Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[C:3]=1[C:4]([NH:6][CH:7]([CH2:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]=[C:18]([C:23]1[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][C:24]=1[Cl:30])[CH:17]=[CH:16]2)[C:8]([O:10]C)=[O:9])=[O:5].Cl[C:37]1C=CC=C(Cl)[C:38]=1C1C=CC2C(=CC=C(CC(NC([C@@H]3CCCCN3S(C3C=CC(C)=CC=3)(=O)=O)=O)C(OC)=O)C=2)N=1.ClC1C=CC=C(Cl)C=1C1C=CC2C(=CC=C(CC(NC([C@@H]3CCCCN3S(C3C=CC(C)=CC=3)(=O)=O)=O)C(O)=O)C=2)N=1>>[Cl:35][C:31]1[CH:32]=[CH:33][CH:34]=[C:2]([Cl:1])[C:3]=1[C:4](=[N:6][CH:7]([CH2:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]=[C:18]([C:23]1[C:24]([Cl:30])=[CH:25][CH:26]=[CH:27][C:28]=1[Cl:29])[CH:17]=[CH:16]2)[C:8]([OH:10])=[O:9])[O:5][CH2:37][CH3:38]
Reactant: COC(=O)C(Cc1ccc2nc(-c3c(Cl)cccc3Cl)ccc2c1)NC(=O)c1c(Cl)cccc1Cl
Reactant: COC(=O)C(Cc1ccc2nc(-c3c(Cl)cccc3Cl)ccc2c1)NC(=O)[C@@H]1CCCCN1S(=O)(=O)c1ccc(C)cc1
Agent: Cc1ccc(S(=O)(=O)N2CCCC[C@H]2C(=O)NC(Cc2ccc3nc(-c4c(Cl)cccc4Cl)ccc3c2)C(=O)O)cc1
Product: CCOC(=NC(Cc1ccc2nc(-c3c(Cl)cccc3Cl)ccc2c1)C(=O)O)c1c(Cl)cccc1Cl

Procedure:
Compound 64 is synthesized according to Chem. Pharm. Bull. (1984), 32, (11), 4466-4477 starting from compound 35 followed by basic hydrolysis, as described for the transformation of compound 46 into compound 90.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:9]([OH:11])=O)=[CH:4][CH:3]=1.[NH2:19][CH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:30]=[C:31]([NH:35][C:36](=[O:40])[CH:37]([CH3:39])[CH3:38])[CH:32]=[CH:33][CH:34]=2)[CH2:25][CH2:24]1>>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[C:9]([NH:19][CH2:20][CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][CH:26]([C:29]3[CH:30]=[C:31]([NH:35][C:36](=[O:40])[CH:37]([CH3:38])[CH3:39])[CH:32]=[CH:33][CH:34]=3)[CH2:25][CH2:24]2)=[O:11])=[CH:13][CH:14]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Reactant: O=C(O)C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCNC(=O)C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)CC2)c1

