Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH2:15])[C:3]=1[CH3:22].[CH3:23][C:24]1([CH3:39])[C:28]2=[N:29][CH:30]=[C:31]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)[CH:32]=[C:27]2[NH:26][CH2:25]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.CC(C)([O-])C.[Na+]>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].C1(C)C=CC=CC=1>[CH3:23][C:24]1([CH3:39])[C:28]2=[N:29][CH:30]=[C:31]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)[CH:32]=[C:27]2[N:26]([C:2]2[C:11]3[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=3[F:12])[N:5]=[C:4]([C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH2:15])[C:3]=2[CH3:22])[CH2:25]1
Reactant: CC1(C)CNc2cc(N3CCOCC3)cnc21
Reactant: C=C(c1ccccc1)c1nc2cc(F)cc(F)c2c(Cl)c1C
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: C=C(c1ccccc1)c1nc2cc(F)cc(F)c2c(N2CC(C)(C)c3ncc(N4CCOCC4)cc32)c1C

Procedure:
4-Chloro-5,7-difluoro-3-methyl-2-(1-phenylvinyl)quinoline (80 mg, 0.253 mmol), 4-(3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)morpholine (59.1 mg, 0.253 mmol), Pd2dba3 (23.2 mg, 0.025 mmol), 2-(dicyclohexylphosphino)-2′,4′,6′-tri-i-propyl-1,1′-biphenyl (24.2 mg, 0.051 mmol), sodium tert-butoxide (73.0 mg, 0.760 mmol), and toluene (2.53 mL) were stirred at 105° C. for 2 h. The reaction mixture was then concentrated and the resulting residue partitioned between EtOAc and saturated aqueous sodium bicarbonate solution. The organic layer was washed with brine and water, then dried (MgSO4) and concentrated. Purification by flash chromatography eluting with a gradient of 0-65% hexane in EtOAc gave 4-(3,3-dimethyl-6-(4-morpholinyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-5,7-difluoro-3-methyl-2-(1-phenylethenyl)quinoline. 1H NMR (400 MHz, chloroform-d) δ ppm 7.72 (1H, m), 7.53 (1H, m), 7.28-7.33 (5H, m), 7.01 (1H, m), 6.02 (1H, d, J=0.8 Hz), 5.63 (1H, br. s.), 5.61 (1H, d, J=1.0 Hz), 3.87 (1H, m), 3.71-3.79 (4H, m), 3.61 (1H, m), 2.96 (4H, d, J=0.8 Hz), 2.02 (3H, s), 1.55 (6H, m). Mass Spectrum (ESI) m/e=513.2 (M+1).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].C(N(CC)CC)C.[C:22]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])(=[O:25])[NH:23][NH2:24]>C(Cl)Cl>[N+:12]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:2]=1[NH:24][NH:23][C:22]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[CH:10][CH:9]=[CH:8][CH:7]=2)([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Reactant: CC(C)(C)OC(=O)NN
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NNc1c([N+](=O)[O-])cnc2ccccc12
Reaction time: 2.5 h
Yield: 68.1 %

Procedure:
A solution of 4-chloro-3-nitroquinoline (5.00 g, 24.0 mmol) in 120 mL of anhydrous CH2Cl2 was treated with triethylamine (6.7 mL, 48.2 mmol) and tert-butyl carbazate (3.20 g, 24.2 mmol). After stirring under nitrogen for 2.5 hour (h), an additional portion of tert-butyl carbazate (3.2 g, 24.2 mmol) was added. After stirring overnight, the deep red solution was washed with H2O (2×) and brine. The organic portion was dried over Na2SO4 and concentrated to give a red foam. The material was passed through a SiO2 column eluting with 2.5% methanol/CH2Cl2. The resulting red powder was treated with 5:1 hexanes/CH2Cl2 and filtered. The solid was washed several times with hexanes and was dried under vacuum to give tert-butyl N′-(3-nitroquinolin-4-yl)hydrazinecarboxylate (4.97 g) as an orange powder.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.[C:22](Cl)(=[O:24])[CH3:23].C(N(CC)CC)C>ClCCl>[C:22]([N:1]1[CH2:2][CH2:3][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:5][CH2:6]1)(=[O:24])[CH3:23]
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CCC2(CC1)CSC1=C(O2)c2ccccc2C(=O)C1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 57.4 %

