Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([OH:9])=O.C(Cl)(=O)C(Cl)=O.O1CCCC1.[NH2:26][C:27]1[CH:28]=[C:29]([CH:46]=[CH:47][CH:48]=1)[O:30][C:31]1[CH:32]=[CH:33][C:34]2[N:35]([CH:37]=[C:38]([NH:40][C:41]([CH:43]3[CH2:45][CH2:44]3)=[O:42])[N:39]=2)[N:36]=1>CN(C)C=O.CN1CCCC1=O>[CH:43]1([C:41]([NH:40][C:38]2[N:39]=[C:34]3[CH:33]=[CH:32][C:31]([O:30][C:29]4[CH:28]=[C:27]([NH:26][C:7](=[O:9])[C:6]5[CH:10]=[CH:11][CH:12]=[C:4]([O:3][C:2]([F:1])([F:14])[F:13])[CH:5]=5)[CH:48]=[CH:47][CH:46]=4)=[N:36][N:35]3[CH:37]=2)=[O:42])[CH2:44][CH2:45]1
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Reactant: O=C(O)c1cccc(OC(F)(F)F)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CN1CCCC1=O
Product: O=C(Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1)c1cccc(OC(F)(F)F)c1
Yield: 53.3 %

Procedure:
Using 3-(trifluoromethoxy)benzoic acid (120 mg, 0.58 mmol), oxalyl chloride (60 μL, 0.68 mmol), N,N-dimethylformamide (1 drop), tetrahydrofuran (3.0 mL), N-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (150 mg, 0.49 mmol) and N-methylpyrrolidone (2.0 mL) as starting materials and in the same manner as in Example 335, the title compound (130 mg, 54%) was obtained as a white powder.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][NH2:5].[C:6](N1C(=O)CCC1=O)([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7].O.C(Cl)(Cl)Cl>O1CCOCC1>[CH3:1][NH:2][CH2:3][CH2:4][NH:5][C:6](=[O:7])[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CNCCN
Reactant: O=C1CCC(=O)N1C(=O)OCc1ccccc1
Solvent: O
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Product: CNCCNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 96 h
Yield: 4.3 %

Procedure:
N-Methylethylenediamine (2.0 g) was dissolved in dioxane (20 ml), the solution was added with N-carbobenzoxysuccinimide (8.07 g), and the mixture was stirred at room temperature for 4 days. The reaction mixture was added with distilled water and chloroform, the layers were separated, and the organic layer was dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1 to 2:1), and then purified again by silica gel column chromatography (chloroform:methanol:28% aqueous ammonia=30:1:0.1) to obtain the title compound (243 mg).
Reaction SMILES: S(Cl)([Cl:3])=O.[Br:5][C:6]1[CH:11]=[C:10]([O:12][CH2:13][C:14]2[N:15]([C:22]3[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:29])[N:16]=[N:17][C:18]=2[CH:19]([CH3:21])[CH3:20])[CH:9]=[CH:8][C:7]=1[C:30]1[CH:35]=[CH:34][C:33]([C:36]([OH:38])=O)=[CH:32][CH:31]=1>>[Br:5][C:6]1[CH:11]=[C:10]([O:12][CH2:13][C:14]2[N:15]([C:22]3[C:23]([Cl:29])=[CH:24][CH:25]=[CH:26][C:27]=3[Cl:28])[N:16]=[N:17][C:18]=2[CH:19]([CH3:20])[CH3:21])[CH:9]=[CH:8][C:7]=1[C:30]1[CH:35]=[CH:34][C:33]([C:36]([Cl:3])=[O:38])=[CH:32][CH:31]=1
Reactant: O=S(Cl)Cl
Reactant: CC(C)c1nnn(-c2c(Cl)cccc2Cl)c1COc1ccc(-c2ccc(C(=O)O)cc2)c(Br)c1
Product: CC(C)c1nnn(-c2c(Cl)cccc2Cl)c1COc1ccc(-c2ccc(C(=O)Cl)cc2)c(Br)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To thionyl chloride (1.5 mL, 20 mmol) is added 2′-bromo-4′-[3-(2,6-dichloro-phenyl)-5-isopropyl-3H-[1,2,3]triazol-4-ylmethoxy]-biphenyl-4-carboxylic acid (0.074 g, 0.13 mmol). The reaction is stirred overnight at room temperature. The reaction mixture is concentrated under reduced pressure to give 2′-Bromo-4′-[3-(2,6-dichloro-phenyl)-5-isopropyl-3H-[1,2,3]triazol-4-ylmethoxy]-biphenyl-4-carbonyl chloride.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])([O-:3])=[O:2].C(OC1C=CC=CC=1O)C1C=CC=CC=1.Br[CH2:27][CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31].C(=O)([O-])[O-].[K+].[K+].C1(O)C=CC=CC=1>CC(C)=O>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH2:27][CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])([O-:3])=[O:2]
Reactant: CCOC(=O)CCCBr
Reactant: O=[N+]([O-])c1ccccc1O
Agent: O=C([O-])[O-]
Agent: Oc1ccccc1OCc1ccccc1
Agent: [K+]
Solvent: CC(C)=O
Solvent: Oc1ccccc1
Product: CCOC(=O)CCCOc1ccccc1[N+](=O)[O-]
Yield: 96 %

