[CH:18][C:19]2=4)[NH:14][C:13]=3[CH3:28])[N:9]([CH3:29])[CH2:8]1)=[O:5])[CH3:2]>CO.[Ni]>[CH2:30]([N:3]([CH2:1][CH3:2])[C:4]([NH:6][C@H:7]1[CH2:21][C@H:20]2[C@@H:10]([CH2:11][C:12]3[C:22]4[C:15](=[CH:16][C:17]([CH3:23])=[CH:18][C:19]2=4)[NH:14][C:13]=3[CH3:28])[N:9]([CH3:29])[CH2:8]1)=[O:5])[CH3:31]
Reactant: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3cc(C4SCCS4)cc4[nH]c(C)c(c34)C[C@H]2N(C)C1
Agent: [Ni]
Solvent: CO
Product: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3cc(C)cc4[nH]c(C)c(c34)C[C@H]2N(C)C1

Procedure:
458 mg of 1,1-diethyl-3-[13-(1,3-dithiolan-2-yl)-2,6- dimethyl-8alpha-ergolinyl)-urea (1 mmol) is dissolved in 50 ml of methanol and treated with several portions of Raney nickel at room temperature until the initial material has disappeared according to thin-layer chromatography. It is filtered by kieselguhr, the solvent is concentrated by evaporation and the residue is chromatographed on silica gel with dichloromethane/methanol, the isolated substance is crystallized from methanol, yield 117 mg (31% of theory).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:11]=[C:10]([C:18](O)=[O:19])[CH:9]=2)=[CH:4][CH:3]=1.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.[NH2:44][C@@H:45]([CH3:48])[CH2:46][OH:47].C(N(CC)C(C)C)(C)C>C(Cl)Cl>[OH:47][CH2:46][C@@H:45]([NH:44][C:18]([C:10]1[CH:9]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=2)[CH:13]=[C:12]([S:14]([CH3:17])(=[O:15])=[O:16])[CH:11]=1)=[O:19])[CH3:48]
Reactant: C[C@H](N)CO
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(S(C)(=O)=O)c2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2cc(C(=O)N[C@@H](C)CO)cc(S(C)(=O)=O)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 4′-methyl-5-(methylsulfonyl)biphenyl-3-carboxylic acid (50 mg, 0.17 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (36 mg, 0.19 mmol), 1-hydroxybenzotriazole hydrate (26 mg, 0.17 mmol), and CH2Cl2 (2 mL) were added (S)-2-aminopropan-1-ol (19 mg, 0.26 mmol) and N,N-diisopropylethylamine (0.045 mL, 0.26 mmol). The mixture was stirred at room temperature overnight and then concentrated in vacuo. The residue was purified by preparative HPLC (100×20.2 mm, C18 column; 30-60% MeCN-water[10 mM Et2NH]) to yield a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.Cl.[NH2:13][CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21].C(N(CC)CC)C.C(O)(=O)C>C(#N)C.O>[NH2:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:13][CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])=[O:6]
Reactant: NC1CCC(=O)NC1=O
Reactant: Cc1cccc(C(=O)O)c1N
Agent: Cl
Solvent: CC(=O)O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1cccc(C(=O)NC2CCC(=O)NC2=O)c1N
Temperature: 25 °C
Reaction time: 5 h
Yield: 51.9 %