Procedure:
A mixture of spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione (0.5 g, 1.66 mmol), acetyl chloride (0.118 ml, 1.67 mmol), triethylamine (1.2 ml, 8.61 mmol), and dichloromethane (50 ml) was stirred for three hours at room temperature. The reaction mixture was washed with 50 ml water. The organic extract was dried with Na2SO4 and concentrated under reduced pressure. The crude product was purified by flash column chromatography (SiO2, 5% EtOAc in dichloromethane) to afford the product as a purple solid (0.327 g, 57%). M.p.=252-255° C.; 400 MHz 1H NMR (CDCl3) δ: 8.09-8.06 (m, 1H), 7.75-7.72 (m, 1H), 7.69-7.64 (m, 1H), 7.54-7.48 (m, 1H), 4.59-4.52 (m, 1H), 3.82-3.68 (m, 1H), 3.55-3.46 (m, 1H), 3.22-3.12 (m, 1H), 3.0-2.91 (m, 2H), 2.26-2.18 (m, 2H), 2.18 (s, 3H), 1.82-1.72 (m, 2H); LCMS: 344 [M+H].
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.N12CCN(CC1)CC2.[CH3:17][N:18]([CH3:22])[C:19](Cl)=[S:20].O>CN(C=O)C>[CH3:17][N:18]([CH3:22])[C:19](=[S:20])[O:8][C:5]1[CH:6]=[CH:7][C:2]([I:1])=[CH:3][CH:4]=1
Reactant: CN(C)C(=S)Cl
Reactant: Oc1ccc(I)cc1
Agent: C1CN2CCN1CC2
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)C(=S)Oc1ccc(I)cc1
Temperature: 75 °C
Reaction time: 3.5 h
Yield: 95.8 %

Procedure:
To a stirred solution of p-iodophenol (20.0 g, 90.9 mmol) in DMF (200 mL) was added 1,4-diazabicyclo[2,2,2]octane (20.4 g, 181.8 mmol) and dimethylthiocarbamoyl chloride (16.9 g, 136.4 mmol). The resulting solution was stirred for 3.5 hr at 75° C. After cooling, 300 mL of water was added. The solid was collected with suction and was dissolved in EtOAc. The EtOAc layer was washed with water, dried over Na2SO4, and evaporated under a reduced pressure. The crude solid was recrystallized from H2O to give the 26.75 g (96%) O-p-iodophenyl dimethylthiocarbamate as a pale a yellow crystalline powder. IR (KBr) 1479, 1207, 827 cm−1; 1H-NMR (400 MHz, CDCl3) δ 3.37 (s, 3H), 3.45 (s, 3H), 6.83 (d, J=8.8 Hz, 2H), 7.69 (d, J=8.3 Hz, 2H); MS (FAB) m/z 307 (M++1); Anal. Calcd for C9H10INOS: C, 35.19; H, 3.28; N, 4.56. Found: C, 35.17; H, 3.35; N, 4.44.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[CH:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=2)=[CH:4][CH:3]=1.O.[O-]S(C(F)(F)F)(=O)=O.[Yb+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O.[CH:45](=[O:49])[CH:46]([CH3:48])[CH3:47].O>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][CH:7]=1)[NH:8][CH:9]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=1)[C:46]([CH3:48])([CH3:47])[CH:45]2[OH:49]
Reactant: CC(C)C=O
Reactant: O=[N+]([O-])c1cccc(C=Nc2ccc(Cl)cc2)c1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)C(O)c2cc(Cl)ccc2NC1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.4 %

