Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[NH:11][C:10]2=[O:20])=[C:4]([N+:21]([O-:23])=[O:22])[C:3]=1[O:24][CH3:25].[C:26](=O)([O-])[O-].[K+].[K+].COS(OC)(=O)=O.O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:18])([F:17])[F:19])[N:11]([CH3:26])[C:10]2=[O:20])=[C:4]([N+:21]([O-:23])=[O:22])[C:3]=1[O:24][CH3:25]
Reactant: O=C([O-])[O-]
Reactant: COc1c(Cl)cc(F)c(-n2c(=O)cc(C(F)(F)F)[nH]c2=O)c1[N+](=O)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: COS(=O)(=O)OC
Solvent: O
Product: COc1c(Cl)cc(F)c(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c1[N+](=O)[O-]
Yield: 83.5 %

Procedure:
3-(4Chloro-6-fluoro-3-methoxy-2-nitrophenyl)-6-trifluoromethyl-2,4(1H, 3H)-pyrimidinedione (9 g, 23.5 mmol) was dissolved in dimethylformamide (90 ml) and to this were added potassium carbonate (3.9 g, 28.2 mmol) and dimethylsulfate (10.2 g, 47 mmol) with stirring. The solution was stirred at ambient temperature for 12 hr and water was added. Product was extracted in ethyl acetate and the organic layer was washed with water and dried over anhydrous sodium sulfate. Removal of the solvent afforded a crude product which was purified by column chromatography on silica gel. Elution of the column with methylene chloride afforded the title compound (7.8 g).
Reaction SMILES: [OH-].[Na+].C([O:5][C:6]([C:8]1[C:9]2[S:17][CH:16]=[C:15]([CH2:18][O:19][C:20]3[CH:25]=[C:24]([C:26]4[O:27][C:28]([C:31]5[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=5)=[N:29][N:30]=4)[CH:23]=[CH:22][C:21]=3[CH3:38])[C:10]=2[C:11]([NH2:14])=[N:12][CH:13]=1)=[O:7])C>O1CCCC1.CO>[NH2:14][C:11]1[C:10]2[C:15]([CH2:18][O:19][C:20]3[CH:25]=[C:24]([C:26]4[O:27][C:28]([C:31]5[CH:32]=[CH:33][C:34]([Cl:37])=[CH:35][CH:36]=5)=[N:29][N:30]=4)[CH:23]=[CH:22][C:21]=3[CH3:38])=[CH:16][S:17][C:9]=2[C:8]([C:6]([OH:7])=[O:5])=[CH:13][N:12]=1
Reactant: CCOC(=O)c1cnc(N)c2c(COc3cc(-c4nnc(-c5ccc(Cl)cc5)o4)ccc3C)csc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc(-c2nnc(-c3ccc(Cl)cc3)o2)cc1OCc1csc2c(C(=O)O)cnc(N)c12
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
An aqueous solution of sodium hydroxide (2 N, 2.0 mL, 1.0 mmol) was added to a solution of 4-amino-3-{5-[5-(4-chloro-phenyl)-[1,3,4]oxadiazol-2-yl]-2-methyl-phenoxymethyl}-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (0.22 g, 0.42 mmol) (from Example 47 supra) in tetrahydrofuran/methanol (3:1, 8 mL) and the mixture was heated at 50° C. for 1 day. The reaction mixture was concentrated and azeotroped with toluene. The solid residue was triturated with ethyl acetate. The solid was then suspended in water and treated with hydrochloric acid (1 N). After stirring 30 minutes, the solid was collected, washed with water and dried to give 4-amino-3-{5-[5-(4-chloro-phenyl)-[1,3,4]oxadiazol-2-yl]-2-methyl-phenoxymethyl}-thieno[3,2-c]pyridine-7-carboxylic acid. (Yield 0.20 g, 95%).
Reaction SMILES: C(OC([NH:8][C:9]1[C:10]([C:16]([OH:18])=[O:17])=[CH:11][C:12]([Cl:15])=[N:13][CH:14]=1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:8][C:9]1[C:10]([C:16]([OH:18])=[O:17])=[CH:11][C:12]([Cl:15])=[N:13][CH:14]=1
Reactant: CC(C)(C)OC(=O)Nc1cnc(Cl)cc1C(=O)O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1cnc(Cl)cc1C(=O)O
Reaction time: 8 h
Yield: 86.9 %

