Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].[C:12]1([C:18](Cl)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:1][C:2]1[N:6]([C:18]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:5]=[N:4][C:3]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)c1nc[nH]c1C
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c1C
Yield: 69.6 %

Procedure:
Ethyl 5-methyl-4-1H-imidazolecarboxylate (6.16 g) in toluene (100 ml), triphenylmethyl chloride (11.12 g) and triethylamine (5.6 ml) were heated at reflux for 18 h. Toluene was removed under reduced pressure and the residue was dissolved in dichloromethane (100 ml), washed with water (4×50 ml) dried (MgSO4) and evaporated. The residue was purified by column chromatography on silica using 1% methanol in dichloromethane as eluant with a trace of triethylamine. This afforded the title compound (11 g), m.p. 188°-190° C. δH (250 MHz, CDCl3) 1.38-1.42 (3 H, t, J=6.5 Hz, CH3), 1.86 (3 H, s, CH3), 4.36-4.40 (2 H, q, J=7.2 Hz, CH2), 7.10-7.46 (16 H, m, ArH); m/z (NoM+), 243 (Ph3C+, 100%).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][CH2:5][C@@H:4]([CH3:8])[NH:3]1.Br[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([OH:26])([C:22]([F:25])([F:24])[F:23])[C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.C(OCC)(=O)C>[CH3:8][C@H:4]1[NH:3][C@@H:2]([CH3:1])[CH2:7][N:6]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]([OH:26])([C:18]([F:19])([F:20])[F:21])[C:22]([F:23])([F:24])[F:25])=[CH:15][CH:16]=2)[CH2:5]1
Reactant: OC(c1ccc(CBr)cc1)(C(F)(F)F)C(F)(F)F
Reactant: C[C@@H]1CNC[C@H](C)N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: C[C@@H]1CN(Cc2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)C[C@H](C)N1
Yield: 59.7 %

Procedure:
2,6-cis-Dimethylpiperazine (40.3 mmol, 4.6 g), 2-(4-(bromomethyl)phenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (40.3 mmol, 13.58 g) and potassium carbonate (81 mmol, 11.13 g) were combined and stirred overnight at room temperature in acetonitrile (25 mL). The reaction mixture was diluted with ethyl acetate and filtered through dicalite. The filtrate was concentrated under vacuum. The resulting residue was purified by silica chromatography (eluting with a solvent gradient from dichloromethane to 90/10/1 dichloromethane/methanol/ammonia) to afford the title compound (8.91 g).
Reaction SMILES: C(O[CH2:5][C:6]1[CH:14]=[CH:13][C:12]2[CH2:15][NH:16][C@@H:17]([CH:20]3[CH:25]4[CH2:26][CH2:27][N:22]([CH2:23][CH2:24]4)[CH2:21]3)[C:18](=[O:19])[N:10]3[C:11]=2[C:7]=1[CH:8]=[CH:9]3)(=O)C.C(O)(=O)C>CO.[Pd]>[CH3:5][C:6]1[CH:14]=[CH:13][C:12]2[CH2:15][NH:16][C@@H:17]([CH:20]3[CH:25]4[CH2:24][CH2:23][N:22]([CH2:27][CH2:26]4)[CH2:21]3)[C:18](=[O:19])[N:10]3[C:11]=2[C:7]=1[CH:8]=[CH:9]3
Reactant: CC(=O)OCc1ccc2c3c1ccn3C(=O)[C@H](C1CN3CCC1CC3)NC2
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: Cc1ccc2c3c1ccn3C(=O)[C@H](C1CN3CCC1CC3)NC2
Reaction time: 8 h