Procedure:
A mixture of 2-amino-3-methylbenzoic acid (2.1 g, 14 mmol) and Cal (1.9 g, 12 mmol) in acetonitrile (25 mL) was stirred at room temperature for 5 hours. To the suspension, was added 3-amino-piperidine-2,6-dione hydrogen chloride (2.3 g, 14 mmol), triethylamine (7.2 mL, 66 mmol) and acetic acid (8 mL, 132 mmol), and the mixture was heated to reflux for 16 hours. To the mixture, was added water (75 mL) and stirred at room temperature for 2 hours. The suspension was filtered and washed with water (50 mL) and ethyl acetate (20 mL) to give 2-amino-N-(2,6-dioxo-piperidin-3-yl)-3-methyl-benzamide as a white solid (1.9 g, 61% yield): 1H NMR (DMSO-d6) δ 1.92-1.99 (m, 1H, CHH), 2.06 (s, 3H, CH3), 2.04-2.14 (m, 1H, CHH), 2.51-2.56 (m, 1H, CHH), 2.73-2.85 (m, 1H, CHH), 4.69-4.78 (m, 1H, NCH), 6.22 (brs, 2H, NH2), 6.50 (t, J=8 Hz, 1H, Ar), 7.10 (d, J=8 Hz, 1H, Ar), 7.40 (d. J=8 Hz, 1H, Ar), 8.47 (d, J=8 Hz, 1H, NH), 10.83 (s, 1H, NH); LCMS: MH=262.
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19](=[O:32])[C:20]3[CH:25]=[CH:24][C:23]([CH:26]4[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]4)=[CH:22][CH:21]=3)[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].[NH2:35][NH2:36]>C(O)C>[CH:26]1([C:23]2[CH:24]=[CH:25][C:20]([C:19]([N:10]3[C:11]4[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=4[CH2:13][N:14]4[C:5]([C:3]([NH:35][NH2:36])=[O:4])=[CH:6][CH:7]=[C:8]4[CH2:9]3)=[O:32])=[CH:21][CH:22]=2)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: O=C(c1ccc(C2CCCCC2)cc1)N1Cc2ccc(C(=O)C(Cl)(Cl)Cl)n2Cc2ccccc21
Reactant: NN
Solvent: CCO
Product: NNC(=O)c1ccc2n1Cc1ccccc1N(C(=O)c1ccc(C3CCCCC3)cc1)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2,2,2-Trichloro-1-[10-cyclohexyl-benzoyl]10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl]-1-ethanone of Example 7 (1.3 g) was added to a solution of anhydrous hydrazine (0.24 g) in absolute ethanol (50 mL). After stirring overnight at room temperature, the volatiles were removed in vacuo and the residue extracted with dichloromethane. The combined extracts were dried over anhydrous sodium sulfate and filtered through a short column of Magnesol®. Removal of the solvent provided the title compound as a pale yellow amorphous solid.
Reaction SMILES: CC1(C)COC([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]2[CH:18]=[CH:17][C:16]([CH2:19][OH:20])=[CH:15][CH:14]=2)=N1.Cl>C(O)C>[OH:20][CH2:19][C:16]1[CH:17]=[CH:18][C:13]([C:8]2[CH:7]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:14][CH:15]=1
Reactant: CC1(C)COC(c2ccccc2-c2ccc(CO)cc2)=N1
Agent: Cl
Solvent: CCO
Product: OCc1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Yield: 100 %

Procedure:
2.0 g (7.11 mmol) of 4,4-dimethyl-2-(4'-hydroxymethylbiphenyl-2-yl)oxazoline was dissolved in ethanol (30 ml). 2N hydrochloric acid (10 ml) was added thereto, followed by heating under reflux for 3 hours. After the reaction liquid was cooled and concentrated, a saturated aqueous solution of sodium hydrogencarbonate (100 ml) was added thereto, followed by the extraction with chloroform. After the organic phase was washed with water and dried, it was subjected to vacuum concentration. A 20% aqueous solution of sodium hydroxide (20 ml) and ethanol (20 ml) were added to the residue, followed by heating under reflux for 8 hours. After the reaction liquid was cooled to room temperature and adjusted to pH 6 with hydrochloric acid, it was extracted with chloroform. After the organic phase was washed with water and dried, it was subjected to vacuum concentration. The residue was purified by silica gel column chromatography (a chloroform/methanol system) to give 1.31 g of the title compound (yield 81%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH2:10][CH2:11][CH2:12][CH3:13])=[C:7]([C:14](=[O:30])[C:15]3[CH:20]=[C:19]([I:21])[C:18]([CH2:22][CH3:23])=[C:17]([I:24])[C:16]=3[O:25][CH2:26][C:27]([OH:29])=[O:28])[C:6]=2[CH:31]=1.[CH3:32][O:33][C:34]1[CH:39]=[CH:38][C:37]([N:40]=[C:41]=[O:42])=[CH:36][CH:35]=1>C1COCC1>[CH2:10]([C:8]1[O:9][C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:41]([NH:40][C:37]3[CH:38]=[CH:39][C:34]([O:33][CH3:32])=[CH:35][CH:36]=3)=[O:42])=[CH:31][C:6]=2[C:7]=1[C:14](=[O:30])[C:15]1[CH:20]=[C:19]([I:21])[C:18]([CH2:22][CH3:23])=[C:17]([I:24])[C:16]=1[O:25][CH2:26][C:27]([OH:29])=[O:28])[CH2:11][CH2:12][CH3:13]
Reactant: CCCCc1oc2ccc(N)cc2c1C(=O)c1cc(I)c(CC)c(I)c1OCC(=O)O
Reactant: COc1ccc(N=C=O)cc1
Solvent: C1CCOC1
Product: CCCCc1oc2ccc(NC(=O)Nc3ccc(OC)cc3)cc2c1C(=O)c1cc(I)c(CC)c(I)c1OCC(=O)O
Yield: 75.3 %

