Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4]/[CH:5]=[CH:6]\[S:7][C:8]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=O)[CH3:2].CN1CCOCC1.C(Cl)(Cl)=O.[N-:38]=[N+:39]=[N-:40].CN(C)C(=[NH2+])N(C)C>ClCCl.C1(C)C=CC=CC=1>[CH3:2][C:1]1[N:4](/[CH:5]=[CH:6]\[S:7][C:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:40]=[N:39][N:38]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CC(=O)N/C=C\SC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CN(C)C(=[NH2+])N(C)C
Agent: O=C(Cl)Cl
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: Cc1nnnn1/C=C\SC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 72.3 %

Procedure:
(Z)-1-Acetamido-2-triphenylmethylthioethene (1.07 g) in dry dichloromethane (30 ml) containing N-methylmorpholine (3.5 ml, 3.22 g) was cooled to -30° and treated with phosgene in toluene (8.4 ml, 12.5% w/w). After warming to room temperature and stirring for 30 minutes tetramethylguanidinium azide (600 mg) in dichloromethane (6 ml) was added. After 45 min. a further quantity of tetramethylguanidinium azide (300 mg) in dichloromethane was added. After a further 45 min. the reaction mixture was washed with water (2×300 ml), followed by saturated brine. After drying (MgSO4) the dichloromethane was evaporated in vacuo. Toluene (30 ml) was added and evaporated in vacuo (2×) and the residual material was crystallised from ethyl acetate/hexane to give (Z)-1-(5-methyltetrazol-1-yl)-2-triphenylmethylthioethene (827 mg), m.p. 208°-210°, νmax. (CHCl3) 1600, 1490, 1445, 1410 cm-1., δ(CDCl3) 2.54 (3 H, s), 6.15 (1H, d, J 9 Hz), 6.59 (1H, d, J 9 Hz), 7.35 (15 H, s) p.p.m. (Found: C, 71.65; H, 5.20; N, 14.41%. C23H20N4S requires C, 71.9; H, 5.21; N, 14.6%).
Reaction SMILES: [CH2:1]([N:7]1[C:11]2[CH:12]=[CH:13][S:14][C:10]=2[C:9]2[S:15][CH:16]=[CH:17][C:8]1=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[Li]CCCC.[CH:23](N1CCCCC1)=[O:24].[NH4+].[Cl-].C1C[O:36][CH2:35]C1>>[CH2:1]([N:7]1[C:11]2[CH:12]=[C:13]([CH:35]=[O:36])[S:14][C:10]=2[C:9]2[S:15][C:16]([CH:23]=[O:24])=[CH:17][C:8]1=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCn1c2ccsc2c2sccc21
Reactant: O=CN1CCCCC1
Reactant: C1CCOC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Product: CCCCCCn1c2cc(C=O)sc2c2sc(C=O)cc21
Temperature: -78 °C
Reaction time: 1.5 h

Procedure:
To a solution of 4-hexyl-4H-dithieno[3,2-b;2′,3′-d]pyrrole (36) (1.100 g, 4.18 mmol) in 126 ml of dry THF are added, at −78° C. under argon over a period of 20 minutes, n-BuLi (1.6 M in hexanes; 5.5 ml, 8.79 mmol). After the addition, the mixture was stirred at −78° C. for a further 90 minutes and then warmed to room temperature. After stirring at RT for a further 1 hour, the mixture was cooled again to −78° C. and N-formylpiperidine (1.045 g, 9.24 mmol) was added rapidly by means of a syringe. The mixture was stirred at −78° C. for a further 30 minutes and then brought to RT within 4 hours. Stirring under argon continued overnight. The reaction was stopped by adding a saturated NH4Cl solution (47 ml). After continuing to stir at RT for 15 minutes, the mixture was transferred to a separating funnel and extracted with dichloromethane (3×80 ml). The combined organic phases were washed with water (2×30 ml) and dried over Na2SO4. After filtration and removal of the solvent, the crude product was purified by means of flash chromatography (silica gel, DCM as eluent, Rf=0.25). After the product fractions had been combined and the solvent had been removed, a yellow solid was isolated (533 mg, 1.67 mmol; 40%). 1H NMR (CDCl2); δ=9.88 (s, 2H, CHO), 7.63 (s, 2H, Th—H), 4.21 (t, 2H, CH2), 1.85 (m, 2H, CH2), 1.12 (m, 6H, 3×CH2), 0.80 (t, 3H, CH3).
Reaction SMILES: COC(OC)N(C)C.[NH:9]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16][NH:15][CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[C:21]1([N:27]=[C:28]=[O:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[OH-].[Na+]>C1(C)C=CC=CC=1.O.C(O)C>[C:21]1([NH:27][C:28]([N:9]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16][NH:15][CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[O:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C=Nc1ccccc1
Reactant: C1CNCCNCCNCCN1
Agent: COC(OC)N(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(Nc1ccccc1)N1CCNCCNCCNCC1
Temperature: 0 °C
Reaction time: 12 h