Procedure:
(S)-(1-Oxo-2-(quinuclidin-3-yl)-1,2,3,4-tetrahydro-[1,4]diazepino[6,7,1-hi]indol-7-yl)methyl acetate (124 mg, 0.34 mmol) from Step C above was dissolved in methanol (7 ml) and glacial acetic acid (3 ml). Excess 10% palladium on carbon was added and the suspension was stirred under an atmosphere of hydrogen (balloon pressure) overnight. The suspension was filtered through Celite and the filtrate was concentrated under reduced pressure and purified by column chromatography (silica gel, 90:10:1 methylene chloride/methanol/concentrated ammonium hydroxide) and preparative TLC (90:10:10 methylene chloride/methanol/concentrated ammonium hydroxide) to afford (S)-7-methyl-2-(quinuclidin-3-yl)-3,4-dihydro-[1,4]diazepino[6,7,1-hi]indol-1(2H)-one. This material was dissolved in methanol and treated with HCl (1.25 M solution in methanol) and the mixture was concentrated under reduced pressure. The residue was lyophilized from water to afford (S)-7-methyl-2-(quinuclidin-3-yl)-3,4-dihydro-[1,4]diazepino[6,7,1-hi]indol-1(2H)-one hydrochloride (100 mg, 85%) as a white solid: 1H NMR (500 MHz, CD3OD) δ 7.80 (d, J=4.0 Hz, 1H), 7.75 (d, J=3.8 Hz, 1H), 7.17 (t, J=8.0 Hz, 1H), 7.17 (t, J=8.0 Hz, 1H), 4.90 (s, 1H), 4.22 (br s, 1H), 4.11 (br s, 1H), 3.77-3.72 (m, 2H), 3.48-3.29 (m, 6H), 2.35 (d, J=8.0 Hz, 1H), 2.21 (s, 3H), 2.06-1.96 (m, 4H); MS (ESI+) m/z 310 (M+H).
Reaction SMILES: C(OCC)(=O)C.[ClH:7].[CH2:8]([O:10][C:11]([C@H:13]([NH:22][C@@H:23]1[C:29](=[O:30])[N:28]([CH2:31][C:32]([O:34]C(C)(C)C)=[O:33])[C:27]2[CH:39]=[CH:40][CH:41]=[CH:42][C:26]=2[S:25][CH2:24]1)[CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:12])[CH3:9]>CCOCC>[ClH:7].[CH2:8]([O:10][C:11]([C@H:13]([NH:22][C@@H:23]1[C:29](=[O:30])[N:28]([CH2:31][C:32]([OH:34])=[O:33])[C:27]2[CH:39]=[CH:40][CH:41]=[CH:42][C:26]=2[S:25][CH2:24]1)[CH2:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:12])[CH3:9]
Reactant: CCOC(=O)[C@@H](CCc1ccccc1)N[C@H]1CSc2ccccc2N(CC(=O)OC(C)(C)C)C1=O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CCOC(=O)[C@@H](CCc1ccccc1)N[C@H]1CSc2ccccc2N(CC(=O)O)C1=O
Reaction time: 8 h

Procedure:
A mixture of 5 ml of 5N hydrogen chloride-ethyl acetate solution and 0.5 g of tert-butyl 3(R)-[1(R)-ethoxycarbonyl-3-phenylpropyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate obtained in Example 1 is allowed to stand at room temperature overnight. Twenty ml of ether and 100 ml of petroleum ether are added to the mixture to deposit colorless powder, which is collected by filtration to give 0.42 g of 3(R)-[1(R)-ethoxycarbonyl-3-phenylpropyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid hydrochloride.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[C:10]1([CH2:16]C(O)=O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.N1CCCCC1.C(=O)([O-])[O-].[Na+].[Na+]>O>[OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH:16][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: O=C(O)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCNCC1
Product: Oc1ccc(C=Cc2ccccc2)cc1
Temperature: 90 °C
Reaction time: 0.2 h