Procedure:
A solution of 5-amino-2-n-butyl-3-(3,5-diiodo-4-ethylcarboxymethoxybenzoyl)-benzofuran (prepared as in Example 1(g), 320 mg, 0.5 mmol) and p-methoxyphenylisocyanate (75 mg, 0.5 mmol) in THF (10 mL) was stirred at room temperature for 3 h. The mixture was concentrated, ethyacetate was added and the organic layer was washed with water, 1M HCl, then NaHCO3 (sat) then brine, dried using MgSO2 and then concentrated. Purification by column chromathography on silica with a 95:5 mixture of methylenechloride--methanol as eluant produced 300 mg (75%) of 2-n-butyl-3-(3,5-diiodo-4-ethyl carboxymethoxybenzoyl)-5-(4-methoxyphenylureido)benzofuran.
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[CH:6][C:7]3[C:12]([C:13]=2[S:15]([Cl:18])(=[O:17])=[O:16])=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[NH:26]1[CH2:32][CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.Cl>C(Cl)Cl>[ClH:18].[CH:1]1[C:14]2[C:5](=[CH:6][C:7]3[C:12]([C:13]=2[S:15]([N:26]2[CH2:32][CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)(=[O:17])=[O:16])=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1
Reactant: C1CNCCNC1
Reactant: O=S(=O)(Cl)c1c2ccccc2cc2ccccc12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(c1c2ccccc2cc2ccccc12)N1CCCNCC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 69 %

Procedure:
Add the product from step 2 (0.35 g, 1.28 mmol) in methylene chloride (20 mL) to a mixture of triethyl amine (0.605 mL, 4.34 mmol) and hexahydro-2H-1,4-diazepine (also known as homopiperazine) (0.326 g, 3.25 mmol) in methylene chloride (7 mL) cooled to 0° C. over 5 min. Stir the reaction mixture for 15 min at 0° C. Add aqueous HCl (25 mL, 1N) to the reaction mixture. Filter the solid and recrystallize from absolute ethanol to give the title compound (0.33 g, 69%) as light yellow needles. Rf=0.54 (5% MeOH in methylene chloride (v/v), 0.2% ammonium hydroxide buffer).
Reaction SMILES: [N+:1]([C:4]1[C:5]([C:9]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[O:10])=[N:6][NH:7][CH:8]=1)([O-:3])=[O:2].[C:17]1(B(O)O)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[N+:1]([C:4]1[C:5]([C:9]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[O:10])=[N:6][N:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:8]=1)([O-:3])=[O:2]
Reactant: OB(O)c1ccccc1
Reactant: O=C(c1n[nH]cc1[N+](=O)[O-])N1CCOCC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Solvent: ClCCl
Product: O=C(c1nn(-c2ccccc2)cc1[N+](=O)[O-])N1CCOCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 3 %

Procedure:
A solution of 4-[(4-nitro-1H-pyrazol-3-yl)carbonyl]morpholine (1.50 g; 6.63 mmol; 1.00 eq.) and copper acetate (1 204.49 mg; 6.63 mmol; 1.00 eq.) in DCM (5 mL) is stirred at rt for 18 h after which phenylboronic acid (808.58 mg; 6.63 mmol; 1.00 eq.) and TEA (1.83 mL) are added and the mixture is stirred at room temperature for 18 h. After this time, reaction mixture is diluted with DCM, ished with sat. aq. NaHCO3 then brine, dried over MgSO4, filtered through a short plug of silica and concentrated in vacuo to give as a pale yellow oil. Purification by column chromatography (DCM to 15% ethyl acetate in DCM) followed by crystallization from MTBE afford 60 mg of the title compound as a white solid. 1H NMR (DMSO) 9.76 (s, 1H), 8.00-7.91 (m, 2H), 7.65-7.54 (m, 2H), 7.53-7.43 (m, 1H), 3.70 (s, 4H), 3.60-3.48 (m, 2H), 3.41-3.32 (m, 2H). MS (ESI+): 303.0.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:11][CH2:12][C:13]3[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=3)=[CH:8][CH:9]=2)[C:4](=[O:19])[N:3]1[CH2:20][C:21]([O:23]C)=[O:22].[ClH:25]>C1COCC1>[ClH:25].[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:11][CH2:12][C:13]3[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=3)=[CH:8][CH:9]=2)[C:4](=[O:19])[N:3]1[CH2:20][C:21]([OH:23])=[O:22]
Reactant: COC(=O)CN1C(=O)c2ccc(OCc3cccnc3)cc2C1=O
Agent: Cl
Solvent: C1CCOC1
Product: O=C(O)CN1C(=O)c2ccc(OCc3cccnc3)cc2C1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 90.1 %

