Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[CH:8]([C:10]1[S:11][CH:12]=[CH:13][CH:14]=1)[OH:9].[CH3:15][C:16]([CH3:21])([CH3:20])[C:17](Cl)=[O:18].[H-].[Na+].[Cl-].[NH4+]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[CH:8]([C:10]1[S:11][CH:12]=[CH:13][CH:14]=1)[O:9][C:17](=[O:18])[C:16]([CH3:21])([CH3:20])[CH3:15]
Reactant: OC(c1cccs1)c1cnccc1Cl
Reactant: CC(C)(C)C(=O)Cl
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)OC(c1cccs1)c1cnccc1Cl
Temperature: 0 °C
Reaction time: 8 h
Yield: 69.2 %

Procedure:
2.0 g of 1-(4-chloropyrid-3-yl)-1-(thien-2-yl)methanol were dissolved in 100 ml of THF and the solution was cooled to 0° C. 3.2 g of trimethylacetyl chloride were added followed by the portionwise addition of 1.0 g of sodium hydride (60%) over a period of 15 minutes. The reaction mixture was allowed to warm to room temperature and then stirred overnight. 100 ml of a saturated ammonium chloride solution were added, and then this mixture was extracted twice with ethyl ether. The combined ether extracts were washed with a 5% aqueous solution of potassium carbonate, dried over magnesium sulfate, filtered, and then concentrated in vacuo to obtain 2.7 g of crude product. This material was then purified via chromatography on a silica gel column using ethyl acetatehexane (1:1) as the eluant to afford 1.9 g of 1-(4-chloropyrid-3-yl)-1-(thien-2-yl)-1-trimethylacetoxymethane as an oil.
Reaction SMILES: [NH:1]([C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:11][CH2:12][CH2:13][NH2:14])[N:9]=1)[C:2]([NH2:4])=[NH:3].C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl.[CH3:29][S:30][C:31](SC)=[CH:32][N+:33]([O-:35])=[O:34]>C(O)(C)C>[N+:33]([CH:32]=[C:31]([S:30][CH3:29])[NH:14][CH2:13][CH2:12][S:11][CH2:10][C:8]1[N:9]=[C:5]([NH:1][C:2]([NH2:4])=[NH:3])[S:6][CH:7]=1)([O-:35])=[O:34]
Reactant: CSC(=C[N+](=O)[O-])SC
Reactant: N=C(N)Nc1nc(CSCCN)cs1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: CC(C)O
Product: CSC(=C[N+](=O)[O-])NCCSCc1csc(NC(=N)N)n1
Reaction time: 54 h

Procedure:
A solution of 2-[(2-guanidinothiazol-4-yl)methylthio]ethylamine (from the dihydrochloride, 20.0 g; 66.0 mmoles) [prepared according to the procedure described in South Africa Pat. No. 78/2129] and 1,1-bis(methylthio)-2-nitroethylene [prepared according to the procedure described in Chem. Ber., 100, 591 (1967) or Acta Chem. Scand., 21 2797 (1967)] (10.9 g; 66.0 mmoles) in isopropanol (600 ml) was stirred at ambient temperature under a positive pressure of nitrogen for 2 hours, at reflux temperature for 1 hour and then at ambient temperature for 54 hours. The reaction mixture was cooled and filtered to give 15.8 g of 1-nitro-2-methylthio-2-{2-[(2-guanidinothiazol-4-yl)methylthio]ethylamino}ethylene as a yellow solid, mp 151°-156°, which was used without further purification in Step B below.
Reaction SMILES: N1(CC2N3C=C(C)C=CC3=NC=2C2C=CC(C)=CC=2)C=CN=C1.Cl.[Cl:25][C:26]1[CH:27]=[CH:28][C:29]2[N:30]([C:32]([CH2:42]Cl)=[C:33]([C:35]3[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=3)[N:34]=2)[CH:31]=1.[NH:44]1[CH:48]=[CH:47][N:46]=[C:45]1[C:49]([O:51][CH2:52][CH3:53])=[O:50]>>[CH2:52]([O:51][C:49]([C:45]1[N:44]([CH2:42][C:32]2[N:30]3[CH:31]=[C:26]([Cl:25])[CH:27]=[CH:28][C:29]3=[N:34][C:33]=2[C:35]2[CH:36]=[CH:37][C:38]([Cl:41])=[CH:39][CH:40]=2)[CH:48]=[CH:47][N:46]=1)=[O:50])[CH3:53]
Reactant: CCOC(=O)c1ncc[nH]1
Reactant: ClCc1c(-c2ccc(Cl)cc2)nc2ccc(Cl)cn12
Agent: Cc1ccc(-c2nc3ccc(C)cn3c2Cn2ccnc2)cc1
Agent: Cl
Product: CCOC(=O)c1nccn1Cc1c(-c2ccc(Cl)cc2)nc2ccc(Cl)cn12