Procedure:
A stirred suspension of 5- [N-(tert-butoxycarbonyl)amino]-2-chloropyridine-4-carboxylic acid (1.91 g, 7 mmol) in CH2Cl2 (200 mL) is treated slowly with trifluoroacetic acid until homogeneous (ca. 12 mL). The solution is stirred overnight and extracted with dilute NH40H, and the aqueous layer is then acidified with dilute HCl to gave a precipitate of 5-amino-2-chloropyridine-4-carboxylic acid (1.05 g, 87% yield). 1H NMR (DMSO) δ 9.01 (2H, m), 8.03 (1H, s), 7.48 (1H, s).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH:5]1[CH2:10][CH2:9][CH2:8][NH:7][CH2:6]1.[CH:11]([CH:14]1[CH:19]2[CH2:20][CH:16]([CH2:17][CH2:18]2)[CH:15]1[CH2:21][CH2:22][C:23](=O)[CH2:24][CH2:25][CH:26]1[CH:31]([CH:32]([CH3:34])[CH3:33])[CH:30]2[CH2:35][CH:27]1[CH2:28][CH2:29]2)([CH3:13])[CH3:12].[C:37](#[N:40])[CH:38]=[CH2:39]>>[NH2:40][CH2:37][CH2:38][CH2:39][N:7]1[CH2:8][CH2:9][CH2:10][CH:5]([CH2:4][CH2:3][CH2:2][NH:1][CH:23]([CH2:22][CH2:21][CH:15]2[CH:14]([CH:11]([CH3:13])[CH3:12])[CH:19]3[CH2:20][CH:16]2[CH2:17][CH2:18]3)[CH2:24][CH2:25][CH:26]2[CH:31]([CH:32]([CH3:34])[CH3:33])[CH:30]3[CH2:35][CH:27]2[CH2:28][CH2:29]3)[CH2:6]1
Reactant: C=CC#N
Reactant: NCCCC1CCCNC1
Reactant: CC(C)C1C2CCC(C2)C1CCC(=O)CCC1C2CCC(C2)C1C(C)C
Product: CC(C)C1C2CCC(C2)C1CCC(CCC1C2CCC(C2)C1C(C)C)NCCCC1CCCN(CCCN)C1

Procedure:
For example, 3-(3-aminopropyl)piperidine may be converted to a Schiff base with 1,5-di-(3-isopropylnorborn-2-yl)-3-pentanone, catalytically reduced, then the resulting amine selectively cyanoethylated on the ring nitrogen with acrylonitrile, followed by catalytic hydrogenation to furnish 1-(3-aminopropyl)-3-{3-[1,5-di-(3-isopropylnorborn-2-yl)-3-pentylamino]propyl}piperidine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]([OH:26])[CH2:9][NH:10][C@H:11]([CH3:25])[CH2:12][C:13]2[C:21]3[C:16](=[C:17]([C:22](O)=[O:23])[CH:18]=[CH:19][CH:20]=3)[NH:15][CH:14]=2)[CH:5]=[CH:6][CH:7]=1.[NH2:27][C@H:28]([C:33]([O:35][CH3:36])=[O:34])[CH2:29][CH:30]([CH3:32])[CH3:31].Cl.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]([OH:26])[CH2:9][NH:10][C@H:11]([CH3:25])[CH2:12][C:13]2[C:21]3[C:16](=[C:17]([C:22]([NH:27][C@@H:28]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:33]([O:35][CH3:36])=[O:34])=[O:23])[CH:18]=[CH:19][CH:20]=3)[NH:15][CH:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H](Cc1c[nH]c2c(C(=O)O)cccc12)NC[C@H](O)c1cccc(Cl)c1
Reactant: COC(=O)[C@@H](N)CC(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CC(C)C)NC(=O)c1cccc2c(C[C@@H](C)NC[C@H](O)c3cccc(Cl)c3)c[nH]c12