Procedure:
Example 2 was prepared from bis(4-chlorophenyl)acetic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2-methylpropanamide according to the procedures described in Scheme 9: 1H NMR (400 MHz, CDCl3) δ 7.64 (s, 1H), 7.34–7.13 (m, 12H), 4.75 (s, 1H), 3.41 (q, 2H, J=4.5 Hz), 2.94 (d, 2H, J=10.2 Hz), 2.51–2.40 (m, 4H), 1.97 (m, 2H), 1.82 (m, 2H), 1.68 (quintet, 2H, J=6.8 Hz), 1.59 (m, 3H), 1.25 (d, 6H, J=6.8 Hz); ESMS m/e: 566.2 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:40]=[C:39]([O:41]COC)[CH:38]=[CH:37][C:16]=2[C:17]([NH:19][C:20]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:21]=2[C:22]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][N:26]=2)=[O:23])=[O:18])[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>CO.O1CCOCC1>[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([NH:24][C:22](=[O:23])[C:21]2[CH:32]=[C:33]([F:36])[CH:34]=[CH:35][C:20]=2[NH:19][C:17](=[O:18])[C:16]2[CH:37]=[CH:38][C:39]([OH:41])=[CH:40][C:15]=2[O:14][CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[N:26][CH:27]=1
Reactant: COCOc1ccc(C(=O)Nc2ccc(F)cc2C(=O)Nc2ccc(Cl)cn2)c(OC2CCN(C(=O)OC(C)(C)C)CC2)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: O=C(Nc1ccc(Cl)cn1)c1cc(F)ccc1NC(=O)c1ccc(O)cc1OC1CCNCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-[2-(1-tert-Butoxycarbonylpiperidin-4-yloxy)-4-(methoxymethoxy)benzoyl-amino]-N-(5-chloropyridin-2-yl)-5-fluorobenzamide (6.70 g, 10.7 mmol) was suspended in methanol (18 mL). 4 N HCl in dioxane (35 mL) was added and the resulting solution stirred at room temperature under nitrogen for 2 h. The reaction was cooled to 0° C. and cautiously quenched with saturated aqueous sodium bicarbonate. The resulting precipitate was collected and dried in a vacuum oven to give a quantitative yield of the title product as a fine white powder.
Reaction SMILES: C(O[C:4](=[O:23])[CH:5]=[C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:11][CH:10]=1)[CH3:7])C>C1C(Cl)=CC=C(Cl)C=1.CCCCC>[CH2:16]([O:15][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:6]([CH3:7])[CH:5]=[C:4]2[OH:23])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CCOC(=O)C=C(C)Nc1ccc(OCc2ccccc2)cc1
Solvent: Clc1ccc(Cl)cc1
Solvent: CCCCC
Product: Cc1cc(O)c2cc(OCc3ccccc3)ccc2n1

Procedure:
3-(4-Benzyloxyphenylamino)but-2-enoic acid ethyl ester (3.1 g; see step (i) above) in dichlorobenzene (12 mL) was heated in a microwave at 220° C. for 45 minutes. The reaction mixture was diluted with pentane and the resulting precipitate was filtered, washed with pentane and dried to give 6-benzyloxy-4-hydroxy-2-methyl-quinoline.
Reaction SMILES: [CH2:1]([NH:6][C:7]1[CH:13]=[CH:12][C:11]([C:14]2[O:15][C:16]3[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=3[N:18]=2)=[CH:10][C:8]=1[NH2:9])[C:2]([CH3:5])([CH3:4])[CH3:3].Cl.[C:24](=N)(OC)[CH3:25].C(=O)([O-])O.[Na+]>CO>[O:15]1[C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=2[N:18]=[C:14]1[C:11]1[CH:12]=[CH:13][C:7]2[N:6]([CH2:1][C:2]([CH3:5])([CH3:4])[CH3:3])[C:24]([CH3:25])=[N:9][C:8]=2[CH:10]=1
Reactant: COC(C)=N
Reactant: CC(C)(C)CNc1ccc(-c2nc3ccccc3o2)cc1N
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: Cc1nc2cc(-c3nc4ccccc4o3)ccc2n1CC(C)(C)C
Yield: 74.7 %

Procedure:
To a methanol (5 mL) solution of 2-(2-neopentylaminoanilin-5-yl)benzoxazole (see Working Example 81-2) (192 mg, 0.650 mmol) was added methyl acetimidate hydrochloride (107 mg, 0.975 mmol), and this was heated to reflux for 2 hours. After the reaction was complete, saturated aqueous sodium hydrogen carbonate solution was added, and this was extracted with ethyl acetate. After the organic layer obtained was dried over anhydrous sodium sulfate, it was filtered and concentrated. The crystals obtained were purified by silica gel column chromatography to yield the title compound (155 mg, 75% yield) as white crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]([C:11]2[C:16]([NH:17][C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)=[CH:15][CH:14]=[C:13]([CH3:24])[N:12]=2)=[O:10])[CH:5]=[CH:4][N:3]=1.Br[C:26]1C=NC=CC=1C.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(Cl)(Cl)Cl>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]([C:11]2[C:16]([NH:17][C:18]3[CH:19]=[N:20][CH:21]=[CH:22][C:23]=3[CH3:26])=[CH:15][CH:14]=[C:13]([CH3:24])[N:12]=2)=[O:10])[CH:5]=[CH:4][N:3]=1
Reactant: Cc1ccncc1Br
Reactant: Cc1cc(NC(=O)c2nc(C)ccc2Nc2cccnc2)ccn1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Product: Cc1cc(NC(=O)c2nc(C)ccc2Nc2cnccc2C)ccn1
Temperature: 130 °C
Yield: 36.5 %