Procedure:
The title compound was prepared according to Method A and the experimentals described for compound 1 from 6-chloro-3-(chloromethyl)-2-(4-chlorophenyl)imidazo[1,2-a]pyridine hydrochloride and ethyl 1H-imidazole-2-carboxylate. m/e+ 416 for C20H17Cl2N4O2 [M+H]+; 1H-NMR (300 MHz, CDCl3) δ 8.04 (dd, J=0.9, 6.3 Hz, 1H), 7.60 (m, 3H), 7.42 (dd, J=6.3, 8.1 Hz, 2H), 7.27 (m, 1H), 7.11 (m, 1H), 6.67 (dd, J=2.1, 3.3 Hz, 1H), 6.07 (d, J=2.1 Hz, 2H), 4.48 (q, J=7.2 Hz, 2H), 1.48 (t, J=7.2 Hz, 3H) ppm; 13C-NMR (75 MHz, CDCl3, δ) 160.222, 135.309, 130.815, 130.735, 129.653, 129.593, 127.897, 123.336, 123.283, 122.261, 121.647, 121.573, 118.475, 62.384, 53.016, 41.598, 41.544, 14.534 ppm.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[CH:8]=[CH:7]1)[CH3:2].[Br:17][C:18]1[C:22]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=2)=[N:21][N:20]([CH3:33])[C:19]=1[CH2:34]O.CN(C)C(N=NC(N(C)C)=O)=O.C(P(CCCC)CCCC)CCC>>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH2:34][C:19]3[N:20]([CH3:33])[N:21]=[C:22]([C:23]4[CH:24]=[CH:25][C:26]([C:29]([F:31])([F:30])[F:32])=[CH:27][CH:28]=4)[C:18]=3[Br:17])[CH:13]=2)[CH:8]=[CH:7]1)[CH3:2]
Reactant: Cn1nc(-c2ccc(C(F)(F)F)cc2)c(Br)c1CO
Reactant: CCOC(=O)Cn1ccc2ccc(O)cc21
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Product: CCOC(=O)Cn1ccc2ccc(OCc3c(Br)c(-c4ccc(C(F)(F)F)cc4)nn3C)cc21

Procedure:
In analogy to the procedure described for example 3 c], (6-hydroxy-indol-1-yl)-acetic acid ethyl ester (example 2 e]) was reacted with [4-bromo-2-methyl-5-(4-trifluoromethyl-phenyl)-2H-pyrazol-3-yl]-methanol in the presence of N,N,N′,N′-tetramethyl azodicarboxamide and tributylphosphine to give {6-[4-bromo-2-methyl-5-(4-trifluoromethyl-phenyl)-2H-pyrazol-3-ylmethoxy]-indol-1-yl}-acetic acid ethyl ester as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:12][O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:20])=[C:6]([CH:11]=1)[C:7]([O:9]C)=[O:8].[OH-].[Na+]>CO.O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:12][O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:20])=[C:6]([CH:11]=1)[C:7]([OH:9])=[O:8]
Reactant: COC(=O)c1cc(Cl)ccc1COc1ccccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cc(Cl)ccc1COc1ccccc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 86.7 %