Procedure:
A solution of 3-{(2R)-2-[2-(3-chlorophenyl)-(2R)-2-hydroxyethyl-amino]propyl}-1H-indole-7-carboxylic acid (22 mg, 0.059 mmol), L-Leu-OMe.HCl (107 mg, 0.59 mmol), 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (113 mg, 0.59 mmol), 1-hydroxybenztriazole (80 mg, 0.59 mmol), triethylamine (164 μL, 1.18 mmol) in dimethylformamide (2 mL) is stirred at room temperature for 18 hours. The mixture is diluted with ethyl acetate, washed with a saturated aqueous sodium hydrogen carbonate solution, water, and a saturated brine, dried over sodium sulfate, and concentrated. The residue is purified by silica gel column chromatography (a saturated ammonia solution in chloroform) and preparative reversed phase HPLC (octadecylsilyl, trifluoroacetic acid/acetonitrile/water) to give the desired methyl (2S)-2-[(3-{(2R)-2-[2-(3-chlorophenyl)-(2R)-2-hydroxyethylamino]propyl}-1H-indole-7-carbonyl)amino]-4-methylpentanoate.trifluoroacetate (23 mg, yield: 63%).
Reaction SMILES: C(N1CCN(C2N=[C:11](Br)[CH:12]=[C:13]3[CH:17]=[CH:16]SC=23)CC1)C.[CH2:19]([N:21]1[CH2:26][CH2:25][N:24]([C:27]2[N:28]=[C:29]([C:36]3[CH:41]=[CH:40][C:39]([CH2:42][O:43]C(=O)CC4CCCCC4)=[CH:38][CH:37]=3)[CH:30]=[C:31]3[CH:35]=[CH:34][S:33][C:32]=23)[CH2:23][CH2:22]1)[CH3:20].[ClH:53].[C:54](OCC)(=O)C>>[ClH:53].[ClH:53].[CH2:19]([N:21]1[CH2:22][CH2:23][N:24]([C:27]2[N:28]=[C:29]([C:36]3[CH:37]=[CH:38][C:39]([CH:42]([CH:11]4[CH2:12][CH2:13][CH2:17][CH2:16][CH2:54]4)[OH:43])=[CH:40][CH:41]=3)[CH:30]=[C:31]3[CH:35]=[CH:34][S:33][C:32]=23)[CH2:25][CH2:26]1)[CH3:20]
Reactant: CCN1CCN(c2nc(-c3ccc(COC(=O)CC4CCCCC4)cc3)cc3ccsc23)CC1
Reactant: CCN1CCN(c2nc(Br)cc3ccsc23)CC1
Reactant: CCOC(C)=O
Agent: Cl
Product: CCN1CCN(c2nc(-c3ccc(C(O)C4CCCCC4)cc3)cc3ccsc23)CC1
Reaction time: 1 h