Procedure:
To a mixture of (4-chloro-phenyl)-(3-nitro-benzylidene)-amine (12 g, 46 mmol) and ytterbium(III) triflate hydrate (2.85 g, 4.6 mmol) in dry tetrahydrofuran (100 mL) at 25° C. was added isobutyraldehyde (4.64 mL, 51 mmol) and water (0.83 mL, 46 mmol) dropwise. The reaction mixture was stirred at 25° C. for 3 h. Then the reaction mixture was concentrated in vacuo and the residue was extracted with ethyl acetate (2×200 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 6-chloro-3,3-dimethyl-2-(3-nitro-phenyl)-1,2,3,4-tetrahydro-quinolin-4-ol (14.3 g, 93%) as a light yellow oil: LC/MS m/e calcd for C17H17ClN2O3 (M+H)+: 333.79, observed: 315.0.
Reaction SMILES: [C:1]1(=[O:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][NH:3][NH:2]1.[CH2:12]([N:19]1C(=O)O[C:22](=[O:23])[C:21]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:20]12)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:12]([NH:19][C:20]1[CH:30]=[CH:29][CH:28]=[CH:27][C:21]=1[C:22]([N:3]1[CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:1](=[O:11])[NH:2]1)=[O:23])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=c1oc(=O)n(Cc2ccccc2)c2ccccc12
Reactant: O=C1NNCc2ccccc21
Product: O=C1NN(C(=O)c2ccccc2NCc2ccccc2)Cc2ccccc21

Procedure:
3,4-Dihydrophthalazin-1(2H)-one was reacted with N-benzylisatoic anhydride according to the general procedure above to produce 3-(o-benzylaminobenzoyl)-3,4-dihydrophthalazin-1(2H)-one as a colorless solid, mp 206°-208° C.
Reaction SMILES: C(OC(=O)[NH:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23](=[O:31])[NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:17][CH:16]=1)C1C=CC=CC=1.C(O)(=O)C>C(O)C.C1COCC1.[Pd]>[NH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]([NH:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:31])=[CH:17][CH:16]=1
Reactant: O=C(COc1ccc(CCCCNC(=O)OCc2ccccc2)cc1)Nc1ccccc1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CCO
Product: NCCCCc1ccc(OCC(=O)Nc2ccccc2)cc1
Yield: 97.1 %

Procedure:
A solution of [4-(4-phenylcarbamoylmethoxyphenyl)butyl]carbamic acid benzyl ester 18 (0.30 g, 0.69 mmol) in ethanol (10 mL), THF (6 mL), and acetic acid (2 mL) was stirred at room temperature for 2 h under hydrogen atmosphere in the presence of 10% Pd/C catalyst (0.2 g, 50% wet). The catalyst was removed by suction filtration and the filtrate was concentrated in vacuo. The residue was purified by flash silica gel column chromatography eluting with CH2Cl2/methanol/concentrated ammonium hydroxide (30:1:0, 30:1:0.3, v/v) to give the desired amine 19 as a white solid (200 mg, 97% yield). 1H NMR (300 MHz, CD3OD) δ 1.60 (m, 4H), 2.55 (m, 2H), 2.70 (m, 2H), 4.60 (s, 2H), 6.88 (d, 2H), 7.15 (m, 3H), 7.35 (m, 2H), 7.58 (d, 2H), 8.25 (s, 1H). m/z (ESI): 299 [C18H22N2O2+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[O-]CC.[Na+].CS(C)=O.[CH2:17](Cl)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(O)C>[Cl:1][C:2]1[C:7]([O:8][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Oc1cccnc1Cl
Reactant: ClCc1ccccc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CS(C)=O
Product: Clc1ncccc1OCc1ccccc1