Procedure:
To a solution of methyl 5-chloro-2-[(2-chlorophenoxy)methyl]benzoate (step 1, 103 mg, 0.33 mmol) in methanol (4 mL) and tetrahydrofuran (4 mL) was 2 N sodium hydroxide (1 mL) and the mixture was stirred at room temperature for 16 hours. After removal of solvent, the residue was diluted with water (5 mL) and the solution was acidified with 2 N hydrochloric acid. Precipitate was collected by filtration, washed with water and dried in vacuo to afford 85 mg (86%) of the title compound:
Reaction SMILES: C([O:5][C:6](=[O:44])[C@H:7]([CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[NH:8][C:9](=[O:36])[C@H:10]([CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[NH:11][C:12](=[O:27])[CH:13]([S:17]CC1C=CC(OC)=CC=1)[CH2:14][CH2:15][CH3:16])(C)(C)C.C1(OC)C=CC=CC=1.C(Cl)(Cl)(Cl)Cl>ClCCl.C([O-])(=O)C.[Hg+2].C([O-])(=O)C>[SH:17][CH:13]([CH2:14][CH2:15][CH3:16])[C:12]([NH:11][C@H:10]([C:9]([NH:8][C@H:7]([C:6]([OH:44])=[O:5])[CH2:37][C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)=[O:36])[CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27]
Reactant: CCCC(SCc1ccc(OC)cc1)C(=O)N[C@@H](CCc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)OC(C)(C)C
Agent: CC(=O)[O-]
Agent: [Hg+2]
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: COc1ccccc1
Product: CCCC(S)C(=O)N[C@@H](CCc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.2 %

Procedure:
Combine 2-(4-methoxybenzylthio)-pentanoyl-(L)-homophenylalanyl-(L)-phenylalanine t-butyl ester (0.20 g, 0.33 mmol), mercury (II) acetate (0.134 g, 0.42 mmol), and anisole (0.37 mL, 3.4 mmol) in dichloromethane (9 mL). Cool in an ice bath and degas by repeatedly applying vacuum and filling the vessel with nitrogen, Add trifluoroacetic acid (4 mL). After 1 hour, warm to ambient temperature. After 3 hours, purge with hydrogen sulfide (gas) for about 10 minutes. Filter and evaporate in vacuo to give a residue. Repeatedly, combine the residue and carbon tetrachloride and evaporate in vacuo to give a residue. Triturate the residue with hexane to give the title compound as a solid (85 mg, 57%).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([SH:7])=[N:5][N:6]=1.[C:8](Cl)(=[O:11])[CH2:9][CH3:10].O>N1C=CC=CC=1>[C:8]([NH:1][C:2]1[S:3][C:4]([SH:7])=[N:5][N:6]=1)(=[O:11])[CH2:9][CH3:10]
Reactant: CCC(=O)Cl
Reactant: Nc1nnc(S)s1
Solvent: O
Solvent: c1ccncc1
Product: CCC(=O)Nc1nnc(S)s1
Temperature: 25 °C
Reaction time: 4 h
Yield: 71.1 %

Procedure:
To a suspension of 20 g of 2-amino-5-mercapto-1,3,4-thiadiazole in 200 ml of pyridine was added 14.6 g of propionyl chloride with cooling over a five minute period. After stirring the reaction mixture for 4 hours at room temperature, water was added and the resulting solid collected by filtration to give 20.2 g of 2-propionamido-5-mercapto-1,3,4-thiadiazole, m.p. 234°-237° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:18]=[CH:17][C:6]2[NH:7][C:8]3[S:9][C:10]([CH3:16])=[CH:11][C:12]=3[C:13]([NH2:15])=[N:14][C:5]=2[CH:4]=1.[CH3:19][O:20][CH2:21][CH2:22][C@H:23]1[CH2:28]N[CH2:26][CH2:25][NH:24]1>CS(C)=O.C1(C)C=CC=CC=1.O.C(OCC)(=O)C>[Cl:2][C:3]1[CH:18]=[CH:17][C:6]2[NH:7][C:8]3[S:9][C:10]([CH3:16])=[CH:11][C:12]=3[C:13]([N:15]3[CH2:26][CH2:25][NH:24][C@@H:23]([CH2:22][CH2:21][O:20][CH3:19])[CH2:28]3)=[N:14][C:5]=2[CH:4]=1
Reactant: COCC[C@H]1CNCCN1
Reactant: Cc1cc2c(s1)Nc1ccc(Cl)cc1N=C2N
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COCC[C@H]1CN(C2=Nc3cc(Cl)ccc3Nc3sc(C)cc32)CCN1
Temperature: 130 °C
Yield: 60 %