Procedure:
In a 10 ml reaction vessel were dissolved 55 mg (0.23 mmol) 3-Amino-6-methyl-pyridine-2-carboxylic acid (2-chloro-pyridin-4-yl)-amide (example 5) and 81 mg (0.45 mmol, 2.0 equiv.) of 3-Bromo-4-methylpyridine in 3 ml of dioxane. Cesium carbonate (148 mg, 0.45 mmol, 2.0 equiv.) were added and argon was bubbled through the suspension for 3 min. Then Xanthphos (43 mg, 0.075 mmol, 0.33 equiv.) and Pd2(dba)3.CHCl3 (23.5 mg, 0.023 mmol, 0.1 equiv.) were added, the vessel was closed and the mixture was heated for 19 h at 130° C. To the mixture was added silicagel (5 g) and the mixture was evaporated to dryness in vaccuo. The powder was charged onto a flash chromatography column and eluted (heptane/ethyl acetate 4:1) to yield the title compound as a yellow crystalline solid (total 28 mg, 28%), MS (ISP): m/e=334.0 (M+H+).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][CH:7]=2)=[CH:2]1.[F:16][C:17]([F:26])([F:25])[C:18]1[CH:23]=[CH:22][C:21](I)=[CH:20][CH:19]=1.C(N)CN.[O-]P(OP(OP([O-])([O-])=O)([O-])=O)(=O)[O-].[K+].[K+].[K+].[K+].[K+]>O1CCOCC1.[Cu]I>[F:16][C:17]([F:26])([F:25])[C:18]1[CH:23]=[CH:22][C:21]([N:1]2[CH:5]=[CH:4][C:3]([C:6]3[CH:7]=[CH:8][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:14][CH:15]=3)=[CH:2]2)=[CH:20][CH:19]=1
Reactant: FC(F)(F)c1ccc(I)cc1
Reactant: COC(=O)c1ccc(-c2cc[nH]c2)cc1
Agent: [Cu]I
Agent: O=P([O-])([O-])OP(=O)([O-])OP(=O)([O-])[O-]
Agent: [K+]
Solvent: NCCN
Solvent: C1COCCO1
Product: COC(=O)c1ccc(-c2ccn(-c3ccc(C(F)(F)F)cc3)c2)cc1
Yield: 52.6 %

Procedure:
To a stirred solution of methyl 4-(1H-pyrrol-3-yl)-benzoate (402 mg, 1.997 mmol, 1.0 eq.) and 4-trifluoromethyl-1-iodobenzene (652 mg, 2.39 mmol, 1.2 eq.) in anhydrous 1,4-dioxane (15 mL) is added copper(I) iodide (38 mg, 0.199 mmol, 0.1 eq.), ethylenediamine (13 μL, 0.199 mmol, 0.1 eq.) and potassium triphosphate (762 mg, 1.66 mmol, 3.31 eq.). The reaction mixture is degassed, flushed with nitrogen and heated to reflux for 18 hr. The reaction mixture is cooled, filtered and washed with ethyl acetate. The filtrate is concentrated and purified by silica gel chromatography (10% ethyl acetate/hexane) to get a white powder, methyl 4-[1-(4-trifluoromethyl-phenyl)-1H-pyrrol-3-yl]-benzoate (363.2 mg, 1.05 mmol, 52.7%). MS (ES+): m/e 345.11. 1H NMR (300 MHz, CDC3): δ 8.04 (2H, d, J=8 Hz), 7.72 (2H, d, J=8 Hz), 7.63 (2H, d, J=8 Hz), 7.54 (2H, d, J=8 Hz), 7.50 (1H, m), 7.18 (1H, m), 6.75 (1H, m), 3.93 (3H, s).
Reaction SMILES: C[Si](C)(C)[O:3][NH2:4].C(=O)([O-])O.[Na+].[CH2:12]([O:14][C:15]([C:17]1[CH:18]=[CH:19][C:20]2[S:25][C@@H:24]([CH2:26][CH2:27][CH2:28][C:29]3[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=3)[C:23](=[O:37])[N:22]([CH2:38][C:39](O)=[O:40])[C:21]=2[CH:42]=1)=[O:16])[CH3:13]>C1COCC1.ClC(OCC(C)C)=O.CN1CCOCC1>[OH:3][NH:4][C:39](=[O:40])[CH2:38][N:22]1[C:21]2[CH:42]=[C:17]([C:15]([O:14][CH2:12][CH3:13])=[O:16])[CH:18]=[CH:19][C:20]=2[S:25][CH:24]([CH2:26][CH2:27][CH2:28][C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=2)[C:23]1=[O:37]
Reactant: C[Si](C)(C)ON
Reactant: CCOC(=O)c1ccc2c(c1)N(CC(=O)O)C(=O)[C@H](CCCc1ccc(OC)cc1)S2
Agent: CC(C)COC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CCOC(=O)c1ccc2c(c1)N(CC(=O)NO)C(=O)C(CCCc1ccc(OC)cc1)S2
Temperature: -15 °C
Reaction time: 0.5 h

