Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH2:17])[CH:12]=2)=[O:10])=[CH:4][CH:3]=1.[C:18](OC(=O)C)(=[O:20])[CH3:19]>CN(C)C1C=CN=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH:17][C:18](=[O:20])[CH3:19])[CH:12]=2)=[O:10])=[CH:6][CH:7]=1
Reactant: Nc1cc(C(=O)Cc2ccc(F)cc2)ccn1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Product: CC(=O)Nc1cc(C(=O)Cc2ccc(F)cc2)ccn1

Procedure:
12.0 g of the compound (28) are suspended in 100 ml of acetic anhydride, a spatula tip of 4-dimethylaminopyridine is added and the reaction mixture is heated under reflux for 5 h. Most of the excess acetic anhydride is distilled off, the residue is hydrolyzed and the mixture is adjusted to pH 7 using conc. ammonia. The resulting clear precipitate (29) is filtered off and dried under reduced pressure over P2O5.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[F:9].[CH3:10][C:11]1([CH2:15]O)[CH2:14][O:13][CH2:12]1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:10][C:11]2([CH3:15])[CH2:14][O:13][CH2:12]2)=[CH:4][C:3]=1[F:9]
Reactant: Oc1ccc(Br)c(F)c1
Reactant: CC1(CO)COC1
Product: CC1(COc2ccc(Br)c(F)c2)COC1

Procedure:
The title compound was prepared from 4-bromo-3-fluorophenol and (3-methyl-oxetan-3-yl)-methanol in analogy to Example 9c): MS (EI): 274 and 276 M+.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([OH:11])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:12][O:13]C(Cl)Cl.Cl.O>C(Cl)Cl>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:12]=[O:13])=[C:7]([OH:11])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(Cl)Cl
Reactant: CC(C)(C)c1cccc(O)c1
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)c1ccc(C=O)c(O)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 52.1 %

Procedure:
A solution of 5.69 g (30 mmol) of titan tetrachloride in 15 ml DCM were added dropwise at 0° C. under nitrogen to 3.76 g (25 mmol) of 3-tert-butylphenol dissolved in 75 ml DCM. After stirring for 30 min 3.16 g (27.5 mmol) of dichloromethyl methyl ether was added. The reaction mixture was stirred for 2 h at 0° C. Carefully 30 ml of 1N aqueous HCl solution and then 90 ml water were added. The reaction mixture was extracted twice with DCM. The combined organic layers were washed with saturated aqueous NaCl solution, dried over sodium sulfate, filtered and the solvent was evaporated. The residue was purified by column chromatography (250 g silica gel, DCM) to yield 2.32 g (52%) 4-tert-butyl-2-hydroxy benzaldehyde as a light yellow oil. 1H NMR (DMSO-d6, 300 MHz): δ 10.62 (br s, 1H), 10.18 (s, 1H), 7.61 (d, 1H), 7.04 (d, 1H), 6.98 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1([CH2:14][N:15]2[CH2:20][CH2:19][N:18]([S:21]([C:24]3[CH:33]=[CH:32][C:31]4[C:26](=[CH:27][CH:28]=[C:29]([Cl:34])[CH:30]=4)[CH:25]=3)(=[O:23])=[O:22])[CH2:17][C:16]2=[O:35])[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[C:36](=[O:52])([O-])[O:37][C:38]1[CH:43]=CC([N+]([O-])=O)=CC=1CCOC.C(N(C(C)C)C(C)C)C.CN([CH:65]=[O:66])C>>[Cl:34][C:29]1[CH:30]=[C:31]2[C:26](=[CH:27][CH:28]=1)[CH:25]=[C:24]([S:21]([N:18]1[CH2:19][CH2:20][N:15]([CH2:14][C:2]3([NH:1][C:36]([O:37][CH2:38][CH2:43][O:66][CH3:65])=[O:52])[CH2:7][CH2:6][N:5]([C:8]4[CH:9]=[CH:10][N:11]=[CH:12][CH:13]=4)[CH2:4][CH2:3]3)[C:16](=[O:35])[CH2:17]1)(=[O:22])=[O:23])[CH:33]=[CH:32]2
Reactant: COCCc1cc([N+](=O)[O-])ccc1OC(=O)[O-]
Reactant: CN(C)C=O
Reactant: NC1(CN2CCN(S(=O)(=O)c3ccc4cc(Cl)ccc4c3)CC2=O)CCN(c2ccncc2)CC1
Solvent: CCN(C(C)C)C(C)C
Product: COCCOC(=O)NC1(CN2CCN(S(=O)(=O)c3ccc4cc(Cl)ccc4c3)CC2=O)CCN(c2ccncc2)CC1