Procedure:
2-Chloro-3-hydroxypyridine (9.47 g; 0.073 moles) was added to a solution of sodium ethoxide in ethanol (from sodium, 1.67 g; 0.073 g. atom). Sufficient dimethyl sulphoxide was added to dissolve all of the solid, and ethanol was removed in vacuo. To the resulting solution was added benzyl chloride (9.3 g; 0.073 moles) with cooling and stirring, and the reaction mixture was left to stir under reflux for 6 hours. Unreacted benzyl chloride, and solvent, were evaporated off under vacuum on a boiling water bath, and the residue was treated with water to precipitate out an oil which was extracted with chloroform, washed with N sodium hydroxide solution and dried over anhydrous magnesium sulfate. After removing the solvent, 2-chloro-3-benzyloxypyridine was obtained as a solid (11.63 g, mp 36°-8°).
Reaction SMILES: [ClH:1].[CH3:2][NH:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].S(=O)(=O)(O)O.[CH2:15](O)[CH3:16]>>[ClH:1].[CH3:2][NH:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH2:15][CH3:16])=[O:8]
Reactant: CNCCCC(=O)O
Reactant: CCO
Agent: Cl
Agent: O=S(=O)(O)O
Product: CCOC(=O)CCCNC
Temperature: 90 °C
Reaction time: 1 h

Procedure:
2.00 g (13.0 mmol) of 4-(methylamino)butanoic acid hydrochloride was dissolved in 40 mL of ethanol and 69 μL (1.30 mmol) of concentrated sulfuric acid was added thereto, followed by stirring of the mixture at 90° C. for 1 hour. The solvent was distilled off under reduced pressure, followed by azeotropy with toluene. 3.02 g of the obtained residue was used for the subsequent reaction as such.
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][CH2:9][OH:10].[H-].[Na+].Cl[C:14]1[N:19]=[CH:18][C:17]([C:20]2[O:21][CH2:22][C:23]([CH2:26][OH:27])([CH3:25])[N:24]=2)=[CH:16][CH:15]=1>CN(C=O)C.C(OCC)(=O)C>[CH3:25][C:23]1([CH2:26][OH:27])[CH2:22][O:21][C:20]([C:17]2[CH:18]=[N:19][C:14]([O:10][CH2:9][CH2:8][CH2:7][N:3]3[CH2:4][CH2:5][CH2:6][CH:2]3[CH3:1])=[CH:15][CH:16]=2)=[N:24]1
Reactant: CC1CCCN1CCCO
Reactant: CC1(CO)COC(c2ccc(Cl)nc2)=N1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC1CCCN1CCCOc1ccc(C2=NC(C)(CO)CO2)cn1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 80 %

Procedure:
A solution of 3-(2-methylpyrrolidin-1-yl)propan-1-ol (1.9 g, 13.4 mmol) in dry DMF (40 ml) is treated at 0° C. with sodium hydride (60% dispersion in mineral oil, 536 mg, 13.4 mmol) and stirred 15 minutes at 0° C. Then, a solution of [2-(6-chloropyridin-3-yl)-4-methyl-4,5-dihydro-1,3-oxazol-4-yl]methanol ax55 (1.8 g, 7.9 mmol) in dry DMF (40 ml) is added dropwise over 15 minutes and the resulting mixture is stirred at room temperature for 1 day. The mixture is then poured into ice-cold water (250 ml) and extracted with ethyl acetate (4×50 ml). The organic layers are combined, dried over sodium sulfate and concentrated. The residue is dried under high-vacuum with heating to leave a solid. This solid is taken up in ethyl acetate, washed with brine and filtered. After phase separation, the aqueous layer is extracted twice with ethyl acetate, the combined organic phases are washed three times with water, dried over magnesium sulfate and concentrated to afford 1.4 g of 80% pure (4-methyl-2-{6-[3-(2-methylpyrrolidin-1-yl)propoxy]pyridin-3-yl}-4,5-dihydro-1,3-oxazol-4-yl)methanol ax56.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][N:9]=[C:10]([C:12]2[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:19])[NH2:11])=[CH:4][CH:3]=1.C(Cl)(Cl)Cl.[S:24](Cl)(Cl)=[O:25]>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[N:9]=[C:10]([C:12]3[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:19])[NH:11][S:24]2=[O:25])=[CH:6][CH:7]=1
Reactant: NC(=NNc1ccc(Br)cc1)c1c(F)cccc1Cl
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: O=S1NC(c2c(F)cccc2Cl)=NN1c1ccc(Br)cc1

