Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:16])[CH2:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[CH:10][C:9]([Br:15])=[CH:8]2.[OH-].[Na+]>>[Br:15][C:9]1[CH:10]=[N:11][C:12]2[C:7]([CH:8]=1)=[CH:6][C:5]([CH2:4][C:3]([OH:16])=[O:2])=[CH:14][CH:13]=2
Reactant: COC(=O)Cc1ccc2ncc(Br)cc2c1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)Cc1ccc2ncc(Br)cc2c1
Temperature: 25 °C
Yield: 73.3 %

Procedure:
A mixture of (3-bromo-quinolin-6-yl)-acetic acid methyl ester (14.8 g, 52.8 mmol) and aqueous 2 N NaOH (80 ml, 160 mmol) was heated under reflux for 1.5 hours until reaction mixture became clear. After cooling down to room temperature the reaction mixture was washed with dichloromethane then the water layer was acidified with concentrated hydrochloric acid to pH 4. A white precipitate was filtered off the stirred in refluxing methanol, filtered and dried in vacuo to give the product title compound as a white solid (10.3 g, 73.5%). (300 MHz, DMSO-d6): 12.52 (b, 1H), 8.91 (d, 1H), 8.69 (d, 1H), 7.99 (d, 1H)), 7.82˜7.70 (m, 2H), 3.80 (s, 2H). ES-MS m/z: 266 (M+H+).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:4]=1[NH:10][NH2:11].[O-:12][C:13]#[N:14].[K+]>O>[Cl:2][C:3]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:4]=1[NH:10][NH:11][C:13]([NH2:14])=[O:12]
Reactant: NNc1ccc(Cl)cc1Cl
Reactant: N#C[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Product: NC(=O)NNc1ccc(Cl)cc1Cl
Reaction time: 4 h

Procedure:
A 20 g portion of 2,4-dichlorophenylhydrazine hydrochloride was added to 200 ml of water and the solution was heated to 80°. Then 6.8 g of potassium cyanate was dissolved in 75 ml of water, and that solution was added dropwise to the first solution. The mixture was stirred for 4 hours at 80°, and it was then cooled. The product was collected by filtration, dried, and recrystallized from ethanol to obtain 11.8 g of the desired intermediate.
Reaction SMILES: C([O:5][C:6]([CH:8]1[CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=2[F:20])[C:11]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=2[O:30][CH3:31])([C:21]#[N:22])[CH:10]([CH2:32][C:33]([CH3:36])([CH3:35])[CH3:34])[NH:9]1)=[O:7])(C)(C)C.[F:37][C:38]([F:43])([F:42])[C:39]([OH:41])=[O:40]>ClCCl>[F:37][C:38]([F:43])([F:42])[C:39]([OH:41])=[O:40].[Cl:19][C:15]1[C:14]([F:20])=[C:13]([CH:12]2[C:11]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=3[O:30][CH3:31])([C:21]#[N:22])[CH:10]([CH2:32][C:33]([CH3:34])([CH3:35])[CH3:36])[NH:9][CH:8]2[C:6]([OH:7])=[O:5])[CH:18]=[CH:17][CH:16]=1
Reactant: COc1cc(Cl)ccc1C1(C#N)C(CC(C)(C)C)NC(C(=O)OC(C)(C)C)C1c1cccc(Cl)c1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(Cl)ccc1C1(C#N)C(CC(C)(C)C)NC(C(=O)O)C1c1cccc(Cl)c1F
Yield: 100 %

Procedure:
In a manner similar to the method described in Example 25a, rac-(2S,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-methoxy-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 58b (1.3 g, 2.4 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2S,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-methoxy-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a white solid (1.5 g, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:5]2[N:6]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)[C:7](=[O:21])[CH:8]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:20])[NH:9][C:10](=O)[C:4]=2[CH:3]=1.CN(C)C1C=CC=CC=1.P(Cl)(Cl)([Cl:44])=O>C1(C)C=CC=CC=1>[Cl:44][C:10]1[C:4]2[CH:3]=[C:2]([Cl:1])[CH:32]=[CH:31][C:5]=2[N:6]([CH2:22][C:23]2[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=2)[C:7](=[O:21])[CH:8]([CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:20])[N:9]=1
Reactant: COc1ccc(CN2C(=O)C(CCc3ccccc3Cl)NC(=O)c3cc(Cl)ccc32)cc1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)c1ccccc1
Solvent: Cc1ccccc1
Product: COc1ccc(CN2C(=O)C(CCc3ccccc3Cl)N=C(Cl)c3cc(Cl)ccc32)cc1
Temperature: 90 °C
Reaction time: 24 h