Procedure:
A solution of 1-[4-amino-1-(4-pyridyl)-4-piperidylmethyl]-4-(6-chloronaphthalene-2-sulfonyl)-2-piperazinone (206 mg), 2-methoxyethyl-4-nitrophenyl carbonate (386 mg) and N-ethyldiisopropylamine (0.278 ml) in DMF (5 ml) was stirred at 60° C. overnight. The reaction mixture was concentrated under reduced pressure, ethyl acetate was added, the mixture was washed successively with a 10% aqueous sodium carbonate solution, an aqueous saturated sodium bicarbonate solution and an aqueous saturated sodium chloride solution, dried, and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate:10% aqueous ammonia-methanol=90:10→80:20), and crystallized from a mixed solution of acetone and ethyl acetate to obtain the colorless crystalline title compound (145 mg).
Reaction SMILES: Cl.[C:2]([C:4]1([NH:7][C:8]([C@@H:10]2[CH2:14][C@@H:13]([S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])(=[O:17])=[O:16])[CH2:12][NH:11]2)=[O:9])[CH2:6][CH2:5]1)#[N:3].Cl[C:26]([O:28][CH3:29])=[O:27]>>[CH3:29][O:28][C:26]([N:11]1[CH2:12][C@H:13]([S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:24])(=[O:17])=[O:16])[CH2:14][C@H:10]1[C:8](=[O:9])[NH:7][C:4]1([C:2]#[N:3])[CH2:6][CH2:5]1)=[O:27]
Reactant: COC(=O)Cl
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3Cl)CN2)CC1
Agent: Cl
Product: COC(=O)N1C[C@H](S(=O)(=O)c2ccccc2Cl)C[C@H]1C(=O)NC1(C#N)CC1

Procedure:
(2S,4R)-4-(2-chloro-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide hydrochloride from experiment K4 was acylated with methyl chloroformate in analogy to experiment L21 to give (2S,4R)-4-(2-chloro-benzenesulfonyl)-2-(1-cyano-cyclopropylcarbamoyl)-pyrrolidine-1-carboxylic acid methyl ester as a colorless oil. MS: 412.1 [M+H]+.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[C:11](=[O:16])[NH:12][CH:13]=[CH:14][N:15]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].CC([O-])(C)C.[K+].CS(O[CH2:28][CH2:29][O:30][C:31]1[CH:36]=[C:35]([F:37])[C:34]([F:38])=[CH:33][C:32]=1[F:39])(=O)=O.O>C1COCC1>[F:39][C:32]1[CH:33]=[C:34]([F:38])[C:35]([F:37])=[CH:36][C:31]=1[O:30][CH2:29][CH2:28][N:12]1[CH:13]=[CH:14][N:15]=[C:10]([N:7]2[CH2:6][CH2:5][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:9][CH2:8]2)[C:11]1=[O:16]
Reactant: CC(C)N1CCN(c2ncc[nH]c2=O)CC1
Reactant: CS(=O)(=O)OCCOc1cc(F)c(F)cc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)N1CCN(c2nccn(CCOc3cc(F)c(F)cc3F)c2=O)CC1
Temperature: 60 °C