Procedure:
The title compound was prepared according to the procedure described in step-4 of Intermediate-1 using N′-(4-bromophenyl)-2-chloro-6-fluorobenzenecarbohydrazonamide (step-3 of Intermediate-1, 0.100 g, 0.292 mmol), CHCl3 (10 mL), pyridine (2.0 mL) and thionyl chloride (1.0 mL). The obtained product was purified with column chromatography on silica gel eluting with 0.5% MeOH:DCM to afford 0.050 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 7.45 (t, J=6.9 Hz, 3H), 7.51-7.68 (m, 4H), 12.05 (br s, 1H); MS (m/z): 388.02 (M)−.
Reaction SMILES: C([O:3][P:4]([CH2:9][CH2:10][N:11]1[CH2:19][CH2:18][CH2:17][NH:16][C:15]2[C:14](=[O:20])[C:13](=[O:21])[C:12]1=2)(=[O:8])[O:5]CC)C.O>C(Cl)Cl>[O:20]=[C:14]1[C:13](=[O:21])[C:12]2[N:11]([CH2:10][CH2:9][P:4](=[O:3])([OH:5])[OH:8])[CH2:19][CH2:18][CH2:17][NH:16][C:15]1=2
Reactant: CCOP(=O)(CCN1CCCNc2c1c(=O)c2=O)OCC
Solvent: ClCCl
Solvent: O
Product: O=c1c2c(c1=O)N(CCP(=O)(O)O)CCCN2
Reaction time: 15 h
Yield: 64.7 %

Procedure:
Under N2 bromotrimethylsilane (83 mL, 96.3 g, 0.63 mole; Aldrich 19,440-9) was added dropwise at a fast rate to a solution of [2-(8,9-dioxo-2.6-diazabicyclo[5.2.0]non-1(7)-en-2-yl)ethyl]phosphonic acid diethyl ester (37.6 g, 0.12 mole) in methylene chloride (350 mL). The reaction mixture was kept in a water bath at approximately 20° C. for 15 hr. The clear solution was concentrated in vacuo and the foamy residue was taken up in acetone (600 mL) with vigorous shaking to result in a thin suspension. Water (50 mL, 2.78 moles) was added to give a gummy precipitate which solidified instantly. The suspension was shaken vigorously for 10 minutes, filtered and washed with acetone to give a yellow solid compound. The solids were taken up in boiling water (450 mL) and the hot solution was filtered through a fluted filter paper to remove a small amount of insoluble material. The clear aqueous solution was cooled in ice and crystallization began at once. The thick crystalline mass was diluted by slow addition of acetone (800 mL), kept cold for 1 hr, filtered and washed with acetone and then hexane to give the title compound as a pale yellow solid (20.2 g). A second crop from the mother liquor (100% purity by LC) yielded an additional amount (6.5 g) for a total yield of 87%. NMR (DMSO-d6, 400 Mhz): 1.90 (m, 4H), 3.25 (m, 2H), 3.36 (m, 2H), 3.84 (q, 2H), 8.45 (s, 1H). LC analysis: (Column: Nova Pak C18, 300×3.9 mm; Eluent: 20/80 MeOH/0.005 M Pic A; Flowrate: 1 mL/min; UV detectors at 210 nm). Analysis: Calc'd. for C9H13N2O5P.0.1H2O: C, 41.26; H, 5.08; N, 10.69%;
Reaction SMILES: [N+:1]([CH2:3][C:4]([O:6][CH3:7])=[O:5])#[C-:2].C(N(CC)CC)C.[O:15]=[CH:16][C:17]([Cl:20])([Cl:19])[Cl:18].C(O)(=O)C>C1C=CC=CC=1>[CH3:7][O:6][C:4]([C@H:3]1[C@H:16]([C:17]([Cl:20])([Cl:19])[Cl:18])[O:15][CH:2]=[N:1]1)=[O:5]
Reactant: [C-]#[N+]CC(=O)OC
Reactant: O=CC(Cl)(Cl)Cl
Solvent: CC(=O)O
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H]1N=CO[C@H]1C(Cl)(Cl)Cl
Yield: 85.7 %