Procedure:
To a stirred solution of 2-nitrophenol. (1) (1.4 g, 10 mM) and ethyl 4-bromobutyrate (2.1 g, 1.57 mL, 11 mM) in 35 mL of dry acetone is added 2 g (14.5 mM) of anhydrous, ground potassium carbonate. The resultant colored mixture is then heated under a nitrogen atmosphere at gentle reflux until the color due to the phenol anion has dissipated and a yellow mixture remains. Concentration of the cooled and filtered mixture yields an oil which on flash chromatography (silica gel, ethyl acetate/hexane- or methylene chloride as eluant) yields 2.4 g (96% yield) of the title compound (3) as an oily liquid.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23]([C:26](=[O:31])[NH:27][CH:28]([CH3:30])[CH3:29])([CH3:25])[CH3:24])[CH:17]=1)[C:10]([CH3:33])([CH3:32])[CH2:9]2)=[O:5])C.Cl>CO.O1CCCC1.[OH-].[Na+].O>[CH:28]([NH:27][C:26]([C:23]([NH:22][C:18]1[CH:17]=[C:16]([CH:11]2[C:10]([CH3:33])([CH3:32])[CH2:9][C:8]3[C:13](=[CH:14][CH:15]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=3)[NH:12]2)[CH:21]=[CH:20][CH:19]=1)([CH3:25])[CH3:24])=[O:31])([CH3:30])[CH3:29]
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(NC(C)(C)C(=O)NC(C)C)c1)N2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)NC(=O)C(C)(C)Nc1cccc(C2Nc3ccc(C(=O)O)cc3CC2(C)C)c1
Temperature: 50 °C
Reaction time: 12 h
Yield: 32.7 %

Procedure:
A mixture of 2-[3-(1-isopropylcarbamoyl-1-methyl-ethylamino)-phenyl]-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (0.85 g, 1.88 mmol) in methanol (10 mL) and tetrahydrofuran (20 mL), 30% sodium hydroxide in water (10 mL) was stirred at 50° C. for 12 h. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×100 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded 2-[3-(1-isopropylcarbamoyl-1-methyl-ethylamino)-phenyl]-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (260 mg, 30%) as a white solid: LC/MS m/e calcd for C25H33N3O3 (M+H)+: 424.56, observed: 424.1.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:10]=[CH:9][NH:8][N:7]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:18][C:19]([N:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[CH2:23][CH2:22]1)=[O:20].CN(C=O)C>CCCCCC.C(OCC)(=O)C>[F:33][C:30]1[CH:29]=[CH:28][C:27]([N:24]2[CH2:23][CH2:22][N:21]([C:19](=[O:20])[CH2:18][N:8]3[CH:9]=[CH:10][C:6]([C:2]4[S:1][CH:5]=[CH:4][CH:3]=4)=[N:7]3)[CH2:26][CH2:25]2)=[CH:32][CH:31]=1
Reactant: O=C(CCl)N1CCN(c2ccc(F)cc2)CC1
Reactant: c1csc(-c2cc[nH]n2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=C(Cn1ccc(-c2cccs2)n1)N1CCN(c2ccc(F)cc2)CC1