Procedure:
7-Chloro-3-(2-chlorophenethyl)-1-(4-methoxybenzyl)-3,4-dihydro-1H-benzo[e][1,4]diazepine-2,5-dione (950 mg) was dissolved in toluene (20 mL) and then N,N-dimethylaniline (564 mg, 2.3 eq) was added followed by phosphorous-oxychloride (403 mg, 1.3 eq). The reaction was heated to 90° C. overnight, then cooled to room temperature and washed with ice cold water, then cold 0.5 M HCl, then cold sodium bicarbonate, then cold water, then brine, and then it was dried over sodium sulfate, and filtered through a plug of silica gel (eluting with 1:1 hexanes:EtOAc), and concentrated, and held under vacuum for 24 h. Crude product was a viscous purple oil. 1H-NMR (300 MHz, CDCl3) δ 7.70 (d, 1H), 7.40 (dd, 1H), 7.30-7.22 (m, 2H), 7.20-7.07 (m, 2H), 7.00 (d, 2H), 6.81-6.70 (m, 3H), 5.28 (d, 1H), 4.82 (d, 1H), 3.75 (s, 3H), 3.55 (t, 1H), 2.95 (s, 2H), 2.90-2.79 (m, 2H), 2.55-2.45 (m, 2H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10](=[O:16])[CH:11]=[CH:12][NH:13]2)=[CH:8][C:7]=1[O:17][CH3:18].[NH:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1>C(#N)C>[CH3:18][O:17][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][C:6]=1[O:5][CH2:4][CH2:3][CH2:2][N:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1)[NH:13][CH:12]=[CH:11][C:10]2=[O:16]
Reactant: COc1cc2c(=O)cc[nH]c2cc1OCCCCl
Reactant: C1CCNC1
Solvent: CC#N
Product: COc1cc2c(=O)cc[nH]c2cc1OCCCN1CCCC1
Yield: 95.1 %

Procedure:
Intermediate V (62 g, 0.232 mol) and tetrahydropyrrole (82.46 g, 1.16 mol) were added to acetonitrile (620 mL). The mixture was heated under reflux for 8 h. After completion of the reaction, a portion of solvent was evaporated off. The reaction vessel was placed in a cold trap. The reaction was filtered by suction. The filtered cake was washed with ethyl acetate to produce a yellow solid (66.74 g) in a yield of 95.3%.
Reaction SMILES: [O:1]1[C:5]2=[CH:6][CH:7]=[CH:8][C:9]([C:10]([OH:12])=O)=[C:4]2[CH2:3][CH2:2]1.[C:13]([O:17][C:18]([N:20]1[C@H:27]([CH2:28][NH2:29])[CH2:26][C@H:25]2[C@@H:21]1[CH2:22][CH2:23][CH2:24]2)=[O:19])([CH3:16])([CH3:15])[CH3:14]>>[C:13]([O:17][C:18]([N:20]1[C@H:27]([CH2:28][NH:29][C:10]([C:9]2[CH:8]=[CH:7][CH:6]=[C:5]3[O:1][CH2:2][CH2:3][C:4]=23)=[O:12])[CH2:26][C@H:25]2[C@@H:21]1[CH2:22][CH2:23][CH2:24]2)=[O:19])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1[C@H](CN)C[C@@H]2CCC[C@@H]21
Reactant: O=C(O)c1cccc2c1CCO2
Product: CC(C)(C)OC(=O)N1[C@H](CNC(=O)c2cccc3c2CCO3)C[C@@H]2CCC[C@@H]21

Procedure:
prepared by reaction of 2,3-Dihydro-benzofuran-4-carboxylic acid with (1S,3S,5S)-3-aminomethyl-2-azabicyclo[3.3.0]octane-2-carboxylic acid tert-butyl ester. LC-MS: tR=1.00 min; [M+H]+=387.1.
Reaction SMILES: O=C1[NH:7][C:6]2[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=2[CH2:4][O:3]1.[OH-].[Na+]>C(OC(C)C)(=O)C.O>[NH2:7][C:6]1[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=1[CH2:4][OH:3]
Reactant: O=C1Nc2ccccc2CO1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)OC(C)C
Solvent: O
Product: Nc1ccccc1CO
Temperature: 45 °C