Procedure:
5.0 g of methyl α-isocyanoacetate and 5.0 g of triethylamine are dissolved in 40 ml of benzene. 7.4 g of chloral are added to the solution at 0° C under stirring. The mixture is stirred at room temperature for 4 hours. Then, the mixture is neutralized with acetic acid, and evaporated under reduced pressure to remove solvent. The residue is dissolved in 50 ml of ethyl acetate. The solution is washed with water, dried, and then evaporated under reduced pressure to remove ethyl acetate. The residue thus obtained is distilled under reduced pressure. 10.6 g of trans-4-methoxycarbonyl-5-trichloromethyl-2-oxazoline are obtained. Yield: 85% B.p. 95° C/1 mmHg
Reaction SMILES: Cl[CH2:2][C:3]1[CH:13]=[CH:12][C:6]2[N:7]=[C:8]([S:10][CH3:11])[S:9][C:5]=2[CH:4]=1.[NH:14]1[CH:18]=[C:17]([C:19]([O:21][CH3:22])=[O:20])[N:16]=[CH:15]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:11][S:10][C:8]1[S:9][C:5]2[CH:4]=[C:3]([CH2:2][N:14]3[CH:18]=[C:17]([C:19]([O:21][CH3:22])=[O:20])[N:16]=[CH:15]3)[CH:13]=[CH:12][C:6]=2[N:7]=1
Reactant: COC(=O)c1c[nH]cn1
Reactant: CSc1nc2ccc(CCl)cc2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cn(Cc2ccc3nc(SC)sc3c2)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 18.5 %

Procedure:
To a stirred mixture of 6-(chloromethyl)-2-(methylthio)benzo[d]thiazole (500 mg, 2.2 mmol) from Example 36 and methyl 4-imidazole carboxylate (400 mg, 3.3 mmol) in DMF (15 mL) was added K2CO3 (0.9 g, 6.5 mmol). After the mixture was stirred for 3 h at rt, it was partitioned between EtOAc (100 mL) and water (50 mL). The EtOAc layer was separated and washed with water (50 mL) and brine (50 mL), then dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with 2% MeOH in CH2Cl2 to afford methyl 1-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)-1H-imidazole-4-carboxylate (130 mg, 19%) as a white solid. The regiochemistry of the alkylation was determined by 2-dimensional nuclear Overhauser effect (NOE) experiment. 1H NMR (300 MHz, DMSO-d6) δ 8.01 (d, J=0.9 Hz, 1H), 7.98 (d, J=1.1 Hz, 1H), 7.93 (d, J=0.9 Hz, 1H), 7.84 (d, J=8.3 Hz, 1H), 7.43 (dd, J=1.7, 8.3 Hz, 1H), 5.35 (s, 2H), 3.72 (s, 3H), 2.78 (s, 3H). LCMS (ESI) m/z 322 (M+H)+.
Reaction SMILES: [NH2:1][CH:2]([C:10]1[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=1[O:18][CH3:19])[CH2:3][CH2:4][CH2:5][C:6]([O:8]C)=O.[N:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=2)[CH:29]=O)=[CH:22][CH:21]=1>>[CH3:19][O:18][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([O:16][CH3:17])[C:10]=1[CH:2]1[N:1]([CH2:29][C:28]2[CH:31]=[CH:32][CH:33]=[C:26]([C:23]3[CH:22]=[CH:21][N:20]=[CH:25][CH:24]=3)[CH:27]=2)[C:6](=[O:8])[CH2:5][CH2:4][CH2:3]1
Reactant: O=Cc1cccc(-c2ccncc2)c1
Reactant: COC(=O)CCCC(N)c1c(OC)cccc1OC
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1cccc(-c2ccncc2)c1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 5-amino-5-(2,6-dimethoxyphenyl)pentanoate with commercially available 3-(pyridin-4-yl)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.59 min.; [M+H]+: 403.35 g/mol.
Reaction SMILES: [SH:1][CH2:2][CH:3]([OH:6])[CH2:4][OH:5].[OH-].[K+].Br[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>C(O)C>[CH2:25]([S:1][CH2:2][CH:3]([CH2:4][OH:5])[OH:6])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH3:10]
Reactant: OCC(O)CS
Reactant: CCCCCCCCCCCCCCCCBr
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCCCCCCCCCCCSCC(O)CO
Reaction time: 24 h
Yield: 950.8 %

