Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]([O:8]S(C(F)(F)F)(=O)=O)([C:4]([F:7])([F:6])[F:5])(=[O:3])=[O:2].[CH3:16][C:17]1[CH:18]=[C:19](O)[CH:20]=[C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:22]=1>N1C=CC=CC=1>[F:5][C:4]([F:7])([F:6])[S:1]([O:8][C:19]1[CH:18]=[C:17]([CH3:16])[CH:22]=[C:21]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:20]=1)(=[O:3])=[O:2]
Reactant: Cc1cc(O)cc(-c2ccccc2)c1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Product: Cc1cc(OS(=O)(=O)C(F)(F)F)cc(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 83 %

Procedure:
Triflic anhydride (26 ml; 0.15 mol) was added to a solution of 3-methyl-5-phenylphenol (22.4 g; 0.15 mol) in pyridine (140 ml), at 0° C. The mixture was stirred at ambient temperature for 4 hours. After evaporation of the pyridine, the residue was acidified to pH 3 with 6N HCl and extracted with ether. The organic phase was evaporated and the residue purified by flash chromatography eluting with petroleum ether/ethyl acetate (94/6) to give 3-trifluoromethanesulfonyloxy-5-phenyltoluene as an oil. Yield=83%.
Reaction SMILES: [CH2:1]([S:3][C:4]1[C:5]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[N:6][C:7]2[C:12]([C:13]=1[C:14]([NH:16][C@H:17]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:18][CH3:19])=[O:15])=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH3:2].C[OH:33]>O.CCOC(C)=O>[CH2:1]([S:3]([C:4]1[C:5]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[N:6][C:7]2[C:12]([C:13]=1[C:14]([NH:16][C@H:17]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[CH2:18][CH3:19])=[O:15])=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:33])[CH3:2]
Reactant: CO
Reactant: CCSc1c(-c2ccccc2)nc2ccccc2c1C(=O)N[C@@H](CC)c1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: CC[C@H](NC(=O)c1c(S(=O)CC)c(-c2ccccc2)nc2ccccc12)c1ccccc1
Temperature: 0 °C
Reaction time: 12 h
Yield: 28.4 %

Procedure:
To a solution of 3-(ethylthio)-2-phenyl-N-[(1S)-1-phenylpropyl]quinolin-4-carboxamide (5) (300 mg, 0.70 mmol) in MeOH (25 mL) was added a solution of NaIO4 (300 mg, 1.4 mmol) in water (15 mL) while it was cooled to 0° C. The cooling bath was removed, and reaction allowed stir for 12 h. LCMS indicated no reaction take place. Added another 2 eq of NaIO4 and the reaction mixture was heated to reflux for 8 h. It was then diluted with EtOAc, washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (10-35% EtOAc/CH2Cl2) to give the desired product (two diastereomers) as a solid (88 mg, 28.4%). 1H NMR (300 MHz, CDCl3) δ 0.97 (t, 3H), 1.21 (t, 3H), 2.01 (m, 2H), 2.71 (m, 2H), 5.21 (q, 1H), 7.21 (d, 2H), 7.34 (d, 2H), 7.39 (m, 2H), 7.78 (m, 2H), 7.84 (m, 2H), 8.00 (m, 1H), 8.11 (m, 2H), 8.14 (m, 1H), 8.16 (m, 1H). MS APCI, m/z=443 (M+1). LCMS: 2.15 min.
Reaction SMILES: [CH2:1]([C:5]1[C:10]([F:11])=[C:9]([F:12])[C:8](F)=[C:7]([F:14])[C:6]=1[F:15])[CH2:2][CH2:3][CH3:4].O.[NH2:17][NH2:18]>C(O)C>[CH2:1]([C:5]1[C:10]([F:11])=[C:9]([F:12])[C:8]([NH:17][NH2:18])=[C:7]([F:14])[C:6]=1[F:15])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1c(F)c(F)c(F)c(F)c1F
Reactant: NN
Solvent: O
Solvent: CCO
Product: CCCCc1c(F)c(F)c(NN)c(F)c1F