Procedure:
A portion (244.24 grams, 2.0 moles) of 4-hydroxybenzaldehyde, phenylacetic acid (272.30 grams, 2.0 moles) and piperidine (51.6 milliliters) are added to a reactor equipped with a reflux condenser and stirred under a nitrogen atmosphere. Heating commences and after 12 minutes and at 93° C., a solution forms. After a total of 27 minutes, the reaction temperature reaches 150° C. and is held therein. After 2 hours at the 150° C. temperature, a solution of sodium carbonate (40.0 grams) in deionized water (800 milliliters) is added to the reactor over a 3 minute period while stirring and heating are maintained. After 10 minutes of mixing with heating, stirring ceases and the aqueous layer is decanted from the reactor. The solid product remaining in the reactor is recovered and dissolved in a solution of sodium hydroxide (100.0 grams) in deionized water (2400 milliliters) which has been heated to 90° C. The resultant solution is held for 16 hours at 4° C. and the resultant crystalline precipitate which forms is recovered by filtration. The crystals are suspended in deionized water (1600 milliliters) which is stirred and then acidified to a pH of one by addition of aqueous concentrated hydrochloric acid. The resultant crystalline product is recovered by filtration, then washed on the filter with deionized water (two 250 milliliter portions). The product recovered on the filter is dried at 80° C. under a vacuum of 2 mm Hg to a constant weight of 87.1 grams of white crystalline powder. Fourier transform infrared spectrophotometric analysis of a potassium chloride pellet of the product reveals the presence of the expected hydroxyl group O--H stretching absorbance centered at 3416 cm-1 (broad), the ethylene C--H out-of-plane deformation at 965 cm-1, the C--H out-of-plane vibration at 819 cm-1 for the para substituted aromatic ring and the C--H out-of-plane vibration at 746 and 686 cm-1 for the monosubstituted aromatic ring. High pressure liquid chromatographic analysis of the 4-hydroxystilbene product using a uv detector set at 254 nm reveals a single sharp peak. Proton magnetic resonance spectroscopy further confirms the product structure.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][N:8]([CH2:10][CH2:11][OH:12])[CH2:7][N:6]([CH2:13][CH2:14][OH:15])[CH2:5]1.C(=O)([O-])[O-].[K+].[K+].[C:22](Cl)(=[O:40])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]/[CH:30]=[CH:31]\[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]>O.C(Cl)Cl>[C:22]([O:12][CH2:11][CH2:10][N:8]1[CH2:9][N:4]([CH2:3][CH2:2][OH:1])[CH2:5][N:6]([CH2:13][CH2:14][OH:15])[CH2:7]1)(=[O:40])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]/[CH:30]=[CH:31]\[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]
Reactant: OCCN1CN(CCO)CN(CCO)C1
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: CCCCCCCC/C=C\CCCCCCCC(=O)OCCN1CN(CCO)CN(CCO)C1
Temperature: 0 °C
Reaction time: 15 h

Procedure:
1,3,5-tris(2-Hydroxyethyl)perhydro-s-triazine (21.6 g, 0.1 mole) and potassium carbonate (35 g) are combined in a mixture of 50 ml of water and 150 ml of methylene chloride at 0° C. Oleic acid chloride (30 g, 0.1 mole) in 50 ml of methylene chloride is added at a rate such that the reaction mixture is retained at a temperature below about 10° C. After complete addition, the mixture is stirred at 0° C. for 15 hours and then at about 25° C. for an additional 16 hours. The organic layer is separated, dried over magnesium sulfate and concentrated to a yellow oil. Analysis by infrared spectroscopy and nuclear magnetic resonance spectroscopy identify the product as 1,3,5-triazine-1,3,5-(2H,4H,6H)triethanol monooleate.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[N:3]=1.[NH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH:13]1[C:18]([O:20][CH2:21][CH3:22])=[O:19].C(N(CC)C(C)C)(C)C>CS(C)=O>[F:9][C:8]([F:11])([F:10])[C:4]1[N:3]=[C:2]([N:15]2[CH2:16][CH2:17][NH:12][CH:13]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14]2)[CH:7]=[CH:6][CH:5]=1
Reactant: FC(F)(F)c1cccc(Br)n1
Reactant: CCOC(=O)C1CNCCN1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1CN(c2cccc(C(F)(F)F)n2)CCN1
Temperature: 80 °C
Reaction time: 96 h

Procedure:
2-Bromo-6-(trifluoromethyl)pyridine (13.56 g, 60 mmol) and ethyl piperazine-2-carboxylate (U.S. Patent App. Publ. US2004/0147559, 9.49 g, 60.0 mmol) were mixed in dry dimethyl sulfoxide (40 mL) and then treated with N,N-diisopropylethylamine (31.1 mL, 180 mmol). The mixture was heated to 80° C. and stirred for 4 days. The solution was concentrated, and the residue was purified on a silica gel column (hexane:ethyl acetate=1:3) to give the title compound. 1H NMR (300 MHz, methanol-d4) δ ppm 1.27 (t, 3H, J=7 Hz), 2.83 (ddd, 1H, J=12, 9, 3 Hz), 3.11 (ddd, 1H, J=12, 5, 3 Hz), 3.33-3.38 (m, 1 H), 3.41-3.50 (m, 1 H), 3.56-3.62 (m, 1 H), 3.81 (ddd, 1H, J=13, 4, 3 Hz), 4.15-4.25 (m, 3 H), 7.00 (t, 2H, J=8 Hz), 7.65-7.75 (m, 1 H); MS (DCI) m/z 304 (M+H)+.
Reaction SMILES: [CH:1]([N:5]=[C:6]=[N:7][C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1)([CH2:3][CH3:4])[CH3:2].C([N:18]=[C:19]=[N:20]C1C=NC=CC=1)(C)(C)C>>[CH:1]([NH:5][C:6]([NH:7][C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1)=[N:20][C:19]#[N:18])([CH2:3][CH3:4])[CH3:2]
Reactant: CCC(C)N=C=Nc1cccnc1
Reactant: CC(C)(C)N=C=Nc1cccnc1
Product: CCC(C)NC(=NC#N)Nc1cccnc1