Procedure:
A mixture of 3-(4-isopropyl-1-piperazinyl)-2(1H)-pyrazinone (0.58 g, 2.6 mmol; from Step 2) and t-BuOK (440 mg, 3.90 mmol) in THF (40 mL) was stirred until the mixture became thick (about 10 min), and then a solution of 2-(2,4,5-trifluorophenoxy)ethyl methanesulfonate (0.90 g, 2.2 mmol; from Example 54, Step 4) in THF (10 mL) was added. After being stirred for 5 days at ambient temperature, HPLC showed only 25% conversion. The reaction solution was then heated to 60° C. overnight which gave almost full conversion. The reaction was worked up according to the following: water was added, THF was evaporated off and the aqueous mixture was extracted twice with EtOAc, dried and concentrated to yield 1.18 g of the crude product as a yellow oil. Purification by chromatography on silica gel (eluent: 2.5% MeOH in CHCl3+NH3 (g)) gave the title compound as a colourless oil, which solidified upon cooling. Yield: 120 mg (14%). HPLC purity: 99%. MS m/z 397 (M+H)+. HRMS m/z calcd for C19H23F3N4O2 (M)+ 396.1773, found 396.1771.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([N:24]2[C:32](=[O:33])[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25]2=[O:34])[C:17]([NH:19][CH2:20][C:21](=O)[CH3:22])=[O:18])=[CH:11][CH:10]=1)[C:2]1C=CC=CC=1.S(=O)(=O)(O)[OH:36].C([O-])(=O)C.[Na+]>C(OC(=O)C)(=O)C>[O:34]=[C:25]1[C:26]2[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:32](=[O:33])[N:24]1[CH:16]([C:17]1[O:18][C:21]([CH3:22])=[CH:20][N:19]=1)[CH2:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][C:1](=[O:36])[CH3:2])=[CH:10][CH:11]=1
Reactant: CC(=O)CNC(=O)C(Cc1ccc(OCc2ccccc2)cc1)N1C(=O)c2ccccc2C1=O
Reactant: O=S(=O)(O)O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Oc1ccc(CC(c2ncc(C)o2)N2C(=O)c3ccccc3C2=O)cc1
Temperature: 57.5 °C
Reaction time: 2 h
Yield: 56 %

Procedure:
To a solution of 3-(4-Benzyloxy-phenyl)-2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-N-(2-oxo-propyl)-propionamide (5) (220 mg, 0.5 mmol) in acetic anhydride (2 mL) at room temperature was added concentrated sulfuric acid (0.2 mL). The mixture was stirred at 55-60° C. for 2 h, then sodium acetate (200 mg) was added, and the mixture was concentrated in vacuo. To the residue was added cold water (10 mL), the precipitated solid was collected, washed with water and dried, and the product was purified by flash chromatography on silica gel (20% ethyl acetate in DCM) to afford acetic acid 4-[2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-2-(5-methyl-oxazol-2-yl)-ethyl]-phenyl ester (110 mg, 56%) as a light yellow solid; 1H NMR (CDCl3): □7.80 (m, 2H), 7.70 (m, 2H), 7.25 (d, 2H), 6.95 (d, 2H), 6.7 (s, 1H), 5.7 (m, 1H), 3.8 (m, 2H), 2.26 (s, 3H), 2.21 (s, 3H); LCMS m/z 391.1 (M+1).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH:8]=O)[CH:5]=[CH:4][CH:3]=1.Cl.[CH:11]1([NH:17][C:18]([CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[O:19])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1>>[CH:11]1([NH:17][C:18]([CH:20]2[CH2:21][CH2:22][N:23]([CH2:8][C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([Br:1])[N:7]=3)[CH2:24][CH2:25]2)=[O:19])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: O=Cc1cccc(Br)n1
Reactant: O=C(NC1CCCCC1)C1CCNCC1
Agent: Cl
Product: O=C(NC1CCCCC1)C1CCN(Cc2cccc(Br)n2)CC1

Procedure:
The title compound is prepared according to the reaction 3.01c described above using 6-bromo-pyridine-2-carboxaldehyde and piperidine-4-carboxylic acid cyclohexylamide hydrochloride as in 3.01c: LC-MS A: tR=0.61 min; [M+H]+=382.20.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]=[CH:6][C:5]2=O.[CH3:13][NH:14][NH2:15].B(F)(F)F.CCOCC>C(O)C>[Br:1][C:2]1[CH:11]=[CH:10][C:9]([OH:8])=[C:4]([C:5]2[N:14]([CH3:13])[N:15]=[CH:7][CH:6]=2)[CH:3]=1
Reactant: O=c1ccoc2ccc(Br)cc12
Reactant: CNN
Agent: FB(F)F
Solvent: CCO
Solvent: CCOCC
Product: Cn1nccc1-c1cc(Br)ccc1O
Yield: 44.6 %