Procedure:
Protocol T was followed using 3-(2-thienyl)pyrazole, K2CO3, 2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate=1/1) afforded the title compound as a white solid. 1H NMR (400 MHz, CDCl3); 7.48-7.52 (d, 1H), 7.24-7.28 (dd, 1H), 7.14-7.2 (dd, 1H), 6.98-7.2 (m, 1H), 6.88-6.96 (m, 2H), 6.78-6.84 (m, 2H), 6.46-6.52 (d, 1H), 5.0 (s, 2H), 3.64-3.8 (m, 4H), 2.94-3.1 (m, 4H). 13C NMR (400 MHz, CDCl3): 164.4, 158, 152.2, 144, 134, 132, 126, 124, 123.8, 118, 116, 115.8, 102.2, 54, 51.2, 50.8, 45.8, 42.2.
Reaction SMILES: [CH:1]([O:4][P:5]([C:7]([CH3:10])([CH3:9])[CH3:8])[OH:6])([CH3:3])[CH3:2].[Na].[C:12](#[N:15])[CH:13]=[CH2:14]>>[C:12]([CH2:13][CH2:14][P:5]([C:7]([CH3:10])([CH3:9])[CH3:8])(=[O:6])[O:4][CH:1]([CH3:3])[CH3:2])#[N:15]
Reactant: CC(C)OP(O)C(C)(C)C
Reactant: C=CC#N
Agent: [Na]
Product: CC(C)OP(=O)(CCC#N)C(C)(C)C

Procedure:
To 15.7 g of t-butylphosphonous acid-isopropylester in 6.3 ml of acrylonitrile are added 21 ml of sodium isopropylate (0.25 molar). After the exothermic reaction (the temperature rises to 100°) the suspension is filtered, the filtrate evaporated and the residue distillated to yield isopropyl 2-cyanoethyl(t-butyl)phosphinate as an oil, b.p. 121°/8 Pa, n20D =1.4480.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.[CH2:9]([OH:13])[CH2:10][C:11]#[CH:12]>C(NCC)C.[Cu]I>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:12]#[C:11][CH2:10][CH2:9][OH:13])=[CH:4][CH:3]=1
Reactant: Fc1ccc(I)cc1
Reactant: C#CCCO
Agent: [Cu]I
Solvent: CCNCC
Product: OCCC#Cc1ccc(F)cc1
Reaction time: 16 h
Yield: 34.2 %

Procedure:
Copper (I) iodide was added to a stirred solution of 1-fluoro-4-iodobenzene (11.09 g), 3-butyn-1-ol (3.5 g), and BTPC (100 g) in diethylamine (70 ml) and the mixture stirred under nitrogen for 16 h. The mixture was evaporated in vacuo and purified by FCC on eluting with H - EA (2:1) gave the title compound as a yellow solid (2.8 g). T.l.c. (H - EA 2:1) RF 0.20.
Reaction SMILES: [Cl:1][CH2:2][C:3]#[N:4].[CH3:5][C:6](O)([CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH3:7].S(=O)(=O)(O)[OH:15]>C(O)(=O)C>[Cl:1][CH2:2][C:3]([NH:4][C:6]([CH3:7])([CH3:5])[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:15]
Reactant: CCCCCC(C)(C)O
Reactant: O=S(=O)(O)O
Reactant: N#CCCl
Solvent: CC(=O)O
Product: CCCCCC(C)(C)NC(=O)CCl
Temperature: -50 °C
Reaction time: 0.5 h