Procedure:
15.9 g (133.5 mmol) of dimethylformamide-dimethylacetal (under nitrogen) is added to 20.0 g (116.1 mmol) of 1,4,7,10-tetraazacyclododecane in 200 ml of absolute toluene. It is refluxed slowly and the solvent is distilled off in this way. Then, it is concentrated by evaporation under reduced pressure. The residue is cooled to 0° C. 16.6 g (139.32 mmol) of phenyl isocyanate is instilled under a nitrogen atmosphere and heated slowly to 100° C. It is stirred for 12 hours at this temperature. It is cooled to room temperature and a mixture of 160 ml of ethanol/40 ml of water is added. Then, it is stirred for 10 minutes at room temperature. Then, 18.58 g (464.4 mmol) of sodium hydroxide is added and it is stirred for 24 hours at 40° C. It is evaporated to dryness in a vacuum and the residue is taken up in 400 ml of water. The aqueous phase is extracted 5 times with 200 ml of methylene chloride, the organic phase is dried on magnesium sulfate and concentrated by evaporation in a vacuum. The residue is chromatographed on silica gel (mobile solvent=methyl-tert-butyl ether/methanol/conc. aqu. ammonia=6/3/1).
Reaction SMILES: [BH4-].[Na+].CO.[C:5]([NH:8][C:9]1[S:10][C:11]2[C:16]([N:17]=1)=[CH:15][CH:14]=[C:13]([O:18][C:19]1[CH:20]=[CH:21][C:22]([Cl:32])=[C:23]([NH:25]C(=O)C(F)(F)F)[CH:24]=1)[N:12]=2)(=[O:7])[CH3:6]>C(O)C.C(OCC)(=O)C>[NH2:25][C:23]1[CH:24]=[C:19]([CH:20]=[CH:21][C:22]=1[Cl:32])[O:18][C:13]1[N:12]=[C:11]2[S:10][C:9]([NH:8][C:5](=[O:7])[CH3:6])=[N:17][C:16]2=[CH:15][CH:14]=1
Reactant: CC(=O)Nc1nc2ccc(Oc3ccc(Cl)c(NC(=O)C(F)(F)F)c3)nc2s1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(=O)Nc1nc2ccc(Oc3ccc(Cl)c(N)c3)nc2s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.8 %