Procedure:
The reaction mixture from Stage A was boiled so as to drive off the isopropyl acetate solvent. A solution of 100 g of sodium hydroxide in 100 ml of water was added to the residue, and the whole was refluxed for 2 hours. After cooling to 45° C., the product was extracted with four 270 ml portions of isopropyl acetate. The isopropyl acetate was then distilled off and the product recrystallized from toluene to give 100 g (63% of theoretical) of 97-98% pure 2-amino-benzyl alcohol; m.p. 83°-83.5° C.
Reaction SMILES: Cl[C:2]([O:4][CH:5]([CH3:7])[CH3:6])=[O:3].[CH3:8][O:9][C:10](=[O:42])[CH2:11][C@H:12]1[C:16]2[CH:17]=[CH:18][C:19]([O:21][C@H:22]3[C:30]4[C:25](=[C:26]([CH2:35][N:36]5[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]5)[C:27]([C:31]([F:34])([F:33])[F:32])=[CH:28][CH:29]=4)[CH2:24][CH2:23]3)=[CH:20][C:15]=2[O:14][CH2:13]1>>[CH3:8][O:9][C:10](=[O:42])[CH2:11][C@H:12]1[C:16]2[CH:17]=[CH:18][C:19]([O:21][C@H:22]3[C:30]4[C:25](=[C:26]([CH2:35][N:36]5[CH2:37][CH2:38][N:39]([C:2]([O:4][CH:5]([CH3:7])[CH3:6])=[O:3])[CH2:40][CH2:41]5)[C:27]([C:31]([F:32])([F:33])[F:34])=[CH:28][CH:29]=4)[CH2:24][CH2:23]3)=[CH:20][C:15]=2[O:14][CH2:13]1
Reactant: CC(C)OC(=O)Cl
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C(F)(F)F)c4CN3CCNCC3)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C(F)(F)F)c4CN3CCN(C(=O)OC(C)C)CC3)ccc21

Procedure:
The title compound is prepared from isopropyl chloroformate and {(S)-6-[(R)-4-piperazin-1-ylmethyl-5-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester following a procedure analogous to that described for Intermediate 27. LC (method 4): tR=1.05 min; Mass spectrum (ESI+): m/z=577 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:14][N:13](C(OCC3C=CC=CC=3)=O)[CH2:12][CH2:11][C:4]=2[N:5]=[C:6]([CH:8]2[CH2:10][CH2:9]2)[N:7]=1.[CH2:25]([Mg]Br)[CH3:26]>>[CH:8]1([C:6]2[N:7]=[C:2]([CH2:25][CH3:26])[C:3]3[CH2:14][NH:13][CH2:12][CH2:11][C:4]=3[N:5]=2)[CH2:9][CH2:10]1
Reactant: O=C(OCc1ccccc1)N1CCc2nc(C3CC3)nc(Cl)c2C1
Reactant: CC[Mg]Br
Product: CCc1nc(C2CC2)nc2c1CNCC2

Procedure:
Benzyl 4-chloro-2-cyclopropyl-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate, which was made using the general route described in footnote 14, was reacted with ethylmagnesium bromide under [1,2-bis(diphenylphosphino)ethane]dichloronickel(II) catalysis. Upon deprotection, the requisite 2-cyclopropyl-4-ethyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine was isolated.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([O:14][C@@H:15]([CH3:20])[C:16]([F:19])([F:18])[F:17])=[CH:12][N:11]=[C:10]([C:21](O)=[O:22])[CH:9]=2)=[CH:4][CH:3]=1.Cl.[CH3:25][O:26][C:27]1[CH:31]=[C:30]([CH2:32][NH2:33])[O:29][N:28]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:13]([O:14][C@@H:15]([CH3:20])[C:16]([F:19])([F:17])[F:18])=[CH:12][N:11]=[C:10]([C:21]([NH:33][CH2:32][C:30]3[O:29][N:28]=[C:27]([O:26][CH3:25])[CH:31]=3)=[O:22])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: C[C@H](Oc1cnc(C(=O)O)cc1-c1ccc(Cl)cc1)C(F)(F)F
Reactant: COc1cc(CN)on1
Agent: Cl
Product: COc1cc(CNC(=O)c2cc(-c3ccc(Cl)cc3)c(O[C@@H](C)C(F)(F)F)cn2)on1