Procedure:
n-Butylpentafluorobenzene [19.0 g; described by J. M. Birchall and R. N. Haszeldine J. Chem. Soc p 3719 (1961)] was added to a solution of hydrazine hydrate (50 ml; 99-100% w/w) in ethanol (100 ml) and the mixture heated at reflux for 72 hours. The reaction mixture was cooled, evaporated to dryness to give a solid which was filtered off and washed with ethanol and hexane to give 4-n-butyl-2,3,5,6-tetrafluorophenylhydrazine (20.5 g), m.p. 80°-81° C., in the form of colourless crystals.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10](/[CH:17]=[CH:18]/[C:19]([OH:21])=O)=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:22][C:23]1[CH:24]=[C:25]([CH:33]=[CH:34][CH:35]=1)[C:26]([NH:28][NH:29][CH:30]([CH3:32])[CH3:31])=[O:27].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C.CCOC(C)=O>[Br:22][C:23]1[CH:24]=[C:25]([CH:33]=[CH:34][CH:35]=1)[C:26]([NH:28][N:29]([C:19](=[O:21])/[CH:18]=[CH:17]/[C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH:9]=1)[CH:30]([CH3:32])[CH3:31])=[O:27]
Reactant: CC(C)(C)OC(=O)n1cc(/C=C/C(=O)O)c2ccccc21
Reactant: CC(C)NNC(=O)c1cccc(Br)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N(NC(=O)c1cccc(Br)c1)C(=O)/C=C/c1cn(C(=O)OC(C)(C)C)c2ccccc12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To solution containing (E)-3-(1-(tert-butoxycarbonyl)-1H-indol-3-yl)acrylic acid (100 mg, 0.35 mmol), 3-bromo-N′-isopropylbenzohydrazide (134.24 mg, 0.52 mmol) and HATU (198.5 mg, 0.52 mmol) dissolved in DMF (4.0 ml), N,N-diisopropylethylamine (DIPEA)(0.09094 ml, 0.52 mmol) was slowly drop-wise added and stirred at room temperature for 12 hr. The reaction mixture was diluted with EtOAc, washed with water and brine, dried with anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was separated through silica gel chromatography (n-hexane:EtOAc=3:1) and dried so that ivory (E)-tert-butyl 3-(3-(2-(3-bromobenzoyl)-1-isopropylhydrazinyl)-3-oxoprop-1-enyl)-1H-indole-1-carboxylate was obtained (53.6 mg, 29.3%).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5](Cl)=[O:6].[CH2:14]([NH2:16])[CH3:15]>>[CH2:14]([NH:16][C:5](=[O:6])[C:4]1[CH:8]=[CH:9][CH:10]=[CH:11][C:3]=1[C:2]([F:13])([F:12])[F:1])[CH3:15]
Reactant: CCN
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Product: CCNC(=O)c1ccccc1C(F)(F)F
Yield: 67 %

Procedure:
2-(Trifluoromethyl)benzoyl chloride and ethyl amine were combined according to General Method E1 and recrystallized from cold hexanes to give 7.7 g N-ethyl-2-(trifluoromethyl)benzamide as a white solid, a 67% yield. m.p. 73°-76° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[N:10][C:11]=1[N:12]1[CH2:17][CH2:16][N:15]([C:18](=[O:23])[C:19]([F:22])([F:21])[F:20])[CH2:14][CH2:13]1)[NH:8][CH:7]=[C:6]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:5]2=[O:29].[CH2:30](I)[CH3:31].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:30]([N:8]1[C:9]2[C:4](=[CH:3][C:2]([F:1])=[C:11]([N:12]3[CH2:13][CH2:14][N:15]([C:18](=[O:23])[C:19]([F:21])([F:20])[F:22])[CH2:16][CH2:17]3)[N:10]=2)[C:5](=[O:29])[C:6]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:7]1)[CH3:31]
Reactant: CCOC(=O)c1c[nH]c2nc(N3CCN(C(=O)C(F)(F)F)CC3)c(F)cc2c1=O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(CC)c2nc(N3CCN(C(=O)C(F)(F)F)CC3)c(F)cc2c1=O