Procedure:
To a solution of methyl 2-(1,3-dioxo-5-(pyridin-3-ylmethoxy)isoindolin-2-yl)acetate (56 mg, 0.172 mmol) in THF (3 ml), aqueous 6N HCl (2002 μL, 12.01 mmol) was added, and the reaction mixture was stirred for 16 hours at room temperature and then heated at 50° C. for 5 hours. The volatiles were removed under vacuum and the crude was dried yielding 2-(1,3-dioxo-5-(pyridin-3-ylmethoxy)isoindolin-2-yl)acetic acid hydrochloride (54 mg, 0.155 mmol, 90% yield, MS/ESI+ 313.0 [MH]+).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:14][CH3:15])[C:4]1[CH:9]=[C:8]2[O:10][CH2:11][O:12][C:7]2=[CH:6][C:5]=1Br.[CH3:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][CH:19]=1>>[CH3:1][O:2][CH:3]([O:14][CH3:15])[C:4]1[CH:9]=[C:8]2[O:10][CH2:11][O:12][C:7]2=[CH:6][C:5]=1[CH:22]([OH:23])[C:21]1[CH:24]=[CH:25][C:18]([O:17][CH3:16])=[CH:19][CH:20]=1
Reactant: COc1ccc(C=O)cc1
Reactant: COC(OC)c1cc2c(cc1Br)OCO2
Product: COc1ccc(C(O)c2cc3c(cc2C(OC)OC)OCO3)cc1
Yield: 82 %

Procedure:
2-bromo-4,5-methylenedioxybenzaldehyde dimethylacetal and 4-methoxybenzaldehyde are reacted in the same manner as described in Example 1-(1), whereby 2-(4-methoxy-α-hydroxybenzyl)-4,5-methylenedioxybenzaldehyde dimethylacetal is obtained as colorless syrup. Yield: 82%
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:8][CH:7]=1)[CH:2]1[O:4][CH2:3]1.[NH2:20][CH2:21][CH2:22][NH:23][C:24]1[N:25]([CH3:34])[C:26](=[O:33])[N:27]([CH3:32])[C:28](=[O:31])[C:29]=1[CH3:30]>>[CH2:13]([O:12][C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:1][CH:2]([OH:4])[CH2:3][NH:20][CH2:21][CH2:22][NH:23][C:24]2[N:25]([CH3:34])[C:26](=[O:33])[N:27]([CH3:32])[C:28](=[O:31])[C:29]=2[CH3:30])=[CH:7][CH:8]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: c1ccc(COc2ccc(OCC3CO3)cc2)cc1
Reactant: Cc1c(NCCN)n(C)c(=O)n(C)c1=O
Product: Cc1c(NCCNCC(O)COc2ccc(OCc3ccccc3)cc2)n(C)c(=O)n(C)c1=O
Yield: 30 %

Procedure:
Yield 30% of theory; colorless oil from 4-benzyloxyphenyl glycidyl ether and 4-(2-aminoethylamino)-1,3,5-trimethylpyrimidine-2,6(1H,3H)-dione.
Reaction SMILES: [NH2:1][CH:2]1[C:8](=[O:9])[N:7]([CH3:10])[C:6]2[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=2[C:4]2[CH:15]=[CH:16][CH:17]=[CH:18][C:3]1=2.[CH3:19][CH:20]([C:24]([NH:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[CH:29]=1)=[O:25])[C:21](O)=[O:22]>>[CH3:19][CH:20]([C:21]([NH:1][CH:2]1[C:8](=[O:9])[N:7]([CH3:10])[C:6]2[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=2[C:4]2[CH:15]=[CH:16][CH:17]=[CH:18][C:3]1=2)=[O:22])[C:24]([NH:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[CH:29]=1)=[O:25]
Reactant: CN1C(=O)C(N)c2ccccc2-c2ccccc21
Reactant: Cc1cccc(CNC(=O)C(C)C(=O)O)c1
Product: Cc1cccc(CNC(=O)C(C)C(=O)NC2C(=O)N(C)c3ccccc3-c3ccccc32)c1