Procedure:
The resulting compound and 7-(1-ethylpiperazin-4-yl)-5-bromothieno[2,3-c]pyridine (0.20 g) were reacted in the same manner as in Example 300-4, to give a reaction solution containing 7-(4-ethylpiperazin-1-yl)-5-[4-(cyclohexylacetoxymethyl)phenyl]thieno[2,3-c]pyridine. To the resulting reaction solution were added ethyl acetate and 2N hydrochloric acid, and then the resulting insoluble matters were filtered off. The aqueous layer was separated, while the organic phase was extracted with 2N hydrochloric acid. The resulting aqueous layers were combined and washed twice with ethyl acetate. The pH of the resulting solution was adjusted to pH 10 by adding 8N sodium hydroxide thereto, and then the solution was extracted with ethyl acetate twice. After washing with brine and drying over magnesium sulfate, the solvent was evaporated. Methanol (10 ml) was added to the resulting residue, dissolved, and then a 5N aqueous solution of sodium hydroxide (1 ml) was added thereto. The resulting solution was left as it was at room temperature for 1 hr, and then the solvent was evaporated. Water was added thereto, and then the mixture was extracted with ethyl acetate thrice. After washing with brine and drying over magnesium sulfate, the solvent was evaporated. The resulting residue was purified by NH silica gel column chromatography (ethyl acetate/n-hexane system), to give 0.12 g of the free compound of the title compound as a colorless amorphous.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[Cl:12].[Cl-].[Ca+2].[Cl-].N1C=CC=CC=1.[S:22](Cl)(Cl)(=[O:24])=[O:23]>C(Cl)Cl>[Cl:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[CH2:5][N:4]1[CH2:3][CH2:2][O:1][S:22]1(=[O:24])=[O:23]
Reactant: OCCNCc1ccccc1Cl
Reactant: O=S(=O)(Cl)Cl
Agent: [Ca+2]
Agent: [Cl-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=S1(=O)OCCN1Cc1ccccc1Cl
Temperature: -50 °C
Yield: 18.5 %

Procedure:
To a solution of N-hydroxyethyl-2-chlorobenzylamine (1.86 g, 10.0 mmole) in dry methylene chloride (6 ml) in a reaction vessel fitted with a calcium chloride (CaCl2) drying tube was added dry pyridine (1.66 ml, 20.5 mmole). The solution was stirred and cooled to -50° C. Sulfuryl chloride (1.35 g, 10.0 mmole) dissolved in dry methylene chloride (4 ml) was added dropwise over 20 minutes while the temperature of the solution was maintained between -45° C. and -50° C. The solution was stirred at -50° C. for 90 minutes and then allowed to warm to 8° C. over 90 minutes. The entire reaction mixture was poured onto a silica gel bed (30 g), slurry-packed in a 60 ml Type "C" sintered glass funnel. The bed was eluted with methylene chloride while collecting 40 ml fractions. Fractions containing the product were combined and the solvent removed by evaporation under vacuum at 40° C. yielding N-(2-chlorobenzyl)-2,2-dioxo-1,2,3-oxathiazolidine as a clear oil (0.40 g, 1.85 mmole), which crystallized. Characteristic analytical data are mp. 61°-62.5° C.; and NMR spectra similar to those of Example 2A (above).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[S:3][C:4]1[CH:5]=[C:6]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:7]=[CH:8][CH:9]=1.[C:18]([O:22][CH3:23])(=[O:21])[CH:19]=[CH2:20].[OH-].C([N+](C)(C)C)C1C=CC=CC=1.[ClH:36]>CO.O.C(O)(C)C>[ClH:36].[CH3:23][O:22][C:18]([CH2:19][CH2:20][N:13]1[CH2:12][CH2:11][N:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([S:3][C:2]([F:1])([F:16])[F:17])[CH:5]=2)[CH2:15][CH2:14]1)=[O:21]
Reactant: C=CC(=O)OC
Reactant: FC(F)(F)Sc1cccc(N2CCNCC2)c1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: Cl
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: CC(C)O
Product: COC(=O)CCN1CCN(c2cccc(SC(F)(F)F)c2)CC1
Reaction time: 48 h
Yield: 80 %