Procedure:
A solution of chloroacetonitrile (15.1 g., 0.2 mol) and 2-methylheptan-2-ol (26.0 g., 0.2 mol) in acetic acid (120 ml) was treatedwith concentrated sulphuric acid (24 ml) with the temperature maintained at40°-50° C. After stirring for 1/2 hour the mixture was pouredinto ice-water (500 ml) and extracted with ether (3×400 ml). The combined extracts were washed with aqueous sodium carbonate until neutral and then evaporated to give 2-chloro-N-(1,1-dimethylhexyl)acetamide as a colourless solid m.p. 36°-37° C., b.p. 60°-62°C. at 0.01 mm Hg.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:16]([CH3:19])([CH3:18])[CH3:17])[C:8]2[O:12][C:11](=[O:13])[CH:10](O)[C:9]=2[CH:15]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:26]=1[CH3:27]>O>[O:12]1[C:8]2[CH:7]=[CH:6][CH:5]=[CH:15][C:9]=2[CH2:10][C:11]1=[O:13].[CH3:20][C:21]1[CH:22]=[C:23]([CH:10]2[C:9]3[CH:15]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:6]=[C:7]([C:16]([CH3:17])([CH3:18])[CH3:19])[C:8]=3[O:12][C:11]2=[O:13])[CH:24]=[CH:25][C:26]=1[CH3:27]
Reactant: Cc1ccccc1C
Reactant: CC(C)(C)c1cc2c(c(C(C)(C)C)c1)OC(=O)C2O
Solvent: O
Product: Cc1ccc(C2C(=O)Oc3c2cc(C(C)(C)C)cc3C(C)(C)C)cc1C
Product: O=C1Cc2ccccc2O1

Procedure:
To a solution of 262.3 g (1.00 mol) of 5,7-di-tert-butyl-3-hydroxy-3H-benzofuran-2-one (compound (201), Table 2, Example 1a) in 500 ml (4.05 mol) of o-xylene are added 40 g of Fulcat 22B and the mixture is refluxed for 1.5 hours on a water separator. The Fulcat 22B catalyst is then removed by filtration and excess p-xylene is removed by distillation on a vacuum rotary evaporator. Crystallisation of the residue from 500 ml of methanol yields 244 g (69%) of 3-(3,4-dimethylphenyl)-5,7-di-tert-butyl)-3H -benzofuran-2-one, m.p. 130-132° C. (compound (103), Table 1), which additionally contains c. 1.3% of the structural isomer [3-(2,3-dimethylphenyl)-5,7-di-tert-butyl-3H-benzofuran-2-one, compound (103A)]. The mother liquor yields a further 42.4 g of product which, according to GC-MS analysis, consists of 12.3% of the compound (103) and 87.7% of the isomeric compound (103A).
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([O:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[C:27](=[O:28])[C:26]([CH2:29][C:30]3[CH:35]=[CH:34][C:33]([C:36]4[C:37]([C:42]#[N:43])=[CH:38][CH:39]=[CH:40][CH:41]=4)=[CH:32][CH:31]=3)=[C:25]([CH2:44][CH2:45][CH3:46])[N:24]=[C:23]2[CH3:47])=[CH:18][C:17]=1[F:48])[CH3:14]>O.C(OCC)(=O)C>[CH2:13]([O:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[C:27](=[O:28])[C:26]([CH2:29][C:30]3[CH:35]=[CH:34][C:33]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=4[C:42]4[NH:3][C:4](=[O:7])[O:5][N:43]=4)=[CH:32][CH:31]=3)=[C:25]([CH2:44][CH2:45][CH3:46])[N:24]=[C:23]2[CH3:47])=[CH:18][C:17]=1[F:48])[CH3:14]
Reactant: [NH3+]O
Reactant: CCCc1nc(C)n(-c2ccc(OCC)c(F)c2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCc1nc(C)n(-c2ccc(OCC)c(F)c2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 70.5 %

Procedure:
A mixture of hydroxylammonium chloride (1.40 g), sodium hydrogen carbonate (2.00 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 4′-{[1-(4-ethoxy-3-fluorophenyl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (0.96 g) was added, and the mixture was stirred at 90° C. for 18 hr. The reaction mixture was allowed to cool to room temperature, ethyl acetate and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was dissolved in tetrahydrofuran (10 mL). N,N′-carbonyldiimidazole (0.42 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.39 mL) were added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.76 g, 70%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[F:9][C:10]1[CH:11]=[C:12]([CH:21]=[C:22]([F:24])[CH:23]=1)[O:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1.Cl[CH2:26][CH2:27][NH:28][C:29](=[O:33])[O:30][CH2:31][CH3:32]>CN(C)C=O>[F:9][C:10]1[CH:11]=[C:12]([CH:21]=[C:22]([F:24])[CH:23]=1)[O:13][C:14]1[CH:15]=[CH:16][C:17]([O:20][CH2:26][CH2:27][NH:28][C:29](=[O:33])[O:30][CH2:31][CH3:32])=[CH:18][CH:19]=1
Reactant: CCOC(=O)NCCCl
Reactant: Oc1ccc(Oc2cc(F)cc(F)c2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)NCCOc1ccc(Oc2cc(F)cc(F)c2)cc1
Yield: 92 %