Procedure:
The title compound was synthesized in analogy to Example 1, using (S)-4-(4-chlorophenyl)-5-(1,1,1-trifluoropropan-2-yloxy)picolinic acid (example AR) and 3-methoxy-5-isoxazolemethanamine hydrochloride as starting materials. MS: 456.1 (M+H)+.
Reaction SMILES: [N:1]([CH:4]([CH2:10][CH2:11][CH3:12])[C:5]([O:7]CC)=[O:6])=[N+:2]=[N-:3].[OH-].[Na+]>CO.O>[N:1]([CH:4]([CH2:10][CH2:11][CH3:12])[C:5]([OH:7])=[O:6])=[N+:2]=[N-:3]
Reactant: CCCC(N=[N+]=[N-])C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCC(N=[N+]=[N-])C(=O)O
Reaction time: 1.5 h
Yield: 92.9 %

Procedure:
A solution of ethyl 2-azidopentanoate (3.082 g, 18.0 mmol) in a mixture of methanol (10 ml) and water (5 ml) was treated dropwise with 20 ml of 1M sodium hydroxide (20 mmol, 1.1 equiv). After 1.5 h at room temperature, the methanol was evaporated under reduced pressure and the remaining aqueous phase was washed with ether (2×10 ml) and acidified with dilute HCl (3N) at 0° C. The aqueous phase was extracted with dichloromethane (3×25 ml). The combined organic phases were washed with water and dried over anhydrous sodium sulfate. Evaporation of the solvent gave an oil which was distilled (bulb to bulb) to give 2.393 g (93%) of a clear liquid: 80°-85° C./0.5 toor (air bath temperature; ir (firm) νmax : 2110 (N3), 1720 cm-1 (C=O); 1Hmr (CDCl3) δ: 3.90 (1H, dd, J= 6, J=7, H-2), 2.0-1.0 (4H, m, H-3, H-4) and 1.00 ppm (3H, distorted t, J=6, H-5); Anal. calcd for C5H9N3O2 : C 41.95, H 6.34, N 29.36; found: C 42.06, H 6.49, N 29.26.
Reaction SMILES: [N+:1]([C:4]1[CH:34]=[CH:33][C:7]([CH2:8][O:9][C:10]([N:12]=[C:13]([NH:19][C:20](=[O:32])[O:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=2)N2C=CC=N2)=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH2:35][CH2:36][C:37]([NH:39][CH:40]1[CH2:43][N:42]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:41]1)=[O:38].C(OCC)(=O)C>O1CCCC1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][O:9][C:10]([N:12]=[C:13]([NH:19][C:20]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=2)=[O:32])[NH:35][CH2:36][C:37]([NH:39][CH:40]2[CH2:43][N:42]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:41]2)=[O:38])=[O:11])=[CH:33][CH:34]=1)([O-:3])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CC(NC(=O)CN)C1
Reactant: O=C(N=C(NC(=O)OCc1ccc([N+](=O)[O-])cc1)n1cccn1)OCc1ccc([N+](=O)[O-])cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC(NC(=O)CNC(=NC(=O)OCc2ccc([N+](=O)[O-])cc2)NC(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 101.6 %