Procedure:
N-(m-trifluoromethylthiophenyl)-piperazine (7 g, 0.0267 g mol.) and freshly distilled methyl acrylate (2.55 g, 0.0295 g mol.) are introduced in a 50 ml round bottomed flask provided with a stirrer and reflux condenser. The temperature rises slightly. The mixture is allowed to cool and 0.1 ml of a 40% solution of benzyltrimethylammonium hydroxide in methyl alcohol is then added with stirring. The mixture is allowed to stand for 2 days at ambient temperature. Boiling isopropyl alcohol (60 ml) is then added and the mixture is acidified by addition of concentrated hydrochloric acid (2.3 ml). The solvents are removed on a water-bath in vacuo and the residue is treated twice with benzene (50 ml each time) which is distilled off to remove water azeotropically. The residue is then taken up in isopropyl alcohol (50 ml) and the solution is filtered hot and allowed to stand several hours in a refrigerator. The precipitate formed is separated and dried in vacuo over phosphorous pentoxide. N-(β-methoxycarbonyl-ethyl)-N'-(m-trifluoromethylthiophenyl)-piperazine hydrochloride (8.2 g, 80% yield) is thus obtained as a white crystalline powder, m.p. 180°C, soluble in water.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17](=O)[C:16]3[C:11](=[CH:12][C:13]([OH:20])=[C:14]([Cl:19])[CH:15]=3)[O:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.O.[NH2:22][NH2:23]>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]([C:16]3[CH:15]=[C:14]([Cl:19])[C:13]([OH:20])=[CH:12][C:11]=3[OH:10])=[N:22][NH:23][CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: NN
Reactant: O=c1c(-c2cccc(Br)c2)coc2cc(O)c(Cl)cc12
Solvent: CCO
Solvent: O
Product: Oc1cc(O)c(-c2n[nH]cc2-c2cccc(Br)c2)cc1Cl
Yield: 80.8 %

Procedure:
This compounds was synthesised in the same manner as described above. 3-(3-Bromo-phenyl)-6-chloro-7-hydroxy-chromen-4-one (0.25 g, 0.71 mmol), hydrazine hydrate (5 ml), ethanol (10 ml). The quenched solution was extracted into ethyl acetate, washed (water), dried (MgSO4), and the solvent removed under vacuum to give a yellow oil which was purified by column chromatography to give 4-[4-(3-Bromo-phenyl)-1H-pyrazol-3-yl]-6-chloro-benzene-1,3-diol as a white solid (0.21 g, 80.8%); Rf 0.8 ethyl acetate/hexane (70/30).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4](=O)[CH:3]=1.[N+:13]([O-:16])(O)=[O:14].P(Cl)(Cl)([Cl:19])=O>S(=O)(=O)(O)O>[Cl:19][C:4]1[CH:3]=[C:2]([CH3:1])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:13]([O-:16])=[O:14])[CH:10]=2)[N:5]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc(=O)[nH]c2ccccc12
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: Cc1cc(Cl)nc2ccc([N+](=O)[O-])cc12

Procedure:
To a solution of 4-methylquinolin-2(1H)-one (11 g, 69 mmol) in concentrated sulfuric acid (100 mL) was added fuming nitric acid (2.7 mL, 80 mol). The temperature of the resulting solution rose to approximately 50°. The reaction mixture was heated at reflux for 1 h, cooled to r.t and carefully poured onto ice. The resulting precipitate was filtered, washed with ice cold water and ether, then dried under vacuum to provide a solid. A mixture of the solid (8.5 g) and phosphorous oxychloride (40 mL) was heated at 100° for 0.45 h at which time the volatiles were removed under vacuum. The residue was cooled in an ice bath. To the cooled mixture was carefully added water (50 mL). The resulting solids were filtered then washed with water and ether and then dried under vacuum to afford the product, MS: m/z 224 (MH+), which was used directly in the next step.
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH3:10])[CH2:7][O:6][C:5]([CH3:9])([CH3:8])[O:4]1.[H-].[Na+].[H][H].[CH2:15](Cl)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1(C)C=CC=CC=1>[CH2:15]([O:1][CH2:2][C:3]1([CH3:10])[CH2:7][O:6][C:5]([CH3:9])([CH3:8])[O:4]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC1(CO)COC(C)(C)O1
Reactant: ClCc1ccccc1
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC1(COCc2ccccc2)COC(C)(C)O1