Procedure:
Ethyl 6-fluoro-1,4-dihydro-4-oxo-7-(4-trifluoroacetyl-1-piperazinyl)-1,8-naphthyridine-3-carboxylate was treated with ethyl iodide and potassium carbonate in dimethylformamide by the same procedure as described in Example 1 to form ethyl 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(4-trifluoroacetyl-1-piperazinyl)-1,8-naphthyridine-3-carboxylate. This product was hydrolyzed by treating with aqueous potassium carbonate in a mixture of chloroform and methanol to give ethyl 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-1,8-naphthyridine-3-carboxylate, m.p. 150°-151° C.
Reaction SMILES: II.[CH3:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[SH:10].COC1C=CC(S([C:22]2[C:30]3[C:25](=[CH:26][CH:27]=[C:28]([CH3:31])[CH:29]=3)[N:24]([CH2:32][C:33]([OH:35])=[O:34])[C:23]=2[CH3:36])(=O)=O)=CC=1>CN(C=O)C>[NH4+:24].[CH3:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10][C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([CH3:31])[CH:29]=2)[N:24]([CH2:32][C:33]([O-:35])=[O:34])[C:23]=1[CH3:36]
Reactant: COc1ccc(S(=O)(=O)c2c(C)n(CC(=O)O)c3ccc(C)cc23)cc1
Reactant: Cc1ccccc1S
Agent: II
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)c(Sc1ccccc1C)c(C)n2CC(=O)[O-]
Product: [NH4+]

Procedure:
Iodine (0.29 g) was added to a solution of 2-methylbenzenethiol (0.16 g) and the product from example 13 step a) (0.2 g) in DMF (5 ml). After 1 h the solution was purified by reverse phase HPLC. The solvent was evaporated in vacuo and the oily residue treated with ether to give a solid. Filtered off and dried to yield the title compound as a white solid (0.19 g).
Reaction SMILES: [CH:1]1(O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=[O:17])=[CH:11][CH:10]=1.C1C=CC=CC=1>O>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][C:16]([O:18][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:17])=[CH:13][CH:14]=1
Reactant: O=C(O)Cc1ccc(O)cc1
Reactant: OC1CCCCC1
Solvent: c1ccccc1
Solvent: O
Product: O=C(Cc1ccc(O)cc1)OC1CCCCC1
Yield: 104.6 %

Procedure:
Cyclohexyl alcohol (6 g), 4-hydroxyphenylacetic acid (7.6 g) p-toluenesulfonic acid (1 g) and benzene (300 mL) were refluxed with continuous water separation for 8 hours. The mixture was cooled and washed with a 10% Na2CO3 solution, then with water. Drying over MgSO4 and evaporation of the solvent in vacuo gave 12.24 g of cyclohexyl 4-hydroxyphenylacetate. That compound can be represented by the formula: ##STR24##
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:6]([CH:16]=1)[C:7]([NH:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)=[O:8].CC1(C)C(C)(C)OB([C:33]2[CH:38]=[CH:37][N:36]=[C:35]([NH2:39])[CH:34]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCOCC1>[NH2:39][C:35]1[CH:34]=[C:33]([C:2]2[CH:3]=[CH:4][C:5]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[C:6]([CH:16]=2)[C:7]([NH:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[O:8])[CH:38]=[CH:37][N:36]=1
Reactant: O=C(Nc1cccnc1)c1cc(Br)ccc1OCc1ccccc1
Reactant: CC1(C)OB(c2ccnc(N)c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Nc1cc(-c2ccc(OCc3ccccc3)c(C(=O)Nc3cccnc3)c2)ccn1
Temperature: 100 °C

Procedure:
To a microwave vial was added 5-bromo-2-[(phenylmethyl)oxy]-N-3-pyridinylbenzamide (may be prepared as described in example 2; 200 mg, 0.52 mmol), 1,4-dioxane (2 ml), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridinamine (201 mg, 0.78 mmol), 1M sodium carbonate (1.04 ml, 1.04 mmol) and tetrakis(triphenylphosphine)palladium(0) (36.2 mg, 0.03 mmol). The vial was sealed and heated to 100° C. for 30 minutes under microwave conditions. The mixture was evaporated in vacuo and the residue was purified using the MDAP to yield the title compound. 41 mg.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[CH2:5][CH2:6][CH2:7]Br)[CH3:2].C(N(CC)CC)C.[F:17][C:18]([F:32])([F:31])[C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[CH:21][CH:20]=1.[I-].[K+]>O1CCCC1.ClCCl>[CH2:1]([O:3][C:4](=[O:9])[CH2:5][CH2:6][CH2:7][N:28]1[CH2:27][CH2:26][N:25]([C:22]2[CH:21]=[CH:20][C:19]([C:18]([F:31])([F:32])[F:17])=[CH:24][CH:23]=2)[CH2:30][CH2:29]1)[CH3:2]
Reactant: FC(F)(F)c1ccc(N2CCNCC2)cc1
Reactant: CCOC(=O)CCCBr
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CCCN1CCN(c2ccc(C(F)(F)F)cc2)CC1
Yield: 98 %