Procedure:
27.6 g of finely pulverulent potassium carbonate and 1.0 g of pulverized potassium iodide are added to a solution of 22.2 g of 4-(3,5-difluorophenoxy)phenol in 80 ml of dimethylformamide. 18.2 g of ethyl 2-chloroethylcarbamate are furthermore added dropwise, and the reaction mixture is heated for 16 hours at +95° C., with stirring. The reaction mixture is then filtered, the filtrate is poured into 400 ml of water, and the mixture is extracted three times using diethyl ether. The combined organic phases are washed with water and dried over sodium sulfate, and the solvent is distilled off. The residue is purified over silica gel (eluent: n-hexane/diethyl ether, 3:1), which gives pure ethyl 2-[4-(3,5-difluorophenoxy)phenoxy]ethylcarbamate as a colourless solid of melting point 54°-56° C., which solidifies in crystalline form; yield: 92% of theory.
Reaction SMILES: [O:1]1[CH:13]2[C@@:14]34[CH2:16][CH2:17][N:18]([CH3:19])[C@@H:8]([C@@H:9]3[CH2:10][CH2:11][CH:12]2[OH:20])[CH2:7][C:6]2=[C:15]4[C:2]1=[CH:3][CH:4]=[CH:5]2.[Br:21]Br>C(O)(=O)C>[Br:21][C:3]1[CH:4]=[CH:5][C:6]2[CH2:7][C@H:8]3[N:18]([CH3:19])[CH2:17][CH2:16][C@:14]45[C:15]=2[C:2]=1[O:1][CH:13]4[CH:12]([OH:20])[CH2:11][CH2:10][C@@H:9]35
Reactant: CN1CC[C@]23c4c5cccc4OC2C(O)CC[C@H]3[C@H]1C5
Reactant: BrBr
Solvent: CC(=O)O
Product: CN1CC[C@]23c4c5ccc(Br)c4OC2C(O)CC[C@H]3[C@H]1C5
Reaction time: 1 h

Procedure:
3.1 g (11.4 mmol) of 4,5-epoxy-17-methylmorphinan-6-ol were dissolved in 150 ml of glacial acetic acid and 11.4 ml of a 1M solution of Br2 in AcOH were added dropwise. After 1 h, AcOH was removed in vacuo, the residue was taken up with water, the aqueous solution was brought to pH 7 with a saturated NAHCO3 solution and extracted with AcOEt. The organic phase was dried over NA2SO4, the solvent was removed in vacuo, yielding 3.6 g of the title product.
Reaction SMILES: [CH2:1]([C:5]1[O:6][C:7]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:8]=2[CH:9]=1)[CH2:2][CH2:3][CH3:4].[C:17](Cl)(=[O:26])[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1.[Sn](Cl)(Cl)(Cl)Cl>>[CH2:1]([C:5]1[O:6][C:7]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:8]=2[C:9]=1[C:17](=[O:26])[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)[CH2:2][CH2:3][CH3:4]
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: CCCCc1cc2cc([N+](=O)[O-])ccc2o1
Agent: Cl[Sn](Cl)(Cl)Cl
Product: CCCCc1oc2ccc([N+](=O)[O-])cc2c1C(=O)c1ccc(OC)cc1