Procedure:
By following the procedure of Example 1, but substituting N-sec-butyl-N'-3-pyridylcarbodiimide for the N-tert-butyl-N'-3-pyridylcarbodiimide, the desired compound was obtained with a melting point of 133.5°-135.0° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:8]([C:11]2[CH:20]=[C:19]3[C:14]([CH2:15][CH2:16][CH:17]([CH2:21][OH:22])[O:18]3)=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[CH3:23][S:24](Cl)(=[O:26])=[O:25].C(N(CC)CC)C>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([S:8]([C:11]2[CH:20]=[C:19]3[C:14]([CH2:15][CH2:16][C@H:17]([CH2:21][O:22][S:24]([CH3:23])(=[O:26])=[O:25])[O:18]3)=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(c1cccc(F)c1)c1ccc2c(c1)OC(CO)CC2
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC[C@H]1CCc2ccc(S(=O)(=O)c3cccc(F)c3)cc2O1
Temperature: -10 °C
Reaction time: 1 h
Yield: 88.6 %

Procedure:
To a solution of [7-(3-fluoro-benzenesulfonyl)-chroman-2-yl]-methanol (10.0 g, 0.032 mol) in 200 mL of methylene chloride at −10° C. was added methanesulfonyl chloride (2.76 mL, 0.036 mol) and triethylamine (4.95 mL, 0.036 mol). The reaction mixture was stirred for one hour at −10° C. and was then quenched by addition of 10% aqueous NaHCO3. The organic layer was separated, washed with water and brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (hexanes:EtOAc 85:15) to give 11.35 g (92%) of methanesulfonic acid (R)-7-(3-fluoro-benzenesulfonyl)-chroman-2-ylmethyl ester.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH:16]3[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[F:23][C:24]1[CH:32]=[C:31]2[C:27]([CH:28]=[CH:29][NH:30]2)=[CH:26][C:25]=1[OH:33].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:23][C:24]1[CH:32]=[C:31]2[C:27]([CH:28]=[CH:29][NH:30]2)=[CH:26][C:25]=1[O:33][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH:16]3[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: COc1cc2c(Cl)ncnc2cc1OCC1CCN(C)CC1
Reactant: Oc1cc2cc[nH]c2cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3cc4cc[nH]c4cc3F)ncnc2cc1OCC1CCN(C)CC1
Temperature: 95 °C
Reaction time: 3.5 h
Yield: 46.7 %

Procedure:
A solution of 4-chloro-6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)quinazoline (213 mg, 0.662 mmol), (prepared as described for the starting material in Example 10), and 6-fluoro-5-hydroxyindole (120 mg, 0.794 mmol) in DMF (3 ml) containing potassium carbonate (137 mg, 0.994 mmol) was stirred at 95° C. for 3.5 hours. After cooling, the mixture was poured onto water. The mixture was filtered and the solid was washed with water. The solid was dissolved in methylene chloride. The organic layer was dried (MgSO4), and evaporated. The residue was triturated with ether/ethyl acetate and the solid was filtered and dried under vacuum to give 4-(6-fluoroindol-5-yloxy)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline (135 mg, 46%).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:18]([OH:20])=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14](Br)=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[Cl:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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>[C:4]([O:3][C:1]([NH:8][C@@H:9]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:26]2[CH:25]=[CH:24][CH:23]=[C:22]([Cl:21])[CH:27]=2)=[CH:13][CH:12]=1)[C:18]([OH:20])=[O:19])=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(Br)cc1)C(=O)O
Reactant: OB(O)c1cccc(Cl)c1
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: COCCOC
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)C(=O)O
Temperature: 85 °C
Reaction time: 3 h
Yield: 66 %