Procedure:
Ethyl-4-bromobutyrate (390 mg, 2.00 mmol) and triethylamine (280 μL; 2.00 mmol) were added to a solution of 1-(4-trifluoromethylphenyl)-piperazine (460 mg; 2.00 mmol) in tetrahydrofuran (3 mL). Potassium iodide (332 mg; 2.00 mmol) was added and the resulting suspension is irradiated in a mono-mode microwave oven for 2 hours at 100° C. The suspension is then diluted with dichloromethane (15 mL) and washed twice with water (5 mL). The organic phase is then dried over sodium sulphate and is concentrated under reduced pressure to afford the desired product (660 mg; 1.96 mmol).
Reaction SMILES: [C:1](=[O:14])([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[O:2][CH:3](Cl)[CH3:4].[C:15]([NH:18][C:19]1[C:20]([I:35])=[C:21]([N:30]([C:32](=[O:34])[CH3:33])[CH3:31])[C:22]([I:29])=[C:23]([C:26]([O-:28])=[O:27])[C:24]=1[I:25])(=[O:17])[CH3:16].[K+].[I-].[Na+]>CN(C=O)C>[C:15]([NH:18][C:19]1[C:20]([I:35])=[C:21]([N:30]([C:32](=[O:34])[CH3:33])[CH3:31])[C:22]([I:29])=[C:23]([C:26]([O:28][CH:3]([O:2][C:1]([O:6][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:14])[CH3:4])=[O:27])[C:24]=1[I:25])(=[O:17])[CH3:16]
Reactant: CC(=O)Nc1c(I)c(C(=O)[O-])c(I)c(N(C)C(C)=O)c1I
Reactant: CC(Cl)OC(=O)OCc1ccccc1
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1c(I)c(C(=O)OC(C)OC(=O)OCc2ccccc2)c(I)c(N(C)C(C)=O)c1I
Temperature: 50 °C
Reaction time: 168 h

Procedure:
1-Chloroethyl benzyl carbonate (prepared according to Synthesis 1986, 627), (2.36 g, 11.0 mmol) was added at room temperature to a solution of potassium 5-(N-acetylamino)-3-(N-acetyl-N-methylamino)-2,4,6-triiodobenzenecarboxylate (6.66 g, 20 mmol) and sodium iodide (0.15 g, 1 mmol) in dry DMF (50 ml). After stirring at 50° C. for 7 hours and at room temperature for 7 days the solvent was removed at reduced pressure. The residue was dissolved in chloroform (100 ml) and washed four times with a saturated sodium hydrogen carbonate solution and twice with water. After treatment with magnesium sulfate the solution was evaporated to dryness. Yield: 6.8 g. Purity by HPLC: 97% 1H-NMR(DMSO-d6): delta=1.64 (CHCH3); 1.66(N(CH3)COCH3); 2.05 (NCOCH3); 5.23 (CH2); 7.00 (CH); 7(CH); 7.30-7.45(arom.); 10.12 ppm (NH).
Reaction SMILES: Cl.[NH2:2][C:3]1[N:4]=[CH:5][N:6]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:14][CH:13]=2)[C:7]=1[C:8]([NH2:10])=[O:9].C(Cl)(=O)C1C=CC=CC=1.[C:31](Cl)(=[O:38])[C:32]1[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=1>>[C:18]([C:15]1[CH:16]=[CH:17][C:12]([CH2:11][N:6]2[C:7]([C:8]([NH2:10])=[O:9])=[C:3]([NH:2][C:31]([C:32]3[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=3)=[O:38])[N:4]=[CH:5]2)=[CH:13][CH:14]=1)([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)c1ccc(Cn2cnc(N)c2C(N)=O)cc1
Reactant: O=C(Cl)c1ccncc1
Agent: Cl
Solvent: O=C(Cl)c1ccccc1
Product: CC(C)(C)c1ccc(Cn2cnc(NC(=O)c3ccncc3)c2C(N)=O)cc1
Yield: 89 %