Procedure:
In THF (40 ml) was dissolved {(2S)-6-(ethoxycarbonyl)-2-[3-(4-methoxyphenyl)propyl]-3-oxo-2,3-dihydro-4H-1,4-benzothiazin-4-yl}acetic acid (the compound of Reference Example 11) (2.06 g), and isobutyl chloroformate (0.72 ml) and N-methylmorpholine (0.51 ml) were added thereto at −20° C. and stirred at −10 to −20° C. for 30 minutes. After O-(trimethylsilyl)hydroxylamine (0.87 ml) was added thereto, the resulting mixture was warmed up to room temperature and stirred for 1 hour. The reaction mixture was poured into a saturated aqueous sodium hydrogencabonate solution and extracted with ethyl acetate, and the organic layer was washed with a saturated aqueous ammonium chloride solution and a saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate. The drying agent was removed by filtration and the solvent was distilled off under reduced pressure. The residue was recrystallized from a mixed solvent of ethyl acetate and diisopropyl ether to obtain (−)-ethyl 4-[2-(hydroxyamino)-2-oxoethyl]-2-[3-(4-methoxyphenyl)propyl]-3-oxo-3,4-dihydro-2H-1,4-benzothiazine-6-carboxylate (1.69 g, 99.9% e.e.). The optical purity analysis conditions are as follows. [Column: AD-H(CHIRALCEL, DAICEL Chemical Industries Ltd.); detecting wavelength (UV): 254 nm; flow rate: 1.0 ml/min; mobile phase: n-hexane/isopropyl alcohol/TFA=80/20/0.1]
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])[CH2:16]2)(=[O:12])=[O:11].[OH:23][CH:24]1[CH2:29][CH2:28][N:27]([CH2:30][C:31]2[C:32]([CH3:39])=[C:33]([CH:37]=O)[NH:34][C:35]=2[CH3:36])[CH2:26][CH2:25]1.N1CCCCC1>C(O)C>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:37]\[C:33]1[NH:34][C:35]([CH3:36])=[C:31]([CH2:30][N:27]2[CH2:26][CH2:25][CH:24]([OH:23])[CH2:29][CH2:28]2)[C:32]=1[CH3:39])(=[O:12])=[O:11]
Reactant: Cc1[nH]c(C=O)c(C)c1CN1CCC(O)CC1
Reactant: O=C1Cc2cc(S(=O)(=O)Cc3c(Cl)cccc3Cl)ccc2N1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1CN1CCC(O)CC1
Temperature: 25 °C

Procedure:
A mixture of 5-(2,6-dichloro-phenylmethanesulfonyl)-1,3-dihydro-indol-2-one (150 mg, 0.42 mmol), 4-(4-hydroxy-piperidin-1-ylmethyl)-3,5-dimethyl-1H-pyrrole-2-carbaldehyde (99 mg, 1 eq.) and piperidine (0.5 eq.) in ethanol (2 mL) was stirred at rt for days. The reaction was concentrated and the residue was purified on a silica gel column to give the titled compound as a pale greenish-brown solid.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1.I[C:25]1[CH:26]=[C:27]([F:31])[CH:28]=[CH:29][CH:30]=1.[CH2:32]([O:34][C:35](=[O:48])[C:36]1[CH:41]=[C:40]([C:42]#[C:43][Si](C)(C)C)[CH:39]=[N:38][CH:37]=1)[CH3:33].[Cl-].[NH4+]>C(OCC)(=O)C.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH2:32]([O:34][C:35](=[O:48])[C:36]1[CH:41]=[C:40]([C:42]#[C:43][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=2)[CH:39]=[N:38][CH:37]=1)[CH3:33]
Reactant: CCOC(=O)c1cncc(C#C[Si](C)(C)C)c1
Reactant: Fc1cccc(I)c1
Agent: [Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cncc(C#Cc2cccc(F)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.9 %