Procedure:
Dissolve 7-chloro-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulen-10-ylamine hydrochloride (1.46 g, 4.86 mmol) and (S)-2-(2-methoxy-ethyl)-piperazine (2.1 g, 14.6 mmol) in dimethylsulfoxide/toluene (1:2)(18 ml), stir under nitrogen and heat in an oil bath at 130° C. for 28.5 hours. Stir 16 hours at ambient temperature. Dilute the mixture with water and ethyl acetate, and extract with ethyl acetate. Combine the ethyl acetate extracts, wash with water and brine, dry the organic phase (Na2SO4), filter and concentrate under reduced pressure. Chromatograph on silica gel (eluent: 0-10% 2N ammonia in methanol/dichloromethane) to give the title compound (1.14 g, 60%), Mass Spectrum (ESMS) 391/393 (M+1), mp 179-183° C. (dec).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-])=O)=[CH:5][C:4]=1[N:12]1[CH2:17][CH2:16][N:15]([C:18](=[O:23])[C:19]([Cl:22])([Cl:21])[Cl:20])[CH2:14][CH2:13]1>Cl.Cl.C(O)C>[NH2:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]([N:12]2[CH2:13][CH2:14][N:15]([C:18](=[O:23])[C:19]([Cl:22])([Cl:20])[Cl:21])[CH2:16][CH2:17]2)[CH:5]=1
Reactant: COc1ccc([N+](=O)[O-])cc1N1CCN(C(=O)C(Cl)(Cl)Cl)CC1
Agent: Cl
Solvent: CCO
Product: COc1ccc(N)cc1N1CCN(C(=O)C(Cl)(Cl)Cl)CC1
Reaction time: 24 h

Procedure:
A solution of stannous chloride dihydrate (27 g) in concentrated HCl (60 ml) was slowly added to a stirred suspension of 1-(2-methoxy-5-nitrophenyl)-4-trichloroacetylpiperazine (D15) (15 g) in concentrated HCl/ethanol (1:2, 120 ml). After 24 hrs, the mixture was filtered, diluted with dichloromethane (600 ml) and basified with Na2CO3 solution. The layers were separated, the organic phase dried, concentrated to ⅓ the volume and acidified with 1M ethereal HCl solution to afford the title compound (D16) as a green solid (2.5 g, 15%). Found MH+ 352.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:9])[CH:5]=[C:6]([NH2:8])[CH:7]=1.CO[CH:12]1[CH2:16][CH2:15][CH:14](OC)O1>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([CH:5]=[C:4]([N:9]2[CH:12]=[CH:16][CH:15]=[CH:14]2)[CH:3]=1)[NH2:8]
Reactant: COC1CCC(OC)O1
Reactant: Nc1cc(N)cc(Cl)c1
Solvent: CC(=O)O
Product: Nc1cc(Cl)cc(-n2cccc2)c1

Procedure:
To a solution of 5-chloro-1,3-phenylenediamine (2.00 g) in acetic acid (20 mL) was added 2,5-dimethoxytetrahydrofuran (1.8 mL). After 4 hours at reflux, the reaction mixture was concentrated. The residue was suspended in satd. NaHCO3 and EtOAc. The reaction mixture was filtered and the organic layer was collected, washed with satd. NaHCO3 and brine, dried (Na2SO4), filtered and concentrated. Purification of the residue by chromatography (silica gel: EtOAc/hexane: 1/4) afforded 0.54 g of 3-chloro-5-(1-pyrrolyl)aniline. MS (m/z) 193 (MH+). (2) To a solution of the compound obtained above (0.35 g) in CH2Cl2 (15 mL) was added a solution of trichloroacetyl chloride (0.17 g) dissolved in CH2Cl2 (2 mL). After 45 minutes at room temperature, 2-(4-cyanobenzyl)proline methyl ester (0.38 g) (prepared in a similar fashion to Example 1 (1) and (2)) dissolved in CH2Cl2 (10 mL) and triethylamine (2 mL) were added. After stirring overnight, the mixture was concentrated. The residue was dissolved in EtOAc, washed with satd. NaHCO3 and brine, dried (Na2SO4), filtered and concentrated. Purification by chromatography (silica gel: EtOAc/hexane: 1/4, Chromatotron) afforded 0.51 g of N-[[3-chloro-5-(1-pyrrolyl)phenyl]carbamoyl]-2-(4-bromobenzyl)proline methyl. MS (m/z) 463 (MH+). (3) The titled compound was prepared from the above compound in a fashion similar to Example 1 (4): MS (m/z) 431 (MH+). mp 266.5° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C@@:4]1([C:17]([N:19]2[CH2:28][CH2:27][C:26]3[N:25]=[CH:24][C:23]([C:29]([F:32])([F:31])[F:30])=[CH:22][C:21]=3[CH2:20]2)=[O:18])[CH2:8][C@H:7]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH:6]=[CH:5]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(=O)(O)[O-].[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[O:1]=[CH:2][CH2:3][C@@:4]1([C:17]([N:19]2[CH2:28][CH2:27][C:26]3[N:25]=[CH:24][C:23]([C:29]([F:32])([F:31])[F:30])=[CH:22][C:21]=3[CH2:20]2)=[O:18])[CH2:8][C@H:7]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH:6]=[CH:5]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1C=C[C@](CCO)(C(=O)N2CCc3ncc(C(F)(F)F)cc3C2)C1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H]1C=C[C@](CC=O)(C(=O)N2CCc3ncc(C(F)(F)F)cc3C2)C1
Reaction time: 1 h