Procedure:
4-Hydroxymethyl-2,2,4-trimethyl-1,3-dioxolane (10g, prepared as in (b)) was added dropwise to a stirred suspension of sodium hydride (3g, 50% dispersion in oil) in dry toluene (150 ml). When the addition was complete the solution was heated under reflux until no more hydrogen was evolved. Benzyl chloride (7.85g) was added to the refluxing solution over a period of 15 minutes, after which the solution was heated under reflux for a further 3 hours. The solution was then cooled, washed with water (3 × 30 ml), dried and the solvent removed under reduced pressure. The residual oil was fractionally distilled to give the desired product as a colorless liquid having a b.p. 80° C at 0.2 mm Hg.
Reaction SMILES: [C:1]1([C:7]2[CH2:8][CH2:9][N:10]([CH2:13][CH2:14][CH2:15][CH2:16][N:17]([C:23]3[CH:31]=[CH:30][CH:29]=[C:28]([N+:32]([O-:34])=[O:33])[C:24]=3[C:25]([OH:27])=[O:26])[C:18]([O:20]CC)=O)[CH2:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Br)(Br)[Br:36]>C(Cl)Cl>[BrH:36].[C:1]1([C:7]2[CH2:8][CH2:9][N:10]([CH2:13][CH2:14][CH2:15][CH2:16][N:17]3[C:23]4[CH:31]=[CH:30][CH:29]=[C:28]([N+:32]([O-:34])=[O:33])[C:24]=4[C:25](=[O:26])[O:27][C:18]3=[O:20])[CH2:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: BrP(Br)Br
Reactant: CCOC(=O)N(CCCCN1CC=C(c2ccccc2)CC1)c1cccc([N+](=O)[O-])c1C(=O)O
Solvent: ClCCl
Product: Br
Product: O=c1oc(=O)n(CCCCN2CC=C(c3ccccc3)CC2)c2cccc([N+](=O)[O-])c12

Procedure:
A mixture of 2-[N-{4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl}-N-ethoxycarbonylamino]-6nitrobenzoic acid (680 mg) and phosphorus tribromide (0.7 ml) in methylene dichloride (30 ml) was refluxed for 3 hours. Excess of phosphorus tribromide was quenched with ethanol (2 ml) on an ice-bath. Then appeared crystalline materials were collected, and washed with ethanol to give 1-[4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl]-5-nitro-1,2-dihydro-4H-3,1-benzoxazine-2,4-dione hydrobromide 414 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:8]([C:11]2[CH:12]=[CH:13][C:14]3[O:28][C:18]4[CH:19](CNC(=O)C)[NH:20][CH2:21][CH2:22][C:17]=4[C:15]=3[CH:16]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.F[C:30]1C=C(S(C2C=CC3OC=C(CCNC(=O)OC(C)(C)C)C=3C=2)(=O)=O)C=CC=1.O1CCOC1[CH2:63][CH2:64][NH:65][C:66](=[O:69])[CH2:67]C.O1CCOC1CCNC.C(OC(=O)C)(=O)C>>[F:1][C:2]1[CH:3]=[C:4]([S:8]([C:11]2[CH:12]=[CH:13][C:14]3[O:28][C:18]4[CH:19]([CH2:63][CH2:64][N:65]([CH3:30])[C:66](=[O:69])[CH3:67])[NH:20][CH2:21][CH2:22][C:17]=4[C:15]=3[CH:16]=2)(=[O:9])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NCCc1coc2ccc(S(=O)(=O)c3cccc(F)c3)cc12
Reactant: CC(=O)NCC1NCCc2c1oc1ccc(S(=O)(=O)c3cccc(F)c3)cc21
Reactant: CCC(=O)NCCC1OCCO1
Agent: CNCCC1OCCO1
Solvent: CC(=O)OC(C)=O
Product: CC(=O)N(C)CCC1NCCc2c1oc1ccc(S(=O)(=O)c3cccc(F)c3)cc21