Procedure:
To a suspension of 6-bromochromone (1.58 g, 0.0070 mol) in ethanol (30 mL) was added methylhydrazine (0.41 mL, 0.0077 mol) and boron trifluoride etherate (1.15 mL, 0.0091 mol). The reaction was heated to reflux for 22 hours. After cooling, the reaction was concentrated in vacuo and the residue purified by automated flash column chromatography using a 0-100% ethyl acetate/hexanes gradient. This provided the title compound (0.79 g, 44%) as a light yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C@H:10]([C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:21]([CH3:26])([CH3:25])[C:22]([OH:24])=O)[CH:19]=2)[NH:14][C:13]=1[C:27]1[CH:32]=[C:31]([CH3:33])[CH:30]=[C:29]([CH3:34])[CH:28]=1)[CH3:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[CH2:57]([NH:59][CH2:60][CH3:61])[CH3:58]>C(Cl)Cl.C(N(CC)CC)C>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C@H:10]([C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:21]([C:22](=[O:24])[N:59]([CH2:60][CH3:61])[CH2:57][CH3:58])([CH3:25])[CH3:26])[CH:19]=2)[NH:14][C:13]=1[C:27]1[CH:28]=[C:29]([CH3:34])[CH:30]=[C:31]([CH3:33])[CH:32]=1)[CH3:11])([CH3:3])([CH3:2])[CH3:4]
Reactant: Cc1cc(C)cc(-c2[nH]c3ccc(C(C)(C)C(=O)O)cc3c2[C@H](C)CNC(=O)OC(C)(C)C)c1
Reactant: CCNCC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCN(CC)C(=O)C(C)(C)c1ccc2[nH]c(-c3cc(C)cc(C)c3)c([C@H](C)CNC(=O)OC(C)(C)C)c2c1
Temperature: 25 °C

Procedure:
To a stirred solution of (S)-2-[3-(2-tert-butoxycarbonylamino-1-methylethyl)-2-(3,5-dimethylphenyl)-1H-indol-5-yl]-2-methylpropionic acid in dry methylene chloride at 0° C. is added 1-hydroxybenzotriazole followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and the reagents allowed to mix for 1 hour. At this time diethylamine is added followed by 1.5 mL triehtylamine and the reaction stirred at room temperature. After completion, the mixture is concentrated in vacuo and purified by flash chromatography on silica gel to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH2:8])=[N:4][CH:5]=[CH:6][CH:7]=1.C([O:12][C:13]1[CH:23]=[CH:22][C:21]([C:24]#[C:25][C:26]2[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=2)=[CH:20][C:14]=1[C:15]([O:17]CC)=[O:16])(=O)C>N1C=CC=CC=1>[OH:12][C:13]1[CH:23]=[CH:22][C:21]([C:24]#[C:25][C:26]2[CH:31]=[CH:30][C:29]([S:32]([NH:8][C:3]3[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][N:4]=3)(=[O:34])=[O:33])=[CH:28][CH:27]=2)=[CH:20][C:14]=1[C:15]([OH:17])=[O:16]
Reactant: CCOC(=O)c1cc(C#Cc2ccc(S(=O)(=O)Cl)cc2)ccc1OC(C)=O
Reactant: Cc1cccnc1N
Solvent: c1ccncc1
Product: Cc1cccnc1NS(=O)(=O)c1ccc(C#Cc2ccc(O)c(C(=O)O)c2)cc1
Reaction time: 18 h

Procedure:
3-methyl-2-pyridinamine (1.3 g, 12 mmol) was dissolved in dry pyridine (20 ml) and ethyl 2- acetyloxy-5-[(4-chlorosulfonylphenyl)ethynyl]-benzoate (4.1 g, 10 mmol) was added. The solution was kept at ambient temperature for 18 h. The solvent was evaporated and the residue dissolved in a small amount of tetrahydrofuran. The solution was added to a refluxing solution of potassium hydroxide (6 g) in water (100 ml) and ethanol (50 ml). After 15 min the solution was acidified with formic acid to produce a precipitate. The solid was collected by filtration, washed with water and dried. Yield 1.2 g, 29%.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1O)([O-:3])=[O:2].Br[C:12]1[O:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=1.C([O-])([O-])=[O:20].[K+].[K+]>CN(C=O)C>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:20][C:12]2[O:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccccc1O
Reactant: O=C([O-])[O-]
Reactant: O=Cc1ccc(Br)o1
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(Oc2ccc([N+](=O)[O-])cc2)o1
Temperature: 80 °C
Yield: 38.3 %