Procedure:
reaction of 2-butyl-5-nitrobenzofuran with anisoyl chloride in the presence of tin tetrachloride based on the Friedel-Crafts reaction conditions and hydrolysis to form 2-butyl-3-(4-methoxybenzoyl)-5-nitrobenzofuran,
Reaction SMILES: [C:1]([C@H:9]1[CH2:14][CH2:13][C@H:12]2[C@H:15]3[C@H:24]([CH2:25][CH2:26][C@:10]12[CH3:11])[C:23]1[CH:22]=[CH:21][C:20]([C:27]([O:29]C)=[O:28])=[CH:19][C:18]=1[CH2:17][CH2:16]3)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].O>CO>[C:1]([C@H:9]1[CH2:14][CH2:13][C@H:12]2[C@H:15]3[C@H:24]([CH2:25][CH2:26][C@:10]12[CH3:11])[C:23]1[CH:22]=[CH:21][C:20]([C:27]([OH:29])=[O:28])=[CH:19][C:18]=1[CH2:17][CH2:16]3)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](C(=O)c3ccccc3)CC[C@@H]12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: C[C@]12CC[C@@H]3c4ccc(C(=O)O)cc4CC[C@H]3[C@@H]1CC[C@@H]2C(=O)c1ccccc1

Procedure:
A mixture of methyl 17β-benzoyl-estra-1,3,5(10)-triene-3-carboxylate, K2CO3, water and methanol is heated at reflux for 5 h. The volatiles are then removed at reduced pressure and the residue is diluted with water, acidified with dilute aqueous HCl, and extracted with EtOAc. The organic extract is washed with water and brine, dried, and evaporated to yield the title compound.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[C:16]([O:20][C:21](=[O:32])[NH:22][C@H:23]1[CH2:28][CH2:27][C@H:26]([CH2:29][CH:30]=O)[CH2:25][CH2:24]1)([CH3:19])([CH3:18])[CH3:17].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:16]([O:20][C:21](=[O:32])[NH:22][C@H:23]1[CH2:24][CH2:25][C@H:26]([CH2:29][CH2:30][N:11]2[CH2:12][CH2:13][CH:8]([C:6](=[O:7])[C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:15][CH:14]=3)[CH2:9][CH2:10]2)[CH2:27][CH2:28]1)([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CC=O)CC1
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CCN2CCC(C(=O)c3ccc(F)cc3)CC2)CC1
Reaction time: 12 h