Procedure:
Sodium borohydride (2.45 g, 64.8 mmol) was suspended in ethanol (43 mL), and methanol (29 mL) was slowly added. To the obtained reaction mixture was added N-(5-{[2-(acetylamino)[1,3]thiazolo[5,4-b]pyridin-5-yl]oxy}-2-chlorophenyl)-2,2,2-trifluoroacetamide (1.5 g, 3.48 mmol) powder in small portions under cooling in a water bath, and then, the mixture was stirred at room temperature for 1 hr. The reaction mixture was diluted with ethyl acetate (100 mL), and partitioned with water (50 mL), and the organic layer was concentrated under reduced pressure. The residue was diluted with ethyl acetate (80 mL), and washed with saturated brine (80 mL). The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=40/60→100/0), and triturated with diisopropyl ether to give the title compound (0.58 g, 50%) as a white solid.
Reaction SMILES: [NH:1]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:2][C:3]([NH:5][C@H:6]([C:14]([NH:16][C@H:17]([C:22](O)=[O:23])[CH2:18][CH:19]([CH3:21])[CH3:20])=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4].ON1C(=O)CCC1=O.C1(N=C=NC2CCCCC2)CCCCC1.[NH2:55][CH2:56][C:57]([O:59][CH2:60][C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1)=[O:58]>CN(C)C=O.S(C1C=CC(C)=CC=1)([O-])(=O)=O.C(N(CC)CC)C>[NH:1]([C:25]([O:27][C:28]([CH3:30])([CH3:31])[CH3:29])=[O:26])[CH2:2][C:3]([NH:5][C@H:6]([C:14]([NH:16][C@H:17]([C:22]([NH:55][CH2:56][C:57]([O:59][CH2:60][C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1)=[O:58])=[O:23])[CH2:18][CH:19]([CH3:21])[CH3:20])=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4]
Reactant: NCC(=O)OCc1ccccc1
Reactant: CC(C)C[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)OC(C)(C)C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: O=C1CCC(=O)N1O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)C[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)OC(C)(C)C)C(=O)NCC(=O)OCc1ccccc1
Temperature: 4 °C
Reaction time: 2 h
Yield: 62.3 %

Procedure:
The Boc-Gly-Phe-Leu-OH obtained in Example 18 (2.4 g) and N-hydroxysuccinimide (656 mg) were dissolved in N,N-dimethylformamide (50 ml), cooled to 4° C., and then added with N,N′-dicyclohexylcarbodiimide (1.17 g) and stirred for 2 hours. To this solution, a N,N-dimethylformamide solution (40 ml), in which tosylate of H-Gly-OBzl (1.9 g) and triethylamine (0.79 ml) had been dissolved, was added and the mixture was allowed to react with stirring at room temperature for 16 hours. This reaction mixture was evaporated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane:methanol=50:1 solution) to give the title compound (2.0 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[NH:6][N:7]=1.[C:9]([O-])([O-])=O.[Cs+].[Cs+].CI>CC#N>[Cl:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[N:6]([CH3:9])[N:7]=1
Reactant: O=C([O-])[O-]
Reactant: O=c1ccc(Cl)n[nH]1
Agent: [Cs+]
Solvent: CI
Solvent: CC#N
Product: Cn1nc(Cl)ccc1=O
Temperature: 70 °C
Reaction time: 8 h
Yield: 749.4 %