Procedure:
To a solution of Boc-4-bromo-L-phenylalanine (15 g, 43.6 mmol) in DME (180 ml) at room temperature was added 3-chlorobenzeneboronic acid (8.52 g, 54.5 mmol) followed by aq. Na2CO3 (32.7 ml, 65.4 mmol) and Pd(PPh3)4 (1.511 g, 1.307 mmol). The mixture was stirred at 85° C. for 3 hours. The reaction mixture was filtered and added EtOAc and acidified by 1M HCl to pH˜5. The combined organic layer was washed with brine and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by flash chromatography (silica gel, 5 to 20% EtOAc/Heptane) and gave the title compound: 12.0 g (yield: 66%). LCMS (condition A): 374.2 (M−1); retention time=1.57 min.
Reaction SMILES: C[N:2](C)[CH:3]=[CH:4][C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[N:8]=1)=O.[NH2:25]N.O.Cl>CO>[NH:25]1[C:5]([C:7]2[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=3)[N:8]=2)=[CH:4][CH:3]=[N:2]1
Reactant: CN(C)C=CC(=O)c1nn(-c2cccc(C(F)(F)F)c2)ccc1=O
Reactant: NN
Agent: Cl
Solvent: O
Solvent: CO
Product: O=c1ccn(-c2cccc(C(F)(F)F)c2)nc1-c1ccn[nH]1
Temperature: 25 °C
Yield: 39.6 %

Procedure:
A solution of 3-[3-(dimethylamino)prop-2-enoyl]-1-[3-(trifluoromethyl)phenyl]pyridazin-4(1H)-one (2.70 g, 8 mmol) and NH2NH2.H2O (1.94 mL, 40 mmol) in MeOH (25 mL) was refluxed overnight. After cooling to room temperature, the reaction mixture was poured into 1 M HCl aqueous solution and extracted with AcOEt. The extract was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography eluting with AcOEt and recrystallized from AcOEt to give the title compound (0.969 g, 40% yield) as an off-white solid: mp 192-194° C.; 1H NMR (300 MHz, CDCl3): δ ppm 6.82 (1H, d, J=7.9 Hz), 7.03 (1H, d, J=1.9 Hz), 7.69 (1H, d, J=1.9 Hz), 7.72-7.76 (2H, m), 7.83-7.89 (1H, m), 7.91-7.93 (1H, m), 8.33 (1H, d, J=7.9 Hz), 12.85 (1H, brs). LC-MS (ESI) m/z 307 [M+H]+. Anal. Calcd for C14H9F3N4O: C, 54.91; H, 2.96; N, 18.29. Found: C, 54.92; H, 2.99; N, 18.33.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH2:3][CH2:2]1.N1C=CC=CC=1.[Cl:12][C:13]([Cl:18])([Cl:17])[C:14](Cl)=[O:15].Cl>CCCCCCC>[Cl:12][C:13]([Cl:18])([Cl:17])[C:14]([C:3]1[CH2:4][CH2:5][O:1][CH:2]=1)=[O:15]
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: C1=COCC1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCCCCCC
Product: O=C(C1=COCC1)C(Cl)(Cl)Cl
Temperature: 10 °C
Reaction time: 0.75 h

Procedure:
To a nitrogen-purged, 5000-mL, three-neck, round-bottom flask equipped with a bottom stopcock, thermometer, mechanical stirrer, addition funnel and ice bath was charged 330.0 g (4.70 moles) of 2,3-dihydrofuran, 391 g (4.95 moles) of pyridine, and 1000 mL of n-heptane. The mixture was cooled to 10° C. then trichloroacetyl chloride (500 mL, 815 g, 4.48 moles) was added dropwise from the addition funnel. An ice bath was used to hold the reaction mixture at 11 to 220° C. during the 190 minute addition. The resulting yellow slurry was stirred at 22 to 28° C. for 45 minutes. To the mixture was added 700 mL of 10% aqueous HCl. After stirring to dissolve the solids, the lower (aqueous) layer was separated and discarded. The organic layer was washed sequentially with 500 mL of 10% HCl, 250 mL of 5% aqueous sodium bicarbonate and finally with 250 mL of water. The solution was placed in a 3000-mL, three-neck, round-bottom flask equipped with a magnetic stirrer, thermowell/thermocouple, heating mantle, and 12-inch Vigreux distillation head. The mixture was heated under vacuum (130 mm) to distill off the water/heptane azeotrope then most of the heptane. The mixture was distilled to a pot temperature of 102° C. (head temperature was 50° C.). A total of 1135 mL of distillate was collected. The resulting crude 2,3-dihydro-4-trichloroacetylfuran (881.38 g, theory 965.26 g) was 98.4% assay by nuclear magnetic resonance (NMR) (89.8% assay-yield). The crude product was used directly in the following example.
Reaction SMILES: [C:1]([C:9]1[S:13][C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=2[C:10]=1[OH:18])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)(Cl)Cl.[CH3:25][NH:26][CH3:27]>>[CH3:25][N:26](/[C:1](/[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[C:9]1\[C:10](=[O:18])[C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=2[S:13]\1)[CH3:27]
Reactant: O=C(c1ccccc1)c1sc2ccccc2c1O
Reactant: CNC
Agent: ClP(Cl)(Cl)(Cl)Cl
Product: CN(C)/C(=C1/Sc2ccccc2C1=O)c1ccccc1
Yield: 7 %