Procedure:
To a stirred solution of 40.0 grams (0.037 mole) 3-mercapto-1,2-propanediol in 300 milliliters of 95% ethanol, 24.9 grams (0.44 mole) of KOH was added under an inert atmosphere of nitrogen. Then, a solution of 135.0 grams (0.44 mole) bromohexadecane in 100 milliliters of 95% ethanol was added dropwise over a one-hour period, and the reaction allowed to proceed at room temperature with vigorous stirring for 24 hours. The precipitate was filtered, taken up in one liter of boiling methanol and cooled to 0° Centigrade for twelve hours. The precipitate was filtered and allowed to air dry, producing 117 grams (95%) of product (mp 72°-74° Centigrade).
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[CH:7]=[C:8]([C:23]2[CH:24]([CH3:30])[CH2:25][C:26](=[O:29])[NH:27][N:28]=2)[CH:9]=[CH:10][C:11]=1[N:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+].[ClH:37]>O.[Cu]Cl>[Cl:37][C:6]1[CH:7]=[C:8]([C:23]2[CH:24]([CH3:30])[CH2:25][C:26](=[O:29])[NH:27][N:28]=2)[CH:9]=[CH:10][C:11]=1[N:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14][CH2:13]1
Reactant: Cl
Reactant: CCOC(=O)N1CCN(c2ccc(C3=NNC(=O)CC3C)cc2N)CC1
Agent: Cl[Cu]
Agent: O=C([O-])[O-]
Agent: O=N[O-]
Solvent: O
Product: CCOC(=O)N1CCN(c2ccc(C3=NNC(=O)CC3C)cc2Cl)CC1
Temperature: 50 °C
Yield: 38 %

Procedure:
An ice cold solution of 0.9 g (8.5 mmol) of sodium nitrite in 5 ml of water is added dropwise over a period of 10 minutes to a solution of 3.0 g (8.3 mmol) of 6-[3-amino-4-(4-ethoxycarbonylpiperazin-1-yl)-phenyl]-4,5-dihydro-5-methyl-3(2H)-pyridazinone in 7 ml of conc. hydrochloric acid and 3 ml of water at -5° C. The resulting reaction mixture is then added to a solution of 1.29 g (13 mmol) of copper-(I) chloride in 5 ml of conc. hydrochloric acid which is at 0° C. When evolution of gas has ceased, the solution is slowly heated to 50° C. and then cooled and adjusted to pH 11 with potassium carbonate. The aqueous phase is extracted three times with 50 ml of dichloromethane and the organic phases are dried, filtered and concentrated by evaporation under vacuum. The residue obtained is chromatographed on silica gel with dichloromethane/methanol (95:5) and after concentration of the lipophilic main fraction under vacuum it yields 1.2 g (38%) of a colourless solid, m.p. 154°-156° C.