Procedure:
To a solution of 6-chloropyridazin-3(2H)-one (780 mg, 6 mmol) in CH3CN (40 mL) was added Cs2CO3 (3.9 g, 12 mmol) and CH3I (1 mL, 12 mmol) and the reaction mixture was stirred at 70° C. overnight. Solid was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane/EA=3/1) to afford the title compound as orange oil (6.5 g, 75%). [LCMS: Rt=1.43 min, m/z 145.1 (M+H)+].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([OH:21])=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:4][C:3]=1[NH:22][C:23](=[O:27])[N:24]([CH3:26])[CH3:25].C(=O)([O-])[O-].[K+].[K+].[Br:34][CH2:35][CH2:36]Br.O>CN(C)C=O>[Br:34][CH2:35][CH2:36][O:21][C:15]1[CH:14]=[C:13]2[C:18]([C:9]([O:8][C:6]3[CH:5]=[CH:4][C:3]([NH:22][C:23](=[O:27])[N:24]([CH3:26])[CH3:25])=[C:2]([Cl:1])[CH:7]=3)=[N:10][CH:11]=[N:12]2)=[CH:17][C:16]=1[O:19][CH3:20]
Reactant: BrCCBr
Reactant: COc1cc2c(Oc3ccc(NC(=O)N(C)C)c(Cl)c3)ncnc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc(NC(=O)N(C)C)c(Cl)c3)ncnc2cc1OCCBr
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A starting compound (N′-{2-chloro-4-[(7-hydroxy-6-methoxy-4-quinazolinyl)oxy]phenyl}-N,N-dimethylurea, 80 mg), potassium carbonate (138 mg), and 1,2-dibromoethane (0.085 ml) were dissolved in N,N-dimethylformamide (1 ml), and the solution was stirred at room temperature for 18 hr. Water was added to the reaction mixture, and the mixture was extracted with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure. The residue was washed with ether to give an intermediate (N′-(4-{[7-(2-bromoethoxy)-6-methoxy-4-quinazolinyl]oxy}-2-chlorophenyl)-N,N-dimethylurea). The intermediate, potassium carbonate (138 mg), and morpholine (0.043 ml) were dissolved in N,N-dimethylformamide (1 ml), and the solution was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure. The residue was purified by HPLC by development with chloroform/methanol to give 72 mg (yield 72%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:17])[CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH3:16].[F:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]=[C:26]=[O:27])=[CH:21][CH:20]=1>C(Cl)Cl>[Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:17][C:26]([NH:25][C:22]2[CH:23]=[CH:24][C:19]([F:18])=[CH:20][CH:21]=2)=[O:27])[CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH3:16]
Reactant: CCOc1ccc(N)cc1-c1c(Br)cnn1C
Reactant: O=C=Nc1ccc(F)cc1
Solvent: ClCCl
Product: CCOc1ccc(NC(=O)Nc2ccc(F)cc2)cc1-c1c(Br)cnn1C
Yield: 61.5 %

Procedure:
3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-ethoxy-phenylamine (0.039 g, 0.13 mmol) was treated with 4-fluorophenyl isocyanate (0.020 g, 16.6 μL, 0.14 mmol, 1.1 equiv.) in CH2Cl2 (1 mL), in a similar manner as described in Example 1.2 to afford Compound 68 (0.034 g, 0.08 mmol, 59%) as a white solid. LCMS m/z (%)=433 (M+H79Br, 100), 435 (M+H81Br, 99). 1H NMR (400 MHz, acetone-d6) δ: 8.13 (s, 1H), 8.11 (s, 1H), 7.66 (dd, J=2.7, 8.9 Hz, 1H), 7.50-7.57 (m, 2H), 7.49 (s, 1H), 7.42 (d, J=2.7 Hz, 1H), 7.11 (d, J=8.9 Hz, 1H), 7.04 (t, J=8.8 Hz, 2H), 3.96-4.18 (m, 2H), 3.71 (s, 3H), 1.28 (t, J=7.1 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([N:8]2[C@@H:15]3[C@@H:10]([CH2:11][CH2:12][N:13](C(OC(C)(C)C)=O)[CH2:14]3)[CH2:9]2)[CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][C:2]1[N:7]=[C:6]([N:8]2[C@@H:15]3[C@@H:10]([CH2:11][CH2:12][NH:13][CH2:14]3)[CH2:9]2)[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc(N2C[C@@H]3CCN(C(=O)OC(C)(C)C)C[C@@H]32)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cccc(N2C[C@@H]3CCNC[C@@H]32)n1
Temperature: 25 °C

Procedure:
To a solution of (1R,6S)-tert-butyl 8-(6-methylpyridin-2-yl)-3,8-diazabicyclo[4.2.0]octane-3-carboxylate (80 mg, 0.26 mmol) in DCM (5 mL) was added TFA (2 mL). The resulting mixture was allowed to stir at ambient temperature. After 16 h the mixture was concentrated under reduced pressure. The resulting trifluoroacetic acid salt of the title compound (80 mg) was used without further purification. MS (ESI) mass calcd. for C12H17N3, 203.2; m/z found, 204.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C@@:11]23[CH2:26][CH2:25][C:24](=[O:27])[CH2:23][C@H:12]2[CH2:13][O:14][C:15]2[C:20]3=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[F:22])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[B-](F)(F)(F)[F:29].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1.O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([C:11]23[CH2:26][CH2:25][C:24](=[O:27])[CH:23]([F:29])[CH:12]2[CH2:13][O:14][C:15]2[C:20]3=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[F:22])(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: F[B-](F)(F)F
Reactant: O=C1CC[C@@]2(S(=O)(=O)c3ccc(Cl)cc3)c3c(F)ccc(F)c3OC[C@@H]2C1
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CN(C)C=O
Solvent: O
Product: O=C1CCC2(S(=O)(=O)c3ccc(Cl)cc3)c3c(F)ccc(F)c3OCC2C1F
Temperature: 50 °C