Procedure:
Add a 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran (0.88 g, 3.38 mmol) to a mixture of 3-iodofluorobenzene (0.50 g, 2.25 mmol), 5-trimethylsilanylethynyl-nicotinic acid ethyl ester (0.84 g, 3.38 mmol), (prepared essentially as described in PREPARATION 16), bis(triphenylphosphine)palladium (II) dichloride (0.03 g, 0.05 mmol) and copper (I) iodide (0.02 g, 0.09 mmol) at −780C. Warm to room temperature, stir overnight and dilute the mixture with ethyl acetate and an aqueous saturated solution of ammonium chloride. Separate the organic layer; dry (magnesium sulfate), filter and concentrate. Purify the resulting residue by silica gel chromatography, eluting with 2.5:45:52.5 ethyl acetate:chloroform:hexanes, to give the title compound as a pale yellow solid (0.46 g, 80%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]=[C:7]([CH2:10][CH2:11]I)[C:6]=2[CH:13]=1.[N:14]1([C:20]2[CH:21]=[CH:22][CH:23]=[C:24]3[C:29]=2[N:28]=[CH:27][CH:26]=[CH:25]3)[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.C(N(CC)C(C)C)(C)C>CS(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]=[C:7]([CH2:10][CH2:11][N:17]3[CH2:18][CH2:19][N:14]([C:20]4[CH:21]=[CH:22][CH:23]=[C:24]5[C:29]=4[N:28]=[CH:27][CH:26]=[CH:25]5)[CH2:15][CH2:16]3)[C:6]=2[CH:13]=1
Reactant: c1cnc2c(N3CCNCC3)cccc2c1
Reactant: Clc1ccc2occ(CCI)c2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: Clc1ccc2occ(CCN3CCN(c4cccc5cccnc45)CC3)c2c1

Procedure:
A mixture of 2-(5-chloro-1-benzofuran-3-yl)ethyl iodide (305 mg. 1 mmol) (obtained by the above mentioned process) and 8-piperazino quinoline (213 mg, 1 mmol) was heated at 120° C. in DMSO in the presence of N,N-diisopropylethylamine (5 ml, excess) for 24 hrs. Afterwards, the reaction mixture was quenched with water and extracted with chloroform. The organic layer was washed with water and dried over anhydrous MgSO4 and concentrated to dryness. The dark colored solid was purified by silica-gel column chromatography by initially eluting it with 70% ethyl acetate:hexane and then with 5% methanol:ethyl acetate. 8-{4-[2-(5-chloro-1-benzofuran-3-yl)ethyl]-1-piperazinyl}-quinoline was isolated as a yellow oil. Yield: 120 mg (30%); (M+H): 392; 1HNMR (400 MHz, CDCl3): δ 8.86˜8.85 (dd, J1=1.8 Hz, J2=1.8 Hz, 1H); 8.03˜8.01 (dd, J1=1.8 Hz, J2=1.8 Hz, 1H); 7.57˜7.10 (m, 8H); 3.51˜2.50 (m, 12H).
Reaction SMILES: Cl[C:2]1[C:10]2[NH:9][C:8]([CH:11]([F:13])[F:12])=[N:7][C:6]=2[C:5]([N+:14]([O-:16])=[O:15])=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18].C(N(CC)CC)C.[C:27]([NH2:31])([CH3:30])([CH3:29])[CH3:28].O>C(O)C>[C:27]([NH:31][C:2]1[C:10]2[NH:9][C:8]([CH:11]([F:13])[F:12])=[N:7][C:6]=2[C:5]([N+:14]([O-:16])=[O:15])=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18])([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(C)N
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c2nc(C(F)F)[nH]c2c1Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCO
Product: CC(C)(C)Nc1c([N+](=O)[O-])cc([N+](=O)[O-])c2nc(C(F)F)[nH]c12