Procedure:
An amidation reaction and post-treatment were carried out following the conditions of Example 1, using 1.63 g (5.28 mmol) of 4-amino-1-(4-t-butylbenzyl)-5-imidazolecarboxamide hydrochloride prepared in the same manner as in Example 57 and, instead of benzoyl chloride, isonicotinic chloride which was prepared separately by a conventional method, to obtain 1.78 g of 1-(4-t-butylbenzyl)-4-(4-pyridylcarbonylamino)-5-imidazolecarboxamide (yield 89%).
Reaction SMILES: [CH3:1][C:2]([CH2:13][C:14]#[CH:15])([C:8]([O:10]CC)=[O:9])[C:3]([O:5]CC)=[O:4].[OH-].[K+]>O.C(O)C>[CH3:1][C:2]([CH2:13][C:14]#[CH:15])([C:3]([OH:5])=[O:4])[C:8]([OH:10])=[O:9]
Reactant: C#CCC(C)(C(=O)OCC)C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: C#CCC(C)(C(=O)O)C(=O)O
Reaction time: 2 h

Procedure:
187 g (0.88 mol) of diethyl 2-methyl-2-propargyl-malonate are added to a solution of 101 g (1.8 mol) of potassium hydroxide in a mixture of 560 ml of water/ethanol (1:1) and the mixture is refluxed with stirring for 2 hours. After the reaction has ended (monitored by TLC) the mixture is evaporated to dryness in vacuo and the residue is then taken up with in water. The aqueous solution is acidified with 50% sulphuric acid and extracted several times with methylene chloride. The combined extracts are dried, evaporated to dryness in vacuo and a colourless product is obtained, m.p. 135° C.
Reaction SMILES: F[C:2]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[F:18][C:19]1[CH:28]=[CH:27][C:26](O)=[C:25]2[C:20]=1[CH:21]=[CH:22][CH:23]=[N:24]2.[N:30]1[C:39]2[C:34](=CC=CC=2N2CCC(=O)CC2)[CH:33]=[CH:32][CH:31]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[F:18][C:19]1[CH:28]=[CH:27][C:26]([N:30]2[CH2:39][CH2:34][CH:33]([N:15]3[CH2:16][CH2:17][N:12]([C:9]4[CH:10]=[CH:11][CH:2]=[C:3]5[C:8]=4[N:7]=[CH:6][CH:5]=[CH:4]5)[CH2:13][CH2:14]3)[CH2:32][CH2:31]2)=[C:25]2[C:20]=1[CH:21]=[CH:22][CH:23]=[N:24]2
Reactant: Oc1ccc(F)c2cccnc12
Reactant: Fc1ccc(N2CCNCC2)c2ncccc12
Reactant: O=C1CCN(c2cccc3cccnc23)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: Fc1ccc(N2CCC(N3CCN(c4cccc5cccnc45)CC3)CC2)c2ncccc12

Procedure:
Using the synthetic methods described in previous examples, 5-fluoro 8-(piperazin-1-yl)quinoline (Prepared from commercially available 5-fluoro-8-hydroxyquinoline using the methodology described for Example R, step 3, above) and 1-quinolin-8-yl-piperidin-4-one (Example A, Step 5, above) were reacted with sodium triacetoxyborohydride to give the desired product as a yellow solid; MP. 222-224° C.; MS (ES) m/z (relative intensity) 442 (M+H)+ (100).
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([O:12][CH3:13])[C:9]2[C:4](=[N:5][CH:6]=[CH:7][N:8]=2)[N:3]=1.[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[S:21]([N:24]=[C:25]=[O:26])(=[O:23])=[O:22].C(OC(C)C)(C)C>C(N(CC)CC)C.C(#N)C>[CH3:13][O:12][C:10]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][N:8]=2)[N:3]=[C:2]([NH:1][C:25]([NH:24][S:21]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[Cl:14])(=[O:22])=[O:23])=[O:26])[N:11]=1
Reactant: COc1nc(N)nc2nccnc12
Reactant: O=C=NS(=O)(=O)c1ccccc1Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: CC(C)OC(C)C
Product: COc1nc(NC(=O)NS(=O)(=O)c2ccccc2Cl)nc2nccnc12
Reaction time: 0.17 h
Yield: 82.6 %