Procedure:
To a solution of trans-10a-(4-chloro-benzenesulfonyl)-1,4-difluoro-6a,9,10,10a-tetrahydro-6H,7H-benzo[c]chromen-8-one in DMF (4 mL) was added Selectfluor®. The reaction mixture was heated at 50° C. overnight, cooled to rt and water was added to precipitate the desired product. The product was isolated by filtration washing with water then dried under vacuum to provide a colorless solid. 1H NMR CDCl3 400 MHz) δ 7.61 (d, 2H), 7.53 (d, 2H), 7.19-7.14 (m, 1H), 6.55-6.49 (m, 1H), 5.20 (d, 1H), 4.74 (dd, 2JH-F=46.7 Hz, 3JH-F=11.8 Hz, 1H) 4.66 (d, 1H), 3.18 (t, 1H), 2.9 (m, 1H), 2.53 (m, 1H), 2.41 (m, 1H), 2.18 (m, 1H); LCMS (MH+) 431.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:16][CH2:15][CH2:14][C@@H:13]3[C@H:8]([O:9][CH2:10][CH2:11][NH:12]3)[C:6]=2[CH:7]=1.O1CCN[C@@H]2CCOC3C=CC=CC=3[C@@H:18]12.[ClH:32]>>[ClH:32].[F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:16][CH2:15][CH2:14][C@@H:13]3[C@H:8]([O:9][CH2:10][CH2:11][N:12]3[CH3:18])[C:6]=2[CH:7]=1
Reactant: c1ccc2c(c1)OCC[C@H]1NCCO[C@H]21
Reactant: Fc1ccc2c(c1)[C@H]1OCCN[C@@H]1CCO2
Agent: Cl
Product: CN1CCO[C@@H]2c3cc(F)ccc3OCC[C@H]21

Procedure:
In a similar way, substituting trans-10-fluoro-3,4,4a,5,6,11b-hexahydro-2H-[1]benzoxepino[5,4-b]-1,4-oxazine for the trans-3,4,4a,5,6,11b-hexahydro-2H-[1]benzoxepino[5,4-b]-1,4-oxazine above and using hydrogen chloride instead of maleic acid, results in the formation of trans-10-fluoro-3,4,4a,5,6,11b-hexahydro-4-methyl-2H-[1]benzoxepino[5,4-b]-1,4-oxazine hydrochloride having a mp. of 244°-245° C.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:12]([O:14][CH2:15][CH2:16][CH3:17])=[O:13])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH2:18]([O:25][C:26]1[CH:35]=[C:34]2[C:29]([C:30](Cl)=[CH:31][CH:32]=[N:33]2)=[CH:28][C:27]=1[O:37][CH3:38])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH2:18]([O:25][C:26]1[CH:35]=[C:34]2[C:29]([C:30]([O:1][C:2]3[C:3]([C:12]([O:14][CH2:15][CH2:16][CH3:17])=[O:13])=[CH:4][C:5]4[C:10]([CH:11]=3)=[CH:9][CH:8]=[CH:7][CH:6]=4)=[CH:31][CH:32]=[N:33]2)=[CH:28][C:27]=1[O:37][CH3:38])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CCCOC(=O)c1cc2ccccc2cc1O
Reactant: COc1cc2c(Cl)ccnc2cc1OCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: Clc1ccccc1Cl
Product: CCCOC(=O)c1cc2ccccc2cc1Oc1ccnc2cc(OCc3ccccc3)c(OC)cc12
Temperature: 120 °C
Reaction time: 5 h
Yield: 50.1 %