Procedure:
Nitrophenol (43.6 mg, 0.31 mmol) and 5-bromofurfural (50 mg, 0.28 mmol) were dissolved in dry DMF (10 ml), anhydrous K2CO3 (81 mg, 0.39 mmol) was added thereto and the resulting mixture was heated under nitrogen atmosphere at 80° C. for 5 hours. The solvent was then evaporated under reduced pressure and a mixture of water (40 ml) and ether (10 ml) was added. After separation of the phases the aqueous phase was extracted with ether (2×10 ml), the combined organic phase was dried over Na2SO4 and the organic solvents were evaporated under reduced pressure. The crude product was purified by silica gel flash chromatography to give 25 mg of pure 5-(4-nitro-phenoxy)-furan-2-carbaldehyde (38% yield).
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([SH:14])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[C:17]([O:21][C:22]([N:24]1[CH2:28][CH2:27][CH2:26][C@@H:25]1[CH2:29]OS(C1C=CC(C)=CC=1)(=O)=O)=[O:23])([CH3:20])([CH3:19])[CH3:18]>CN(C=O)C>[C:17]([O:21][C:22]([N:24]1[CH2:28][CH2:27][CH2:26][C@@H:25]1[CH2:29][S:14][C:11]1[CH:12]=[CH:13][C:8]([O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:9][CH:10]=1)=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: Sc1ccc(Oc2ccccc2)cc1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CCCN2C(=O)OC(C)(C)C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1CSc1ccc(Oc2ccccc2)cc1
Temperature: 2.5 °C
Reaction time: 0.25 h
Yield: 71.4 %

Procedure:
To a solution of 4-phenoxy benzenethiol (200 mg, 0.988 mmol) in DMF (3 mL) at 0-5° C. was added 60% NaH (73 mg, 1.83 mmol) at 0-5° C. The reaction mixture was stirred at rt for 15 min at 0-5° C. A solution of (R)-2-(Toluene-4-sulfonyloxymethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (357 mg, 1 mmol) in DMF (2 mL) was added to the above mixture at 0-5° C. The reaction mixture was warmed to rt and then heated at 90° C. for 15 h. The mixture was concentrated, diluted with saturated aq NaHCO3 and extracted with ethyl acetate. The aqueous layer was re-extracted with ethylacetate. The combined organic layers were dried over anhy. MgSO4 and the solvent was removed in vacuo to obtain the crude mixture, which was purified by silica gel flash chromatography to obtain the title product (272 mg, 71%).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][C:6]([C:13]([O:15][CH3:16])=[O:14])=[CH:7][CH:8]=2)[N:3]=1.CCN(C(C)C)C(C)C.O>CCOC(C)=O.[Pd]>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([C:13]([O:15][CH3:16])=[O:14])=[CH:7][CH:8]=2)[N:3]=1
Reactant: COC(=O)c1ccc2c(Cl)nc(Cl)nc2c1
Agent: [Pd]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1ccc2cnc(Cl)nc2c1
Reaction time: 1 h

Procedure:
To a solution of methyl 2,4-dichloroquinazoline-7-carboxylate (1250 mg, 4.86 mmol) in EtOAc (100 mL) at R.T. was added Hunig's base (0.847 mL, 4.86 mmol) to form a pale yellow solution. The Pd catalyst was added and the mix hydrogenated with a H2 balloon for 1 hour. Water (20 mL) was added to solubilize salts, and mix filtered to remove Pd. The aqueous layer separated and organics dried over MgSO4, filtered and stripped to yield a residue (yellow solid) that was purified by Biotage 40M chromatography (loaded in DCM) eluting with 15-60% EtOAc/Hex over 2000 mL to afford the title compound as a pale yellow solid, 724 mg, 67%. 1H NMR (400 MHz, DMSO-D6) δ ppm 9.75 (1H, s) 8.45 (1H, s) 8.37 (1H, d, J=8.34 Hz) 8.13-8.30 (1H, m) 3.96 (3H, s); MS (API+) for C10H7N2ClO2 m/z 223.1 (M+H)+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH:4]1[CH2:8][CH2:7][CH:6]=[CH:5]1.[Mg].Cl.[CH3:11][C:12]([CH3:14])=[O:13]>C1COCC1>[CH:4]1([CH2:3][CH2:2][C:12]([CH3:14])([OH:13])[CH3:11])[CH2:8][CH2:7][CH:6]=[CH:5]1
Reactant: ClCCC1C=CCC1
Reactant: CC(C)=O
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: CC(C)(O)CCC1C=CCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 47 %