Procedure:
4-Chloro-5,7-dinitro-2-difluoromethylbenzimidazole (1.9 grams), triethylamine (0.7 gram), and tert-butylamine (0.5 gram) were mixed in ethanol and refluxed overnight. The mixture was then poured into water, acidified, and filtered to separate the expected 4-tert-butylamino-5,7-dinitro-2-difluoromethylbenzimidazole product, m.p., 189°-196° C. After recrystallization from ethanol, it melted at 199°-201° C. The identity of the product was confirmed by NMR analysis.
Reaction SMILES: [C:1](Cl)(Cl)=[S:2].C(=O)([O-])[O-].[K+].[K+].[CH3:11][C:12]1[CH:13]=[C:14]([CH2:19][CH:20]([NH2:29])[C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[C:22]=2[CH3:28])[CH:15]=[C:16]([CH3:18])[CH:17]=1.ClCCl>C(Cl)(Cl)Cl.O>[CH3:11][C:12]1[CH:13]=[C:14]([CH2:19][CH:20]([N:29]=[C:1]=[S:2])[C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[C:22]=2[CH3:28])[CH:15]=[C:16]([CH3:18])[CH:17]=1
Reactant: Cc1cc(C)cc(CC(N)c2cccc(C)c2C)c1
Reactant: S=C(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Solvent: ClC(Cl)Cl
Product: Cc1cc(C)cc(CC(N=C=S)c2cccc(C)c2C)c1

Procedure:
A solution of thiophosgene (39.5 g) in 200 ml of chloroform was treated with a solution of potassium carbonate (99 g) in water (200 ml) at room temperature. To this mixture was added a solution of 2-(3,5-dimethylphenyl)-1-(2,3-dimethylphenyl)-ethylamine (72.5 g) in chloroform (600 ml) with vigorous stirring. After completion of the reaction the mixture was poured into dichloromethane (500 ml) and washed three times with water, dried over sodium sulphate and the solvent evaporated in vacuo. This yielded the title compound [2-(3,5-Dimethyl-phenyl)-1-(2,3-dimethyl-phenyl)-ethyl]-isothiocyanate in form of a yellow oil (81.9 g).
Reaction SMILES: [C:1](=O)([O-])[O-].[Cs+].[Cs+].[CH2:7]([O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH:23]([S:29]([CH3:32])(=[O:31])=[O:30])[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:17][CH:16]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.IC.Cl>CN(C=O)C>[CH2:7]([O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][C:23]([CH3:1])([S:29]([CH3:32])(=[O:30])=[O:31])[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:17][CH:16]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)C(CCc1ccc(OCc2ccccc2)cc1)S(C)(=O)=O
Agent: Cl
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCOC(=O)C(C)(CCc1ccc(OCc2ccccc2)cc1)S(C)(=O)=O
Reaction time: 0.5 h
Yield: 91 %

Procedure:
Cesium carbonate (9.30 g, 28.5 mmol) was added to ethyl 4-[4-(benzyloxy)phenyl]-2-(methylsulfonyl)butanoate (8.86 g, 23.5 mmol) in DMF (100 mL) and stirred for 30 minutes. Iodomethane was added to the reaction followed by stirring overnight at room temperature. The reaction mixture was poured into 1N aqueous HCl (100 mL) and extracted with EtOAc (3×100 mL). The combined organics were washed with saturated aqueous sodium thiosulfate (100 mL) then dried (MgSO4), filtered and concentrated in vacuo to afford a crude solid. The crude product was purified via silica gel chromatography using an eluant of ethyl acetate in heptane (10-100%) to afford the title compound as a white solid (8.35 g, 90.9%). LC-MS m/z 391.2 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.CCN(CC)CC.[Br:15][CH2:16][C:17](Br)=[O:18]>C1COCC1>[Br:15][CH2:16][C:17]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1)=[O:18]
Reactant: Nc1ccccn1
Reactant: O=C(Br)CBr
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(CBr)Nc1ccccn1
Reaction time: 8 h