Procedure:
1.5 g (0.0069 mol) of 2-amino-4-methoxypteridine and two drops of triethylamine were added to a mixture of 1.77 g (0.01 mol) of 2-chlorophenylsulfonyl isocyanate in 20 ml of acetonitrile and the mixture was refluxed for 30 minutes, cooled and mixed with diisopropyl ether. After standing for 10 minutes, the mixture was vacuum filtered to obtain 2.25 g (87% of theory) of N-(4-methoxypteridin-2-yl)-N'-(2-chlorophenylsulfonyl)-urea melting at 212° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17](=[O:18])[C:16]3[C:11](=[C:12]([F:20])[C:13](F)=[CH:14][CH:15]=3)[O:10][C:9]=2[CH:21]([CH3:23])[CH3:22])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:31]([CH2:33][NH2:34])[OH:32]>CN(C)C(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:17](=[O:18])[C:16]3[C:11](=[C:12]([F:20])[C:13]([NH:34][CH2:33][CH2:31][OH:32])=[CH:14][CH:15]=3)[O:10][C:9]=2[CH:21]([CH3:22])[CH3:23])=[CH:6][CH:7]=1
Reactant: NCCO
Reactant: CC(C)c1oc2c(F)c(F)ccc2c(=O)c1-c1ccc(Cl)cc1
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Product: CC(C)c1oc2c(F)c(NCCO)ccc2c(=O)c1-c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
A stirred solution of 3-(4-chlorophenyl)-7,8-difluoro-2-isopropyl-chromen-4-one (3.94 g, 11.8 mmol), triethylamine (2.4 g, 3.2 ml, 23.6 mmol, 2 eq.) and ethanolamine (0.72 g, 0.71 ml, 11.8 mmol, 1 eq.) in N,N-dimethylacetamide (200 ml) is heated at 150° C. overnight. The reaction mixture is allowed to cool to room temperature and the solvent is removed by evaporation in vacuo. The residue is dissolved in ethyl acetate and washed with 2M HCl solution. The organic layer is washed with brine, dried over anhydrous magnesium sulfate, filtered and evaporated to dryness in vacuo to afford a brown oil. The oil is purified by flash chromatography (cyclohexane/ethyl acetate=9:1 to 4:6) to afford the title compound.
Reaction SMILES: [H-].[Li+].[F:3][C:4]1[CH:13]=[C:12]2[C:7]([N:8]=[CH:9][C:10](=[O:14])[NH:11]2)=[CH:6][CH:5]=1.Br[CH2:16][CH2:17][CH:18]1[O:22][CH2:21][CH2:20][O:19]1.O>CN(C)C=O>[O:19]1[CH2:20][CH2:21][O:22][CH:18]1[CH2:17][CH2:16][N:11]1[C:12]2[C:7](=[CH:6][CH:5]=[C:4]([F:3])[CH:13]=2)[N:8]=[CH:9][C:10]1=[O:14]
Reactant: BrCCC1OCCO1
Reactant: O=c1cnc2ccc(F)cc2[nH]1
Agent: [H-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1cnc2ccc(F)cc2n1CCC1OCCO1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 29.1 %

Procedure:
Lithium hydride (88 mg, 011 mmol) was added to a solution of 7-fluoroquinoxalin-2(1H)one (1.3 g, 7.8 mmol) in N,N-dimethylformamide (40 ml) under cooling on ice and the mixture was stirred at room temperature for 30 minutes. The mixture was cooled on ice and 2-(2-bromoethyl)-1,3-dioxolane (1.33 ml, 11 mmol) was added thereto. The obtained mixture was stirred at room temperature for 24 hours, water was then gradually added thereto and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (dichloromethane/methanol) to yield 0.6 g (29%) of the title compound.
Reaction SMILES: [CH2:1]([CH:3]([CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][CH:7]=1)[NH2:4])[CH3:2].BrCC(=O)C(OCC)=O.Br[CH2:25][C:26](=O)[C:27]([O:29][CH2:30][CH2:31][CH3:32])=[O:28]>>[CH2:30]([O:29][C:27]([C:26]1[C:7]2[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[C:6]=2[CH2:5][CH:3]([CH2:1][CH3:2])[NH:4][CH:25]=1)=[O:28])[CH2:31][CH3:32]
Reactant: CCC(N)Cc1c[nH]c2ccccc12
Reactant: CCCOC(=O)C(=O)CBr
Agent: CCOC(=O)C(=O)CBr
Product: CCCOC(=O)C1=CNC(CC)Cc2c1[nH]c1ccccc21