Procedure:
The title compound, MS: m/e=442.3 (M+H+), was prepared in analogy to example 16 from 7-amino-5-methyl-5H,7H-dibenzo[b,d]azepin-6-one and 2-methyl-N-(3-methyl-benzyl)-malonamic acid.
Reaction SMILES: [F:1][C:2]1[C:7]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+].[C:24](#N)[CH3:25]>>[CH2:24]([N:15]1[CH2:16][CH2:17][CH:12]([C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([S:8]([CH3:11])(=[O:10])=[O:9])[C:2]=2[F:1])[CH2:13][CH2:14]1)[CH3:25]
Reactant: CS(=O)(=O)c1cccc(C2CCNCC2)c1F
Reactant: CC#N
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCN1CCC(c2cccc(S(C)(=O)=O)c2F)CC1

Procedure:
Preparation according to Example 1: 4-[2-fluoro-3-(methylsulfonyl)phenyl]-piperidine (0.185 g, 0.72 mmol), acetonitrile (10 ml), potassium carbonate (0.2 g, 1.44 mmol) 1-iodoethane (0.06 ml, 0.75 mmol). Yield: 0.15 g (73%). The amine was converted to several different salts and recrystallized from ethanol/diethyl ether. Hydrochloric acid salt m.p. 273-275° C., hydrobromic acid salt m.p. 267-268° C., fumaric acid salt m.p. 204-206° C., oxalic acid salt m.p. 163-165° C., sulfate salt m.p. 263-265° C., maleic acid salt m.p. 112-113° C. MS m/z (relative intensity, 70 eV) 285 (M+, 12), 271 (15), 270 (bp), 147 (7) 133 (8).
Reaction SMILES: C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[OH:12][CH2:13][CH2:14]/[CH:15]=[CH:16]\[CH2:17][C:18]([O:20][CH:21]([CH3:23])[CH3:22])=[O:19].Cl.C(=O)([O-])[O-].[Na+].[Na+].[S:31]([C:35]1[CH:41]=[CH:40][C:38]([CH3:39])=[CH:37][CH:36]=1)([O-:34])(=[O:33])=[O:32]>N1C=CC=CC=1>[C:38]1([CH3:39])[CH:37]=[CH:36][C:35]([S:31]([OH:34])(=[O:32])=[O:33])=[CH:41][CH:40]=1.[OH:12][CH2:13][CH2:14]/[CH:15]=[CH:16]\[CH2:17][C:18]([O:20][CH:21]([CH3:23])[CH3:22])=[O:19]
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: CC(C)OC(=O)C/C=C\CCO
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)O)cc1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
p-Toluene sulfonyl chloride (1.425 g., 7.5 mm.) was added at 0°C to a solution of 1.00 g. (5.8 mm.) of isopropyl cis 6-hydroxy-3-hexenoate in 2.37 g. of dry pyridine. The resulting mixture was stirred at 0°C for 4 hours. The crude product was poured on ice and concentrated hydrochloric acid, sodium carbonate till neutral and dried over potassium carbonate. Evaporation of the solvent produced 1.32 g. (70% of theory) of crude tosylate.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:13]=2[F:19])[CH:8]=[C:9](I)[CH:10]=1)=[O:4].C[C:21]1[N:22]=[CH:23][S:24][CH:25]=1.CC(O[K])=O>CC(N(C)C)=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>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:13]=2[F:19])[CH:8]=[C:9]([C:25]2[S:24][CH:23]=[N:22][CH:21]=2)[CH:10]=1)=[O:4]
Reactant: Cc1cscn1
Reactant: COC(=O)c1cc(I)cc(-c2ccc(C)cc2F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)O[K]
Solvent: CC(=O)N(C)C
Product: COC(=O)c1cc(-c2cncs2)cc(-c2ccc(C)cc2F)c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 67.9 %

Procedure:
To a stirred solution of 2′-fluoro-5-iodo-4′-methyl-biphenyl-3-carboxylic acid methyl ester (50 mg, 0.135 mmol) and 4-methylthiazole (57.4 mg, 0.675 mmol) in 10 ml of dimethylacetamide was added Pd(PPh3)4 (8 mg, 0.00675 mmol) and CH3COOK (20 mg, 0.2 mmol). The reaction mixture was heated to 100° C. and stirred overnight. After cooling down to room temperature, the mixture was filtered through celite and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (hexanes/EtOAc=1:5) to afford 30 mg (68%) of 2′-fluoro-4′-methyl-5-thiazol-5-yl-biphenyl-3-carboxylic acid methyl ester, MS (M+H)=328.