Procedure:
To a solution of 2-aminopyridine (48.8 mmol) in anhydrous THF (98 mL) at room temperature was added Et3N (58.6 mmol) and bromoacetyl bromide (58.6 mmol) dropwise The mixture was stirred overnight and quenched with sat. NaHCO3 (aq). EtOAc was added to the mixture and the layers separated. The aqueous phase was extracted with EtOAc and the combined organics dried (MgSO4) and concentrated in vacuo to a brown solid.
Reaction SMILES: [CH2:1]([O:4][P:5]([O:11][CH2:12][C:13]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:14]=1[C:15]([O:17]CC1C=CC(OC)=CC=1)=[O:16])([O:7][CH2:8][CH:9]=[CH2:10])=[O:6])[CH:2]=[CH2:3].C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>>[CH2:8]([O:7][P:5]([O:11][CH2:12][C:13]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:14]=1[C:15]([OH:17])=[O:16])([O:4][CH2:1][CH:2]=[CH2:3])=[O:6])[CH:9]=[CH2:10]
Reactant: C=CCOP(=O)(OCC=C)OCc1cc(F)ccc1C(=O)OCc1ccc(OC)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: C=CCOP(=O)(OCC=C)OCc1cc(F)ccc1C(=O)O

Procedure:
According to a similar procedure to that described in Example 4-(6), 4-methoxybenzyl 2-[[bis(allyloxy)phosphoryl]oxymethyl]-4-fluorobenzoate (1.41 g, 3.12 mmol) obtained from Example 7-(1) was reacted with anisole (2 g, 18.5 mmol) and trifluoroacetic acid (5 ml), and the reaction mixture was worked up to afford 2-[[bis(allyloxy)phosphoryl]oxymethyl]-4-fluorobenzoic acid as a crude product. According to a similar procedure to that described in Example 4-(6), the crude product obtained above was reacted with oxalyl chloride (1.98 g, 15.6 mmol) and N,N-dimethylformamide (15 μl), and the reaction mixture was worked up to afford 2-[[bis(allyloxy)phosphoryl]oxymethyl]-4-fluorobenzoyl chloride as a crude product.
Reaction SMILES: [CH:1]1[C:6]([NH2:7])=[CH:5][C:4]([NH2:8])=[C:3]([OH:9])[CH:2]=1.Cl.Cl.[C:12]1([C:22](O)=O)[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1.[OH-].[Na+]>>[C:12]1([C:22]2[O:9][C:3]3[CH:2]=[CH:1][C:6]([NH2:7])=[CH:5][C:4]=3[N:8]=2)[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: Nc1ccc(O)c(N)c1
Reactant: O=C(O)c1cccc2ccccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Nc1ccc2oc(-c3cccc4ccccc34)nc2c1
Temperature: 180 °C
Reaction time: 3.5 h
Yield: 76.8 %

Procedure:
8 mmol of 2,4-diaminophenol.2HCl and 8 mmol of naphthalene-1-carboxylic acid were dissolved in 10 g of polyphosphoric acid (PPA), and then, the mixed solution was stirred at a temperature of 180° C. for 3 to 4 hours. After completion of the reaction, the reaction solution was cooled, neutralized with 10% NaOH, and filtered by using distilled water for recrystallization in a slow manner, thereby obtaining 1.6 g of 2-(naphthalene-1-yl)benzo[d]oxazole-5-amine (Derivative #2) (yield: 77%).
Reaction SMILES: C(O[C:4](=[O:10])[C:5]([O:7][CH2:8][CH3:9])=[O:6])C.[Mg].[C:12]1([CH:18]([CH3:21])[CH2:19]Cl)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[Cl-].[NH4+]>C(OCC)C>[CH2:8]([O:7][C:5](=[O:6])[C:4](=[O:10])[CH2:19][CH:18]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:21])[CH3:9]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(CCl)c1ccccc1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Product: CCOC(=O)C(=O)CC(C)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A Grignard solution, to which 15 ml of oxalic acid diethyl ester is added at −30° C. within 30 minutes, is prepared from 2.6 g of magnesium chips and 15 ml of 2-phenyl-1-chloropropane in diethyl ether. It is stirred for one hour at −20° C. and for 2 hours at 0° C., and then mixed with saturated ammonium chloride solution. The diethyl ether phase is separated, dried (Na2SO4) and concentrated by evaporation and distilled in a vacuum. 17.7 g of 2-oxo-4-phenylvaleric acid ethyl ester, boiling point 98-100° C./0.03 hpa, is obtained.