Procedure:
Under ice cooling, a solution of 4-nitrobenzyl [(4-nitrobenzyloxy)carbonyliminopyrazol-1-ylmethyl]carbamate (1.42 g) in tetrahydrofuran (12 ml) was added to a solution of tert-butyl 3-(aminoacetylamino)-1-azetidinecarboxylate (785 mg) in tetrahydrofuran (13 ml) and the mixture was stirred at room temperature for 3 hours. Ethyl acetate was added to the reaction mixture. The resulting mixture was washed with water, an aqueous solution of potassium hydrogensulfate and saturated saline, dried over anhydrous magnesium sulfate and concentrated by evaporation under reduced pressure. The residue was crystallized from diisopropyl ether, followed by washing, whereby 1.94 g of the title compound were obtained as a colorless crystals.
Reaction SMILES: [C:1]1([CH:7]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:8]2[CH:9]=[CH:10][C:11](=[O:32])[N:12]([CH2:14][CH2:15][CH2:16][S:17][C:18]3[CH:19]=[C:20]([CH:29]=[CH:30][CH:31]=3)[O:21][CH:22]([CH3:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC1C=C(C=CC=1)C(OO)=[O:44]>C(Cl)Cl>[C:1]1([CH:7]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:8]2[CH:9]=[CH:10][C:11](=[O:32])[N:12]([CH2:14][CH2:15][CH2:16][S:17]([C:18]3[CH:19]=[C:20]([CH:29]=[CH:30][CH:31]=3)[O:21][CH:22]([CH3:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:44])[CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOC(=O)C(C)Oc1cccc(SCCCn2cc(C(c3ccccc3)c3ccccc3)ccc2=O)c1
Solvent: ClCCl
Product: CCOC(=O)C(C)Oc1cccc(S(=O)CCCn2cc(C(c3ccccc3)c3ccccc3)ccc2=O)c1
Yield: 94.3 %

Procedure:
To a solution of ethyl 2-[3-({3-[5-(diphenylmethyl)-2-oxopyridin-1(2H)-yl]propyl}sulfanyl)phenoxy]propanoate (175 mg) in DCM (5 mL) was added 3-chloroperoxybenzoic acid (82 mg) at 0° C. for 20 minutes. The resulting mixture was extracted with EtOAc. The organic layer was washed with saturated NaHCO3 aqueous solution and brine, dried over anhydrous MgSO4, filtered and evaporated in vacuo. The residue was purified by silica gel column chromatography (n-hexane: EtOAc=1:1-1:10) to afford ethyl 2-[3-({3-[5-(diphenylmethyl)-2-oxopyridin-1(2H)-yl]propyl}sulfinyl)phenoxy]propanoate (170 mg) as a colorless oil.
Reaction SMILES: Br[C:2]1[C:11]([F:12])=[C:10]([F:13])[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:23])[C:5]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:17][CH2:16]1.C([Sn]([C:37]#[C:38][Si:39]([CH3:42])([CH3:41])[CH3:40])(CCCC)CCCC)CCC>C1(C)C=CC=CC=1>[CH:15]1([N:7]2[C:8]3[C:3](=[C:2]([C:37]#[C:38][Si:39]([CH3:42])([CH3:41])[CH3:40])[C:11]([F:12])=[C:10]([F:13])[C:9]=3[F:14])[C:4](=[O:23])[C:5]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:6]2)[CH2:17][CH2:16]1
Reactant: CCOC(=O)c1cn(C2CC2)c2c(F)c(F)c(F)c(Br)c2c1=O
Reactant: CCCC[Sn](C#C[Si](C)(C)C)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cn(C2CC2)c2c(F)c(F)c(F)c(C#C[Si](C)(C)C)c2c1=O

Procedure:
1.95 g of ethyl 5-bromo-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate, 2.7 g of tributylstannyl-trimethylsilyl-acetylene and 0.29 g of tetrakis-(triphenylphosphine)palladium(0) are refluxed for 4 hours in 20 ml of absolute toluene under a nitrogen atmosphere. The reaction mixture is filtered at room temperature; the solid is washed with a small amount of toluene and dried 1.6 g of the title compound are obtained (78% of theory).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([F:14])[CH:12]=3)[C:7](=[O:15])[C:6]([C:16]([O:18]CC)=[O:17])=[CH:5]2)[CH2:3][CH2:2]1.O.S(=O)(=O)(O)O>C(O)(=O)C>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([F:14])[CH:12]=3)[C:7](=[O:15])[C:6]([C:16]([OH:18])=[O:17])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)c1cn(C2CC2)c2cc(F)ccc2c1=O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)c1cn(C2CC2)c2cc(F)ccc2c1=O
Temperature: 0 °C