Procedure:
Prepared as described for N-({6-[(3-fluorophenyl)sulfonyl]-1,2,3,4-tetrahydro[1]benzofuro[2,3-c]pyridin-1-yl}methyl)acetamide using tert-butyl (2-{5-[(3-fluorophenyl)sulfonyl]-1-benzofuran-3-yl}ethyl)carbamate and N-(2-[1,3]dioxolan-2-yl-ethyl)-methyl-acetamide, which was prepared from (2-[1,3]dioxolan-2-yl-ethyl)-methyl-amine and acetic anhydride. MS m/z 431 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([NH:10][C:11](=[O:13])[CH3:12])[CH:7]=[CH:6][C:5]=1[O:14][CH3:15])([O-])=O.C(O)C.N.[H][H]>[Pd].O>[CH3:15][O:14][C:5]1[CH:6]=[CH:7][C:8]([NH:10][C:11](=[O:13])[CH3:12])=[CH:9][C:4]=1[NH2:1]
Reactant: [H][H]
Reactant: COc1ccc(NC(C)=O)cc1[N+](=O)[O-]
Agent: [Pd]
Agent: N
Solvent: O
Solvent: CCO
Product: COc1ccc(NC(C)=O)cc1N
Reaction time: 2 h

Procedure:
104 parts of 2-nitro-4-acetamidoanisole, 160 parts of ethanol, 12.5 parts of a 30% aqueous solution of ammonia and 1 part of a 50% suspension of palladium on charcoal, moist with water, in 2 parts of water are charged to an autoclave equipped with an aerating stirrer. The autoclave is pressurised with hydrogen and, at a pressure of 8 bar and a temperature of 100° C., hydrogenation is carried out for 2 hours. 2-Methoxy-5-acetamidoaniline is obtained in quantitative yield in a purity of >97% (analysis by liquid chromatography).
Reaction SMILES: I[C:2]1[N:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=2)[N:4]([CH3:17])[C:3]=1[C:18]([N:20]1[CH2:25][CH2:24][CH:23]([N:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)[CH2:22][CH2:21]1)=[O:19].[OH:31][C:32]1[N:37]=[CH:36][C:35](B2OC(C)(C)C(C)(C)O2)=[CH:34][CH:33]=1>>[OH:31][C:32]1[N:37]=[CH:36][C:35]([C:2]2[N:6]=[C:5]([C:7]3[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=3)[N:4]([CH3:17])[C:3]=2[C:18]([N:20]2[CH2:25][CH2:24][CH:23]([N:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)[CH2:22][CH2:21]2)=[O:19])=[CH:34][CH:33]=1
Reactant: CC1(C)OB(c2ccc(O)nc2)OC1(C)C
Reactant: Cn1c(-c2ccc(C(F)(F)F)cc2)nc(I)c1C(=O)N1CCC(N2CCCC2)CC1
Product: Cn1c(-c2ccc(C(F)(F)F)cc2)nc(-c2ccc(O)nc2)c1C(=O)N1CCC(N2CCCC2)CC1

Procedure:
In analogy to the procedure described for example 7, [5-iodo-3-methyl-2-(4-trifluoromethyl-phenyl)-3H-imidazol-4-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (example 104) was reacted with 6-hydroxy-pyridin-3-yl-boronic acid pinacol ester to give the title compound as off-white solid. MS: 500.2 (MH+).
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1.C([O-])([O-])=O.[K+].[K+].[Cl:18][CH2:19][CH2:20]Cl>CN(C=O)C>[Cl:18][CH2:19][CH2:20][O:9][C:8]1[CH:10]=[CH:11][C:3]([CH:2]=[O:1])=[CH:4][C:5]=1[O:6][CH3:7]
Reactant: COc1cc(C=O)ccc1O
Reactant: ClCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(C=O)ccc1OCCCl
Temperature: 67.5 °C
Reaction time: 16 h
Yield: 85.4 %