Procedure:
To a solution of the product of Example 1, Step D (417 mg, 0.92 mmol, 1 eq) in DCM (20 mL) at 0° C. was added Dess-Martin periodinane (427 mg, 1.01 mmol, 1.1 eq). After 1 hr, saturated sodium bicarbonate and sodium thiosulfate were added, after 10 minutes, the aqueous was extracted with DCM, the organics combined, dried over MgSO4 and concentrated. Purification by chromatography (12 g column) eluting with 30 to 60% EtOAc/heptane afforded the title compound of Step A. 1H NMR (CHLOROFORM-d) δ: 9.74 (s, 1H), 8.70 (s, 1H), 7.72 (s, 1H), 6.31 (dd, J=5.6, 1.7 Hz, 1H), 5.91 (dd, J=5.6, 1.5 Hz, 1H), 5.01 (d, J=17.1 Hz, 1H), 4.65-4.87 (m, 3H), 4.07-4.21 (m, 1H), 3.79-3.95 (m, 1H), 3.10 (q, J=5.6 Hz, 2H), 3.03 (d, J=16.6 Hz, 1H), 2.63 (dd, J=13.6, 7.2 Hz, 1H), 2.52 (dd, J=16.6, 1.5 Hz, 1H), 2.11 (dd, J=13.1, 7.7 Hz, 1H), 1.44 (s, 9H). Calculated for C22H26F3N3O4: 454.2 (M+1). found: 454.2.
Reaction SMILES: [Br:1][C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.[C:7](Cl)(=[O:14])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[Al+3].[Cl-].[Cl-].[Cl-]>C1C=CC=CC=1>[C:7]([C:4]1[S:3][C:2]([Br:1])=[CH:6][CH:5]=1)(=[O:14])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCC(=O)Cl
Reactant: Brc1cccs1
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Product: CCCCCCC(=O)c1ccc(Br)s1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
2-Bromothiophene (1.63 g, 10.0 mmol) and heptanoyl chloride (1.78 g, 12.0 mmol) were dissolved in dry benzene (15 mL) and AlCl3 was added in portions with stirring over 10 min. The resulting dark brown solution was refluxed for 1 hr and left to cool down to room temperature. The mixture was quenched with 2M HCl (15 mL) carefully while stirred. The organic layer was separated, washed with 2M HCl, 2M NaOH, and water, and passed through silica column (d=3 cm, l=8 cm). The solution was dried over MgSO4, and concentrated in vacuo (2.40 g, 87%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]3[C:12](=[O:31])[NH:13][C:14](=[O:30])[C:15]=3[C:16]3[C:26]4=[C:27]5[C:22](=[CH:23][CH:24]=[CH:25]4)[CH2:21][CH:20]([CH2:28]O)[CH2:19][N:18]5[CH:17]=3)=[CH:7][NH:8]2)=[CH:4][CH:3]=1.C(Br)(Br)(Br)[Br:33].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C)C=O.O>[Br:33][CH2:28][CH:20]1[CH2:21][C:22]2[C:27]3=[C:26]([C:16]([C:15]4[C:14](=[O:30])[NH:13][C:12](=[O:31])[C:11]=4[C:6]4[C:5]5[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=5)[NH:8][CH:7]=4)=[CH:17][N:18]3[CH2:19]1)[CH:25]=[CH:24][CH:23]=2
Reactant: O=C1NC(=O)C(c2cn3c4c(cccc24)CC(CO)C3)=C1c1c[nH]c2cc(F)ccc12
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: O=C1NC(=O)C(c2cn3c4c(cccc24)CC(CBr)C3)=C1c1c[nH]c2cc(F)ccc12
Temperature: 25 °C
Reaction time: 6 h
Yield: 61 %