Procedure:
2.75 g (0.01 mol) of ethyl 1-cyclopropyl-7-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate are refluxed for four hours in a mixture of 12 ml of acetic acid, 12 ml of water and 1.2 ml of concentrated sulphuric acid. The cooled reaction mixture is poured into ice-water, and the precipitate is filtered off, washed with water and dried at 100° C. in a drying cupboard.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.Cl[CH2:12][C:13]([N:15]([CH3:17])[CH3:16])=[O:14].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[C:3]2[O:10][C:12]([C:13]([N:15]([CH3:17])[CH3:16])=[O:14])=[CH:5][C:4]=2[CH:7]=[CH:8][CH:9]=1
Reactant: CN(C)C(=O)CCl
Reactant: O=Cc1cccc(Br)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1cc2cccc(Br)c2o1
Yield: 99.4 %

Procedure:
A mixture of 3-bromo-2-hydroxybenzaldehyde (5 g, 24.87 mmol), 2-chloro-N,N-dimethylacetamide (3.33 ml, 32.34 mmol) and potassium carbonate (6.88 g, 49.75 mmol) in DMF (60 ml) was heated at reflux for 1 h. The solids were filtered off and the filtrate was concentrated. The residue was taken up in ethyl acetate and washed with sat. NaCl(aq). The layers were separated and the aqueous layer was extracted with ethyl acetate (2×50 mL). The combined organic layer was dried with sodium sulfate, filtered and concentrated to give the title compound (6.63 g, 99%) as a crude product which was used as such in subsequent reaction.
Reaction SMILES: [CH2:1]([C:8]1[O:9][C:10]2[CH:26]=[CH:25][C:24]([CH2:27][CH3:28])=[CH:23][C:11]=2[C:12]=1[S:13]([C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)(=[O:15])=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:29]([N:31]([CH2:36][CH3:37])[CH2:32][CH2:33][CH2:34]Cl)[CH3:30]>>[CH2:1]([C:8]1[O:9][C:10]2[CH:26]=[CH:25][C:24]([CH2:27][CH3:28])=[CH:23][C:11]=2[C:12]=1[S:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:34][CH2:33][CH2:32][N:31]([CH2:36][CH3:37])[CH2:29][CH3:30])=[CH:18][CH:17]=1)(=[O:14])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN(CC)CCCCl
Reactant: CCc1ccc2oc(Cc3ccccc3)c(S(=O)(=O)c3ccc(O)cc3)c2c1
Product: CCc1ccc2oc(Cc3ccccc3)c(S(=O)(=O)c3ccc(OCCCN(CC)CC)cc3)c2c1

Procedure:
Reaction of 2-benzyl-5-ethyl-3-(4-hydroxyphenylsulfonyl)benzofuran with 3-diethylaminopropyl chloride as described above gives the title compound.
Reaction SMILES: [Li]CCCC.C(NC(C)C)(C)C.N#N.[Br:15][C:16]1[CH:17]=[N:18][CH:19]=[C:20]([F:22])[CH:21]=1.CN([CH:26]=[O:27])C>C1COCC1>[Br:15][C:16]1[CH:17]=[N:18][CH:19]=[C:20]([F:22])[C:21]=1[CH:26]=[O:27]
Reactant: Fc1cncc(Br)c1
Reactant: CN(C)C=O
Agent: N#N
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: O=Cc1c(F)cncc1Br
Temperature: -50 °C
Reaction time: 0.17 h
Yield: 62.1 %

Procedure:
n-BuLi (1.6 M in hexanes, 2.250 mL, 3.60 mmol) was added dropwise to a solution of diisopropylamine (0.556 mL, 3.90 mmol) in THF (20 mL) at −78° C. under inert gas (N2). The resulting mixture was warmed up to ˜−50° C. and stirred for 10 min and cooled again to −78° C. A solution of 3-bromo-5-fluoropyridine (528 mg, 3 mmol) in THF (5 mL) was added dropwise at this temperature. The reaction mixture turned from clear light brown to heterogenous light brown. After 30 min, DMF (0.256 mL, 3.30 mmol) was added dropwise and the resulting mixture was stirred for 30 min. The reaction was quenched by MeOH then NH4Cl (saturated solution) and warmed up to room temperature. After concentration, the residue was dissolved in CH2Cl2 and washed with NaHCO3 (Saturated solution). After drying over Na2SO4, concentration, the residue was purified by column (Heptane to CH2Cl2) and yielded slightly yellow crystal (380 mg). 1H NMR (400.3 MHz, CDCl3): δ 8.58 (s, 1H), 8.72 (s, 1H), 10.33 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]([CH:6]=[CH:7][CH2:8][Cl:9])=[CH:4][CH:3]=1.[CH2:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][NH:13]1.Cl>C(O)C>[ClH:9].[CH3:1][C:2]1[CH:11]=[CH:10][C:5]([CH:6]=[CH:7][CH2:8][N:13]2[CH2:14][C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:12]2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(C=CCCl)cc1
Reactant: c1ccc2c(c1)CNC2
Agent: Cl
Solvent: CCO
Product: Cc1ccc(C=CCN2Cc3ccccc3C2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.8 %