Procedure:
A mixture of vanillin (10.00 g, 65.7 mmol), K2CO3 (45.4 g, 329 mmol), 1,2-dichloroethane (104 mL, 1.31 mol), and DMF (300 mL) was stirred at 65-70° C. for 16 h. The dichloroethane was evaporated and the remaining slurry was poured onto ice. The oil that separated was extracted with Et2O (×4) and EtOAc (×3). The combined extracts were washed with water (×3), dried (Na2SO4 /MgSO4), and evaporated to give a clear oil that solidified upon trituration with hexanes. Crystallization from Et20 gave 4-(2-chloroethoxy)-3-methoxybenzaldehyde (12.04 g, 85%) as white needles, mp 60-61° C. 1H NMR (CDCl3) δ 9.87 (s, 1 H, CHO), 7.46 (dd, J=8.0, 2.0 Hz, 1 H, H-6), 7.43 (d, J=2.0 Hz, 1 H, H-5), 6.99 (d, J=8.0 Hz, 1 H, H-2), 4.36 (t, J=6.1 Hz, 2 H, OCH2), 3.94 (s, 3 H, OCH3), 3.89 (t, J=6.1 Hz, 2 H, CH2Cl); 13C NMR δ 190.8 (CHO), 153.9 (C-4), 150.0 (C-3), 130.8 (C-1), 126.3 (C-6), 112.3 (C-2), 109.8 (C-5), 68.9 (OCH2), 56.0 (OCH3), 41.2 (CH2Cl).
Reaction SMILES: [O:1]=[C:2]1[NH:8][CH2:7][C@H:6]2[C:9]3[C:14]([CH2:15][CH2:16][C@H:5]2[CH2:4][CH2:3]1)=[CH:13][CH:12]=[CH:11][CH:10]=3.CC(C)([O-])C.[K+].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.O>C1COCC1>[CH2:23]([N:8]1[C:2](=[O:1])[CH2:3][CH2:4][C@@H:5]2[CH2:16][CH2:15][C:14]3[C:9]([C@@H:6]2[CH2:7]1)=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: BrCc1ccccc1
Reactant: O=C1CC[C@@H]2CCc3ccccc3[C@@H]2CN1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: O=C1CC[C@@H]2CCc3ccccc3[C@@H]2CN1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.5 %

Procedure:
To a suspension of cis-1,3,4,5,5a,6,7,11b-octahydro-3-oxo-2H-naphth[1,2-c]azepine (1.0 g, 4.65 mmol), from Step 3 of Example 75, in 20 mL of dry THF, was added potassium t-butoxide (0.78 g, 6.9 mmol). The reaction mixture was stirred at ambient temperature for 0.5 h and then cooled to 0° C. and benzyl bromide (0.8 mL, 6.7 mmol) was added. The reaction mixture was allowed to warm to ambient temperature, stirred for 3 h and then poured into water and extracted three times with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was crystalized from ether/hexane to afford 1.1 g (79% yield) of the title compound, m.p. 114°-115° C.; MS DCl--NH3M/Z: 306 (M+H)+ ; 1H NMR (CDCl3) δ1.5-2.2 (5H, m), 2.42-2.54 (1H, m), 2.58-3.03 (5H, m), 3.79 (1H, dd, J=9.5, 13.6 Hz), 4.44 (1H, d, J=13.6 Hz), 4.95 (1H, d, J=13.6 Hz), 6.47-6.5 (1H, m), 6.97-7.45 (8H, m).