Procedure:
A mixture of 3-(6-fluoro-1H-indol-3-yl)-4-(5-hydroxymethyl-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)pyrrole-2,5-dione (500 mg, 1.2 mmol), carbon tetrabromide (796 mg, 2.4 mmol), and triphenylphosphine (314 mg, 1.2 mmol) in 15 mL of dimethylformamide was stirred at room temperature for 6 hours. The reaction mixture was diluted with water and extracted with ethyl acetate (40 mL). The organic layer was washed with saturated aqueous sodium chloride (20 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was subjected to reverse phase HPLC to provide 350 mg (61%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.[NH2:24][CH2:25][CH2:26][N:27]1[CH2:31][CH2:30][NH:29][C:28]1=[O:32]>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([NH:24][CH2:25][CH2:26][N:27]2[CH2:31][CH2:30][NH:29][C:28]2=[O:32])=[O:21])=[CH:17][N:16]=1
Reactant: NCCN1CCNC1=O
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)NCCN2CCNC2=O)cn1
Yield: 64 %

Procedure:
As described for example 191, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (200 mg, 0.65 mmol) was converted, using (1-(2-aminoethyl)imidazolidin-2-one instead of 2-aminoethyl isopropylether, to the title compound (175 mg, 64%) which was obtained as a white solid. MS: m/e=422.1 [M+H]+.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:20]=[CH:19][C:6]([O:7][CH2:8][C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)=[CH:5][CH:4]=1.[C:21]([C:27]1[O:28][C:29]2[CH:37]=[CH:36][C:35]([Cl:38])=[C:34]([OH:39])[C:30]=2[C:31](=[O:33])[CH:32]=1)([O:23][CH2:24][CH2:25][CH3:26])=[O:22].[I-].[K+]>CC(C)=O.CN(C)C=O>[C:21]([C:27]1[O:28][C:29]2[CH:37]=[CH:36][C:35]([Cl:38])=[C:34]([O:39][CH2:2][C:3]3[CH:20]=[CH:19][C:6]([O:7][CH2:8][C:9]4[CH:18]=[CH:17][C:16]5[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=5)[N:10]=4)=[CH:5][CH:4]=3)[C:30]=2[C:31](=[O:33])[CH:32]=1)([O:23][CH2:24][CH2:25][CH3:26])=[O:22]
Reactant: CCCOC(=O)c1cc(=O)c2c(O)c(Cl)ccc2o1
Reactant: ClCc1ccc(OCc2ccc3ccccc3n2)cc1
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: CCCOC(=O)c1cc(=O)c2c(OCc3ccc(OCc4ccc5ccccc5n4)cc3)c(Cl)ccc2o1

Procedure:
0.78 g of 2-(4-chloromethylphenoxy)methylquinoline, 0.76 g of 2-carbopropoxy-6-chloro-5-hydroxy-4-oxo-4H-1-benzopyran and a catalytic amount of potassium iodide are combined in 50 ml of acetone and 2 ml of dimethylformamide, and refluxed for 19 hours. The crude solid obtained on cooling is purified by flash chromatography to give 2-carbopropoxy-6-chloro-5-(4-(quinolin-2-ylmethoxy)benzyloxy) 4-oxo-4H-1-benzopyran having an m.p. of 173°-74° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]([F:14])([F:13])[F:12])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[F:12][C:11]([F:14])([F:13])[S:8]([C:5]1[CH:6]=[CH:7][C:2]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[CH:3][CH:4]=1)(=[O:10])=[O:9]
Reactant: C1CNCCN1
Reactant: O=S(=O)(c1ccc(Br)cc1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: O=S(=O)(c1ccc(N2CCNCC2)cc1)C(F)(F)F