Procedure:
Propyl 3-hydroxy-naphthalene-2-carboxylate (460 mg), 7-benzyloxy-4-chloro-6-methoxyquinoline (200 mg), and 4-dimethylaminopyridine (244 mg) were suspended in o-dichlorobenzene (4 ml), and the mixture was stirred at 120° C. for 5 hr. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was washed with saturated brine and was dried over anhydrous sodium sulfate, the solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-acetone to give propyl 3-(7-benzyloxy-6-methoxy-quinolin-4-yloxy)-naphthalene-2-carboxylate (165 mg, yield 50%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[C:9]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:14]=[CH:13][C:12]([C@H:15]2[CH2:19][O:18][C:17](=[O:20])[NH:16]2)=[CH:11][CH:10]=1.[H-].[Na+].O>CN(C=O)C.CCOC(C)=O.[Cl-].[Na+].O>[C:9]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:14]=[CH:13][C:12]([C@H:15]2[CH2:19][O:18][C:17](=[O:20])[N:16]2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=2)=[CH:11][CH:10]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: O=C1N[C@@H](c2ccc(-c3ccccc3)cc2)CO1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C1OC[C@H](c2ccc(-c3ccccc3)cc2)N1c1ccnc(Cl)n1
Reaction time: 1.5 h
Yield: 45.1 %

Procedure:
To a solution of 2,4-dichloropyrimidine (46.5 mg, 0.312 mmol) and (S)-4-(biphenyl-4-yl)oxazolidin-2-one (74.7 mg, 0.312 mmol) in DMF (700 μL) was added NaH (60% wt., 10.49 mg, 0.437 mmol) in two portions within ˜5 min [Caution: exotherm; gas development] at room temperature (water bath). The reaction mixture was stirred for 1.5 hour. The mixture was diluted with EtOAc (25 mL), stirred for 5 min and then diluted slowly with diluted brine (10 mL; 1:1 brine/water). The mixture was poured into diluted brine (40 mL) and EtOAc (25 mL). The separated organic phase was washed with diluted brine (3×40 ml), dried over Na2SO4, filtered off and concentrated under reduced pressure. The residue was purified by column chromatography [SiO2, 40 g, EtOAc/heptane] to provide (S)-4-(biphenyl-4-yl)-3-(2-chloropyrimidin-4-yl)oxazolidin-2-one (49.5 mg). LCMS m/z 352.2 (M+H)+, Rt 1.06 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[O:10][C:9]=2[C:17](=[O:25])[C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[CH2:26]([N:28]([CH2:33][CH3:34])[CH2:29][CH2:30][CH2:31]Cl)[CH3:27].C(=O)([O-])[O-].[K+].[K+]>CCC(=O)CC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[O:10][C:9]=2[C:17](=[O:25])[C:18]2[CH:19]=[CH:20][C:21]([O:24][CH2:31][CH2:30][CH2:29][N:28]([CH2:33][CH3:34])[CH2:26][CH3:27])=[CH:22][CH:23]=2)=[CH:6][CH:7]=1
Reactant: CCN(CC)CCCCl
Reactant: O=C(c1ccc(O)cc1)c1oc2ccccc2c1-c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(=O)CC
Product: CCN(CC)CCCOc1ccc(C(=O)c2oc3ccccc3c2-c2ccc(Cl)cc2)cc1

Procedure:
(0.009 mol.) of 3-(4-chlorophenyl)-2-(4-hydroxybenzoyl)benzofuran with 1.4 g. (0.009 mol.) of 3-diethylaminopropyl chloride in 50 ml. of dry 3-pentanone containing 5.2 g. (0.04 mol.) of potassium carbonate by the method described in Example 1 gives the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[C:4]([NH2:11])[N:3]=1.[C:12]([OH:17])(=O)[CH2:13][CH2:14][CH3:15].C(Cl)Cl>CO.O.[NH4+].[OH-].[Pd]>[C:12]([NH:11][C:4]1[N:3]=[C:2]2[N:1]=[C:4]([CH2:5][CH2:6][CH3:7])[NH:8][C:7]2=[CH:6][CH:5]=1)(=[O:17])[CH2:13][CH2:14][CH3:15]
Reactant: CCCC(=O)O
Reactant: Nc1ccc([N+](=O)[O-])c(N)n1
Agent: [Pd]
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: CCCC(=O)Nc1ccc2[nH]c(CCC)nc2n1
Temperature: 80 °C
Reaction time: 16 h
Yield: 49.1 %