Procedure:
2-Ethyl 1,2,3,6-tetrahydroazepino[4,5-b]indole-5-carboxylic acid n-propyl ester was prepared in a manner similar to that described in Example 1A but replacing tryptamine hydrochloride with a-ethyl tryptamine and ethyl 3-bromopyruvate with n-propyl 3-bromopyruvate; MS (ESI): 303 (MH+).
Reaction SMILES: [I:1][C:2]1[C:3]([O:11][CH3:12])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](O)=[O:6].S(Cl)([Cl:15])=O>>[I:1][C:2]1[C:3]([O:11][CH3:12])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([Cl:15])=[O:6]
Reactant: O=S(Cl)Cl
Reactant: COc1c(I)cccc1C(=O)O
Product: COc1c(I)cccc1C(=O)Cl
Temperature: 82 °C
Reaction time: 0.03 h

Procedure:
To 3-iodo-2-methoxy-benzoic acid (8.29 g, 29.8 mmol) was added thionyl chloride (15 mL). The resulting solution was stirred for 2 minutes then heated to 82° C. and stirred at this temperature for 30 minutes. The solution was then concentrated under reduced pressure to give the title compound. This material was used without further purification.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[NH:10]1[CH:14]=[CH:13][N:12]=[CH:11]1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CS(C)=O>[N:10]1([C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)[CH:14]=[CH:13][N:12]=[CH:11]1
Reactant: O=Cc1ccc(F)cc1
Reactant: c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: O=Cc1ccc(-n2ccnc2)cc1
Temperature: 110 °C
Reaction time: 8 h
Yield: 33.8 %

Procedure:
A mixture of 4-fluorobenzaldehyde (4.96 g, 40 mmol), imidazole (2.86 g, 42 mmol), and potassium carbonate (6.08 g, 44 mmol) in DMSO (40 ml) was stirred at 110° C. overnight. The reaction mixture was allowed to return to room temperature, and poured into ice water (100 ml). The resulting precipitates were collected by filtration and washed with water and then with ethyl acetate to afford 4-(imidazol-1-yl)benzaldehyde (2.33 g, yield 34%) as a pale yellow crystalline powder.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:12]([N:14]([CH3:39])[C@H:15]([C:19]([N:21]([CH3:38])[C@H:22]([C:35]([NH2:37])=[O:36])[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[C:26]([C:31]([CH3:34])([CH3:33])[CH3:32])[CH:25]=1)=[O:20])[CH:16]([CH3:18])[CH3:17])=[O:13])[CH2:3][C:4]1[C:5]([F:11])=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1>C(Cl)Cl.C(O)(C(F)(F)F)=O>[NH2:1][C@H:2]([C:12]([N:14]([CH3:39])[C@H:15]([C:19]([N:21]([CH3:38])[C@H:22]([C:35]([NH2:37])=[O:36])[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[C:26]([C:31]([CH3:32])([CH3:34])[CH3:33])[CH:25]=1)=[O:20])[CH:16]([CH3:18])[CH3:17])=[O:13])[CH2:3][C:4]1[C:5]([F:11])=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1
Reactant: CC(C)[C@@H](C(=O)N(C)[C@@H](Cc1ccc(O)c(C(C)(C)C)c1)C(N)=O)N(C)C(=O)[C@H](Cc1ccc(O)cc1F)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)[C@@H](C(=O)N(C)[C@@H](Cc1ccc(O)c(C(C)(C)C)c1)C(N)=O)N(C)C(=O)[C@@H](N)Cc1ccc(O)cc1F
Reaction time: 0.25 h
Yield: 97.4 %

Procedure:
To a solution of Boc-Tyr(2-F)-N-Me-Val-N-Me-Tyr(3-tBu)-NH2 (0.21 g, 0.326 mmol) in methylene chloride (3 ml), TFA (1.5 ml) was added and stirred for 15 min. The reaction mixture was concentrated under reduced pressure, mixed with a saturated aqueous NaHCO3 solution, and extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate. The resultant was evaporated to remove the solvent under reduced pressure, giving the titled compound (173 mg, 82%).