Procedure:
A mixture of 1 mmol 1-Bromo-4-trifluoromethanesulfonyl-benzene [Nodiff et al., J. Org. Chem. 25, 60 (1960)], 3 mmol of piperazine and 2 mmol of potassium carbonate in 5 ml of acetonitrile was refluxed for 2 hours. The resulting mixture was poured into water, extracted with ethyl acetate, dried, concentrated and purified by column chromatography (SiO2; Et2O/cyclohexane) to yield the title compound as a colorless solid. MS (m/e): 295.2 (MH+, 100%)
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:18]=[C:17]([C:19](O)=[O:20])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1.Cl.[CH3:23][O:24][C:25]1[C:34]([O:35][CH3:36])=[CH:33][CH:32]=[C:31]2[C:26]=1[CH2:27][CH2:28][NH:29][CH2:30]2>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:18]=[C:17]([C:19]([N:29]2[CH2:28][CH2:27][C:26]3[C:31](=[CH:32][CH:33]=[C:34]([O:35][CH3:36])[C:25]=3[O:24][CH3:23])[CH2:30]2)=[O:20])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1
Reactant: O=C(O)c1nc(-c2ccc(F)cc2F)nc2ccccc12
Reactant: COc1ccc2c(c1OC)CCNC2
Agent: Cl
Product: COc1ccc2c(c1OC)CCN(C(=O)c1nc(-c3ccc(F)cc3F)nc3ccccc13)C2
Yield: 12 %

Procedure:
Reaction of 2-(2,4-difluorophenyl)quinazoline-4-carboxylic acid with 5,6-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 59 (12% yield) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 2.72 and 2.97 (2t, 2H), 3.50 and 4.01 (2t, 2H), 3.68-3.81 (m, 6H), 4.42 and 4.92 (2s, 2H), 6.64 and 7.00 (2d, 1H), 6.82 and 7.07 (2d, 1H), 7.28-7.49 (m, 2H), 7.75-7.84 (m, 1H), 7.93-8.10 (m, 1H), 8.13-8.26 (m, 3H); MS (ESI) m/z 462 ([M+H]+).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[N:10]=[CH:11][C:12]2[CH:13]=[CH:14][CH:15]=[C:16](C(OC)=O)[C:17]=2[CH:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C[AlH]CC(C)C)C.[C@H](O)(C([O-])=O)[C@@H](O)[C:34]([O-])=[O:35].[Na+].[K+]>C1COCC1>[OH:35][CH2:34][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:12]=1[CH:11]=[N:10][C:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[CH:18]2
Reactant: COC(=O)c1cccc2cnc(NC(=O)OC(C)(C)C)cc12
Reactant: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: CC(C)C[AlH]CC(C)C
Agent: [K+]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1cc2cccc(CO)c2cn1
Temperature: 25 °C

Procedure:
A 10 mL round bottom flask with methyl 3-((tert-butoxycarbonyl)amino)isoquinoline-5-carboxylate (0.473 g, 1.56 mmol) in 15 mL THF was charged with DIBAL (7.8 mL, 7.83 mmol), The reaction mixture was stirred at rt. After stirring for 2 h, the reaction mixture was added with Rochelle's salt and stirred for 1 h and then extracted with EtOAc (3×20 mL). Combined organic layer was dried, filtered and then concentrated in vacuo. Purified by silica gel chromatography (0-100% EtOAc in hexane) yielded tert-butyl (8-(hydroxymethyl)isoquinolin-3-yl)carbamate (27-4).
Reaction SMILES: C([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)C1C=CC=CC=1>[Pd].C1COCC1.CO>[C:24]1([C:9]2([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:10]3[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH2:16][CH2:17][NH:8]2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: c1ccc(CN2CCc3ccccc3C2(c2ccccc2)c2ccccc2)cc1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: c1ccc(C2(c3ccccc3)NCCc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 24.6 %

Procedure:
10% Pd-supported carbon (900 mg) was added to a solution of 2-benzyl-1,1-diphenyl-1,2,3,4-tetrahydroisoquinoline (1.81 g) in a 2:1 THF-MeOH mixture (30 mL). The mixture was stirred under a hydrogen atmosphere at room temperature for 16 hours. Further, 10% Pd-supported carbon (900 mg) was added to the mixture, followed by stirring for 8 hours. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-EtOAc) to obtain 1,1-diphenyl-1,2,3,4-tetrahydroisoquinoline (339 mg).