Procedure:
The process for the preparation of this compound and its physical properties will be given below. A solution of 5 grams of p-methylcinnamyl chloride in 50 milliliters of ethanol is added dropwise to a solution of 8.93 grams of isoindoline in 50 milliliters of ethanol, following which the mixture is stirred overnight at room temperature. After completion of the reaction, the reaction mixture is concentrated followed by adding chloroform to the residue and filtering the insolubles off. Next, the solvent is distilled off, and the residue is purified by silica gel column chromatography to obtain an oily product, which is transformed into a hydrochloride in a customary manner and recrystallized from a methanol-ether mixture to obtain 4.1 grams (yield 47.8%) of N-(p-methylcinnamyl)-isoindoline hydrochloride as crystals having a melting point of 213°-214° C. (decomposition).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C([O-])([O-])=O.[K+].[K+].I[CH:23]([CH3:25])[CH3:24]>C(#N)C>[CH:23]([N:13]1[CH2:12][CH2:11][CH:10]([C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[CH2:15][CH2:14]1)([CH3:25])[CH3:24]
Reactant: CC(C)I
Reactant: O=[N+]([O-])c1ccc(C2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)N1CCC(c2ccc([N+](=O)[O-])cc2)CC1
Yield: 99.8 %

Procedure:
4-(4-Nitrophenyl)piperidine (250 mg, 1.21 mmol), K2CO3 (170 mg, 1.21 mmol) and 2-iodopropane (240 μL, 2.4 mmol) are stirred in acetonitrile (3 mL) in a sealed tube at 120° C. for 45 min. The mixture is cooled and the solvent removed under reduced pressure. The residue is partitioned between DCM (20 mL) and water (5 mL), the layers are separated and the DCM is washed with water (5 mL) and brine (5 mL) and dried over MgSO4. Evaporation of the solvent affords the title compound (300 mg) which is used without further purification.
Reaction SMILES: C[O-].[Na+].[C:4]([O:8][CH3:9])(=[O:7])[CH2:5][SH:6].[CH3:10][C:11]([C:14]1[CH:15]=[C:16]([CH2:24][CH2:25][C@H:26]2[CH2:30][CH2:29][CH2:28][C@H:27]2C2C=C(C)C=CC=2S([O-])(=O)=O)[CH:17]=[C:18]([C:20]([CH3:23])([CH3:22])[CH3:21])[CH:19]=1)([CH3:13])[CH3:12]>CO>[CH3:13][C:11]([C:14]1[CH:15]=[C:16]([CH2:24][CH2:25][C@@H:26]2[CH2:27][CH2:28][CH2:29][C@H:30]2[S:6][CH2:5][C:4]([O:8][CH3:9])=[O:7])[CH:17]=[C:18]([C:20]([CH3:21])([CH3:22])[CH3:23])[CH:19]=1)([CH3:10])[CH3:12]
Reactant: COC(=O)CS
Reactant: Cc1ccc(S(=O)(=O)[O-])c([C@@H]2CCC[C@@H]2CCc2cc(C(C)(C)C)cc(C(C)(C)C)c2)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)CS[C@@H]1CCC[C@H]1CCc1cc(C(C)(C)C)cc(C(C)(C)C)c1

Procedure:
To a solution of sodium methoxide (prepared from 38 mg of sodium) in 10 ml of methanol is added 174 mg (1.64 mmoles) of methyl thioglycolate. After stirring for a few minutes, a solution of 500 mg (1.09 mmoles) of the title product of Example 38 in 5 ml of methanol is added, and stirring is continued until TLC indicates the reaction is complete. The mixture is then partitioned between diethyl ether and water, the organic layer dried over sodium sulfate, filtered, and evaporated. Chromatography of the residue over silica gel using mixtures of ethyl acetate and hexane as eluents gives the title compound.