Procedure:
Prepared as in Example 1 from 2-benzoyl-benzo[b]thiophen-3-ol, phosphorus(V) chloride and 40% aqueous dimethylamine solution with a yield of 7% of theory.
Reaction SMILES: [NH2:1][NH2:2].[O:3]1[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][C:11]([O:13]C)=O)[CH2:5][CH2:4]1>>[N:6]1([CH2:9][CH2:10][C:11]([NH:1][NH2:2])=[O:13])[CH2:7][CH2:8][O:3][CH2:4][CH2:5]1
Reactant: COC(=O)CCN1CCOCC1
Reactant: NN
Product: NNC(=O)CCN1CCOCC1
Reaction time: 16 h
Yield: 61.4 %

Procedure:
Hydrazine (64.1 g, 2 mol) was added dropwise, over 8-10 min, to methyl 3-morpholinopropionate (35 g, 0.202 mol) and the reaction mixture was refluxed for 16 h. The excess hydrazine was removed under reduced pressure and the material was dried in vacuo at room temperature for 16 h to give the crude product as an oil. The 1H NMR showed the presence of hydrazine, so the crude material was dried using a lyophilizer. Then the oil was refluxed in benzene/water (using a Dean-Stark distilling receiver). The benzene was then removed under reduced pressure, and the product was triturated with petroleum ether. After sitting in petroleum ether at room temperature for 16 h, the oil solidified. The petroleum ether was decanted and the solid was dried under house vacuum at room temperature to give the desired product (21.5 g, 61.4%), which was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24]O)=[CH:18][CH:17]=1.C1C=CC=CC=1.P(Br)(Br)[Br:33]>O>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24][Br:33])=[CH:18][CH:17]=1
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(CCCO)cc1
Reactant: BrP(Br)Br
Solvent: c1ccccc1
Solvent: O
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc(CCCBr)cc1
Temperature: 70 °C
Reaction time: 2 h
Yield: 31.8 %

Procedure:
To a mixture of 3-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]phenyl]propan-1-ol (2.6 g) and benzene (50 ml) was added phosphorus tribromide (PBr3) (2.1 g), which was stirred for 2 hours at 70° C. The reaction mixture was poured into water, which was subjected to extraction with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO4), then the solvent was distilled off to leave 3-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]phenyl]propyl bromide (0.98 g, 32%), which was recrystallized from ethyl acetate--hexane to give colorless needles, m.p.78°-79° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]([N+:9]#[C-:10])[CH2:7][CH3:8].[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH:18]=[C:19]([O:23][CH3:24])[C:20]=1[O:21][CH3:22])[CH2:16]Cl>>[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH:18]=[C:19]([O:23][CH3:24])[C:20]=1[O:21][CH3:22])[CH2:16][C:6]([N+:9]#[C-:10])([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)[CH2:7][CH3:8]
Reactant: [C-]#[N+]C(CC)c1cccs1
Reactant: COc1cc(CCl)cc(OC)c1OC
Product: [C-]#[N+]C(CC)(Cc1cc(OC)c(OC)c(OC)c1)c1cccs1
Yield: 67.5 %

Procedure:
2.5 g of 1-(2-thienyl)propyl isocyanide and 4.4 g of 3,4,5-trimethoxybenzyl chloride are treated in the same manner as described in Example 1-(1) to give 3.7 g of 1-(3,4,5-trimethoxybenzyl)-1-(2-thienyl)propyl isocyanide as a colorless oil. yield; 67.5%