Procedure:
A mixture of 4-(4-fluorobenzoyl)piperidine (0.850 g, 3.4 mmol), Trans-[4-(2-Oxo-ethyl)-cyclohexyl]-carbamic acid tert-butyl ester (0.926 g, 4 mmol), in 1, 2 dichloroethane (10 mL) was stirred for 4 h at room temperature and sodium triacetoxyborohydride (1.33 g, 6 mmol) was added and the resulting solution was stirred for 12 hours until the TLC indicated completion of the reaction. The mixture was filtrated and concentrated to dryness and purified with column chromatography on silica gel using CH2Cl2-CH2Cl2/MeOH (1-9:1). The product fractions were concentrated to give 1.4 g (3.25 mmol, 93.2% yield) of a light yellow solid. MS (m/e): 433.4 (M+H+).
Reaction SMILES: I.[S:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7](SC)=[NH:8].[NH2:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[N:18]([CH2:22][CH2:23][N:24]([CH3:34])[C:25](=[O:33])[O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:17](=[O:35])[CH2:16][CH2:15]2>C(O)C>[CH3:34][N:24]([CH2:23][CH2:22][N:18]1[C:19]2[C:14](=[CH:13][C:12]([NH:11][C:7]([C:3]3[S:2][CH:6]=[CH:5][CH:4]=3)=[NH:8])=[CH:21][CH:20]=2)[CH2:15][CH2:16][C:17]1=[O:35])[C:25](=[O:33])[O:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CSC(=N)c1cccs1
Reactant: CN(CCN1C(=O)CCc2cc(N)ccc21)C(=O)Oc1ccccc1
Agent: I
Solvent: CCO
Product: CN(CCN1C(=O)CCc2cc(NC(=N)c3cccs3)ccc21)C(=O)Oc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl thiophene-2-carbimidothioate hydroiodide (1.62 g, 5.71 mmol) was weighed into a round bottom flask with a stirbar. Phenyl 2-(6-amino-2-oxo-3,4-dihydroquinolin-1(2H)-yl)ethyl(methyl)carbamate (0.969 g, 2.85 mmol) was dissolved in ethanol (50 mL) and added to the flask. The resulting suspension was stirred overnight at room temperature. When the reaction was finished, argon was bubbled through the reaction mixture for 1 h, then the mixture was neutralized with sodium carbonate (sat. aq. solution). The product was extracted with dichloromethane (3×). The combined organics were dried over sodium sulfate, filtered and concentrated. The residue was chromatographed in (1:1) ethyl acetate:CH2Cl2 then 10% (2M NH3 in methanol) in dichloromethane. Yield: 700 mg, 55%. 1H NMR (DMSO-d6) δ 7.91 (m, 2H), 7.38 (m, 2H), 7.26 (m, 3H), 7.04 (m, 4H), 4.23 and 4.14 (2m, 2H), 3.63 and 3.51 (2m, 2H), 3.06 and 2.92 (2s, 3H), 2.84 (t, 2H, J=6.9 Hz), 2.56 (t, 2H, J=6.9 Hz); ESI-MS (m/z, %): 449 (MH+, 100).
Reaction SMILES: CO[C:3]1[CH:15]=[C:14]2[C:6]([C:7]3[CH2:8][CH2:9][NH:10][C:11](=[O:23])[C:12]=3[N:13]2[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[CH:5][CH:4]=1.[H-].[Na+].Br[CH2:27][C:28]1[C:29]([F:45])=[C:30]([O:35][C:36]2[CH:37]=[C:38]([CH:41]=[C:42]([Cl:44])[CH:43]=2)[C:39]#[N:40])[C:31]([Cl:34])=[CH:32][CH:33]=1.C(O)(=O)C[C:48](CC(O)=O)(C(O)=O)[OH:49]>C1COCC1.CCOC(C)=O>[Cl:34][C:31]1[CH:32]=[CH:33][C:28]([CH2:27][N:10]2[CH2:9][CH2:8][C:7]3[C:6]4[C:14](=[CH:15][CH:3]=[C:4]([O:49][CH3:48])[CH:5]=4)[N:13]([C:16]([O:18][C:19]([CH3:21])([CH3:22])[CH3:20])=[O:17])[C:12]=3[C:11]2=[O:23])=[C:29]([F:45])[C:30]=1[O:35][C:36]1[CH:37]=[C:38]([C:39]#[N:40])[CH:41]=[C:42]([Cl:44])[CH:43]=1
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CBr)c2F)c1
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reactant: COc1ccc2c3c(n(C(=O)OC(C)(C)C)c2c1)C(=O)NCC3
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc2c(c1)c1c(n2C(=O)OC(C)(C)C)C(=O)N(Cc2ccc(Cl)c(Oc3cc(Cl)cc(C#N)c3)c2F)CC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 24 %

Procedure:
1,1-Dimethylethyl 7-(methyloxy)-1-oxo-1,2,3,4-tetrahydro-9H-β-carboline-9-carboxylate (0.075 g, 0.23 mmol) was dissolved in THF (2 mL) and cooled to 0° C. Sodium hydride (60% dispersion in oil, 0.01 g, 0.25 mmol) was added and the mixture was stirred for 15 min. 3-{[3-(Bromomethyl)-6-chloro-2-fluorophenyl]oxy}-5-chlorobenzonitrile (0.09 g, 0.23 mmol) was added. The reaction mixture was allowed to warm to RT and stirred for 1 h. 10% Aqueous citric acid and EtOAc were added. The layers were separated and the aqueous layer extracted with EtOAc (3×5 mL). The organic extracts were combined, dried over Na2SO4, filtered and evaporated. Purification was accomplished by column chromatography (hexane/EtOAc) to afford the title compound (0.034 g, 24%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 7.83 (s, 1H), 7.81 (d, 1H), 7.52 (d, 1H), 7.45-7.51 (m, 2H), 7.34 (t, 1H), 7.20 (d, 1H), 7.07 (dd, 1H), 4.79 (s, 2H), 3.79 (s, 3H), 3.71 (t, 2H), 2.94 (t, 2H), 1.48 (s, 9H). MS: m/z 632.2 (M+23).