Procedure:
5.3 g (40.6 mmol) of 3-(2-chloroethyl)-1-cyclopentene (obtained according to Hill et al. in J. Org. Chem., 1969, 3681), dissolved into 30 ml of dry THF, were added dropwise into a three necks 200 ml flask containing 1.2 g (48.7 mmol) of magnesium and 5 ml of dry THF. After a 2 hours stirring at room temperature, 2.8 g (48.7 mmol) of acetone were slowly added to the reaction mixture. 15 Minutes after the addition of the acetone, the reaction mixture was slowly hydrolysed using 1 M aqueous HCl, and extracted with ether. Then, the organic phase was washed twice with water and twice with brine, dried over MgSO4 and concentrated. The crude product was purified by chromatography over silica (eluant: cyclohexane/ethyle acetate=9/1). It was thus obtained 2.7 g of the title compound (yield=47%).
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@@H:9]([CH2:20][O:21][C:22](=[O:24])[CH3:23])[O:8][C@@H:6]1[SH:7])(=[O:3])[CH3:2].I[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][O:32][C@H:33]1[CH2:57][CH2:56][C@@:55]2([CH3:58])[C:35](=[CH:36][CH2:37][C@@H:38]3[C@@H:54]2[CH2:53][CH2:52][C@@:51]2([CH3:59])[C@H:39]3[CH2:40][CH2:41][C@@H:42]2[C@H:43]([CH3:50])[CH2:44][CH2:45][CH2:46][CH:47]([CH3:49])[CH3:48])[CH2:34]1.C(N(CC)CC)C>ClCCl>[C:1]([O:4][C@H:5]1[C@@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@@H:9]([CH2:20][O:21][C:22](=[O:24])[CH3:23])[O:8][C@@H:6]1[S:7][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][O:32][C@H:33]1[CH2:57][CH2:56][C@@:55]2([CH3:58])[C:35](=[CH:36][CH2:37][C@@H:38]3[C@@H:54]2[CH2:53][CH2:52][C@@:51]2([CH3:59])[C@H:39]3[CH2:40][CH2:41][C@@H:42]2[C@H:43]([CH3:50])[CH2:44][CH2:45][CH2:46][CH:47]([CH3:49])[CH3:48])[CH2:34]1)(=[O:3])[CH3:2]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OCCCCCCI)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: CC(=O)OC[C@H]1O[C@H](S)[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)OC[C@H]1O[C@H](SCCCCCCO[C@H]2CC[C@@]3(C)C(=CC[C@H]4[C@@H]5CC[C@H]([C@H](C)CCCC(C)C)[C@@]5(C)CC[C@@H]43)C2)[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.7 %