Procedure:
A mixture of 2,6-diamino-3-nitropyridine (878 mg, 5.7 mmol) and Pd-C (10%, 100 mg) in MeOH (100 mL) was stirred under 1 atm. H2 for 16 hours. The mixture (containing the air sensitive triamine) was filtered, evaporated, and to this flask was added polyphosphoric acid (15 mL) and butyric acid (1.05 mL, 11.5 mmol). This mixture was heated to 80° C. for 5 hours, cooled to room temperature, diluted with water and neutralized with concentrated NH4OH. Extractive workup (CH2Cl2) gave 345 mg of 5-(butyramido)-2-propylimidazo[4,5-b]pyridine: 1H NMR (300 MHz, CDCl3) δ7.94 (d, 1H, J=8.5 Hz), 7.65 (d, 1H, J=8.5 Hz), 2.96 (t, 2H J=7.5 Hz), 2.30 (t, 2H J=7 Hz), 1.98-1.84 (m, 2H), 1.68-1.55 (m, 2H), 0.99 (t, 3H, J=7.5 Hz), 0.80 (t, 3H, J=7.0 Hz).
Reaction SMILES: F[C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH3:11][S-:12].[Na+]>C1(C)C=CC=CC=1>[F:10][C:8]1[CH:7]=[CH:6][C:3]([CH:4]=[O:5])=[C:2]([S:12][CH3:11])[CH:9]=1
Reactant: C[S-]
Reactant: O=Cc1ccc(F)cc1F
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CSc1cc(F)ccc1C=O
Temperature: 80 °C
Reaction time: 7 h
Yield: 37.6 %

Procedure:
To a solution of 2,4-difluorobenzaldehyde (3.0 g, 21.1 mmol, CAS RN 1550-35-2) in toluene (29 mL) was added sodium thiomethoxide (2.03 g, 28.9 mmol) and the resulting suspension was stirred at 80° C. for 7 hours. Heating was removed and stirring continued at room temperature for another 18 hours. The reaction mixture was treated with diethyl ether (50 mL) and water (15 mL) and the layers were separated. The aqueous layer was extracted twice with ethyl acetate (50 mL each). The organic layers were washed with saturated aqueous sodium hydrogencarbonate solution and with brine, dried over magnesium sulfate, filtered and evaporated. The residue was dissolved in 50 mL n-heptane and 50 mL diethyl ether and the clear solution was evaporated slowly until a turbid solution formed. The originally oily precipitation turned into a white solid which was filtered, washed with n-heptane and dried under high vacuum to give the compound as a colourless solid (1.35 g, 37%). MS (ESI+): m/z=170.0 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].Cl[CH2:29][C:30]#[N:31].O>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[CH:15][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:21][CH:22]=2)[CH2:29][C:30]#[N:31])=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(OCCCNc2ccc(Cl)cc2)cc1
Reactant: N#CCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(OCCCN(CC#N)c2ccc(Cl)cc2)cc1
Temperature: 90 °C
Reaction time: 168 h
Yield: 74.3 %

Procedure:
Methyl 4-[3-[N-(4-chlorophenyl)amino]propoxy]benzoate (1.2 g) was dissolved in DMF (10 ml), and under heating with stirring at 90° C., sodium bicarbonate (7.6 g) and chloroacetonitrile (6.63 g) were added thereto in 8-10 portions respectively over a period of 7 days. The reaction mixture was cooled, and water and ethyl acetate were added thereto and the mixture was separated into layers. The organic layer was washed with aqueous sodium chloride solution, and concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel and eluted with chloroform to give the oily desired product (1.00 g).