Procedure:
To a solution of 2,3,4,6-tetra-O-acetyl-1-thio-α-D-mannopyranose (287 mg, 0.79 mmol) in dichloromethane (6 ml) was added cholest-5-en-3β-yl 6-iodohexyl ether (470 mg, 0.79 mmol) and triethylamine (0.11 ml, 0.79 mmol). After stirring under dry nitrogen atmosphere overnight at room temperature, the solvent was removed at reduced pressure and the residue chromatographed on silica gel eluted with 5-25% ethyl acetate in hexanes to give 6-(cholest-5-en-3β-yloxy)hexyl 2,3,4,6-tetra-O-acetyl-1-thio-α-D-mannopyranoside (0.36 g, 55% yield), m.p. 103°-103.5° C. This product was dissolved in 1:1 (v/v) ethanol-tetrahydrofuran (10 ml) and treated with a suspension of Bio-Rad AG-1-X2 OH- ion-exchange resin (2.5-3 fold excess) in ethanol (5 ml). After stirring a room temperature for 45 minutes, the resin was filtered and washed with warm tetrahydrofuran (3×5 ml), and the combined filtrates concentrated to give 6-(5-cholesten-3β -yloxy)hexyl 1-thio-α-D-mannopyranoside (250 mg, 91% yield) as needles from warm tetrahydrofuran, m.p. (endothermic transitions) 64-64, 81-82, and 226°-227° C.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[CH2:3][C:4]#[C:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][C:7]=1[C:15]([F:18])([F:17])[F:16].CC(O)=O.O.N>[Fe].CCO>[CH3:19][N:2]([CH3:1])[CH2:3][C:4]#[C:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][C:7]=1[C:15]([F:16])([F:17])[F:18]
Reactant: CN(C)CC#Cc1ccc([N+](=O)[O-])cc1C(F)(F)F
Agent: [Fe]
Agent: N
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: CN(C)CC#Cc1ccc(N)cc1C(F)(F)F
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
A mixture of dimethyl-[3-(4-nitro-2-trifluoromethyl-phenyl)-prop-2-ynyl]-amine (2.0 g, 7.4 mmol), iron powder (1.65 g, 29.4 mmol, 4 equiv), AcOH (5 mL), H2O (10 mL), and EtOH (40 mL) is stirred for 30 min at 80° C. The reaction mixture is allowed to cool to rt, basified by addition of a 1 M aqueous solution of NH3, and filtered through Celite. The filtrate is partially concentrated and extracted with EtOAc. The organic phase is washed with brine, dried (Na2SO4), filtered and concentrated. The residue is purified by silica gel column chromatography (CH2Cl2/NH3 (2 N in MeOH), 95:5) to provide the title compound as a brown oil: ES-MS: 243.0 [M+H]+; single peak at tR=2.49 min (System 1); Rf=0.10 (CH2Cl2/NH3 (2 N in MeOH), 95:5).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([O:12][C:13]1[CH:26]=[CH:25][C:16]([O:17][CH:18]([CH3:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:15][CH:14]=1)=[CH:5]2.[CH3:27][I:28]>ClCCl>[I-:28].[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:27])[CH2:7][C:6]([O:12][C:13]1[CH:14]=[CH:15][C:16]([O:17][CH:18]([CH3:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:25][CH:26]=1)=[CH:5]2
Reactant: CCOC(=O)C(C)Oc1ccc(Oc2cnc3ccc(Cl)cc3c2)cc1
Reactant: CI
Solvent: ClCCl
Product: CCOC(=O)C(C)Oc1ccc(OC2=Cc3cc(Cl)ccc3N(C)C2)cc1
Product: [I-]

Procedure:
Ethyl 2-{4-[(6-chloro-1-methylquinolin-3-yl)oxy]phenoxy}propionate iodide salt (8) was prepared by reacting a mixture of ethyl 2-{4-[(6-chloroquinolin-3-yl)oxy]phenoxy}propionate (see Example 7) and methyl iodide in dichloromethane at ambient temperature for a period of four days. The product, a viscous oil, was characterized by its proton magnetic resonance spectrum. Pmr spectrum (CDCl3 ; in ppm): 10.1 (1H, d); 8.8 (1H, d); 8.65 (1H, d); 8.5 (1H, d); 8.05 (1H, d of d); 7.3 (4H, d of d); 4.95 (4H, m); 4.25 (2H, q); 1.6 (3H, d); 1.2 (3H, t).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[F:16][C:17]([F:41])([F:40])[CH2:18][NH:19][C:20]([C:22]1([CH2:35][CH2:36][CH2:37][CH2:38]Br)[C:34]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:28]2[C:23]1=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:21]>>[F:16][C:17]([F:40])([F:41])[CH2:18][NH:19][C:20]([C:22]1([CH2:35][CH2:36][CH2:37][CH2:38][N:13]2[CH2:14][CH2:15][N:10]([C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=3)[CH2:11][CH2:12]2)[C:34]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:28]2[C:23]1=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:21]
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2-c2ccccc21
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Product: O=C(NCC(F)(F)F)C1(CCCCN2CCN(c3ccc([N+](=O)[O-])cc3)CC2)c2ccccc2-c2ccccc21

Procedure:
Prepared analogously to Example 2 b from 1-(4-nitro-phenyl)-piperazine and 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoroethyl)-amide.