Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6](=[O:24])[CH:7]([O:19][CH2:20][CH2:21][CH2:22][CH3:23])[NH:8][C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])CCC.CO.C(=O)(O)[O-].[Na+].C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C>O>[CH2:12]([O:11][C:9]([NH:8][CH:7]([O:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:6]([OH:24])=[O:5])=[O:10])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CCCCOC(=O)C(NC(=O)OCc1ccccc1)OCCCC
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: CCCCOC(NC(=O)OCc1ccccc1)C(=O)O

Procedure:
A solution of 0.002 mol. of N-benzyloxycarbonyl-2-n-butoxyglycine n-butyl ester is stirred with 10 ml. of methanol and 10 ml. of 5% aqueous sodium bicarbonate-sodium carbonate solution for five hours at 25°. The reaction mixture is then diluted with water and shaken with ethyl acetate. The layers are separated and the aqueous layer is acidified to pH 2.0 and extracted with ethyl acetate containing 10% ethanol. The extracts are dried (Na2SO4) and concentrated in vacuo to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:7]=[C:8]=[S:9])=[CH:4][S:5][CH:6]=1.[NH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[NH2:17]>>[NH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[NH:17][C:8]([NH:7][C:3]1[C:2]([CH3:1])=[CH:6][S:5][CH:4]=1)=[S:9]
Reactant: Nc1ccccc1N
Reactant: Cc1cscc1N=C=S
Product: Cc1cscc1NC(=S)Nc1ccccc1N

Procedure:
is obtained analogously to the reaction described in example 1 b) from 4-methyl-3-thienyl isothiocyanate and 1,2-diaminobenzene. Crystalline solid having a 1st m.p. of 177-182° C., followed by another crystallization and 2nd m.p. 285-290° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH3:14])[N:11]=[C:10]([N:15]3[CH:19]=[C:18]([Sn](CCCC)(CCCC)CCCC)[N:17]=[CH:16]3)[N:9]=2)=[CH:4][C:3]=1[CH3:33].[CH3:34][C:35]([NH:38][S:39]([C:42]1[S:46][C:45](Br)=[CH:44][CH:43]=1)(=[O:41])=[O:40])([CH3:37])[CH3:36].CCCCCCC>C1(C)C=CC=CC=1>[C:35]([NH:38][S:39]([C:42]1[S:46][C:45]([C:18]2[N:17]=[CH:16][N:15]([C:10]3[N:9]=[C:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([CH3:33])[CH:4]=4)[CH:13]=[C:12]([CH3:14])[N:11]=3)[CH:19]=2)=[CH:44][CH:43]=1)(=[O:40])=[O:41])([CH3:37])([CH3:34])[CH3:36]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn(-c2nc(C)cc(-c3ccc(Cl)c(C)c3)n2)cn1
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(Br)s1
Solvent: Cc1ccccc1
Solvent: CCCCCCC
Product: Cc1cc(-c2ccc(Cl)c(C)c2)nc(-n2cnc(-c3ccc(S(=O)(=O)NC(C)(C)C)s3)c2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 104.4 %

Procedure:
A stirred mixture of 4-(4-chloro-3-methyl-phenyl)-6-methyl-2-(4-tributylstannanyl-imidazol-1-yl)-pyrimidine (Example G.8) (0.59 g, 1.03 mmol), commercially available 5-bromothiophene-2-N-tert-butylsulfonamide (0.34 g, 1.13 mmol), tetrakis(triphenyl-phosphine)palladium (0.071 g, 0.062 mmol) in toluene (8 ml) was heated under reflux conditions for 15 h, heptane (10 ml) was added and the mixture was stirred at RT for 1 h. The precipitate was collected by filtration and dried to yield 5-{1-[4-(4-chloro-3-methyl-phenyl)-6-methyl-pyrimidin-2-yl]-1H-imidazol-4-yl}-thiophene-2-sulfonic acid tert-butyl amide (0.54 g) as a white solid.
Reaction SMILES: C[O:2][C:3](=[O:16])[CH2:4][O:5][C:6]1[CH:14]=[CH:13][C:12]([SH:15])=[C:11]2[C:7]=1[CH2:8][CH2:9][CH2:10]2.Cl[CH2:18][C:19]1(F)[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:21][CH2:20]1.OCC1C=CC(O)=CC=1.BrCC1C=C[C:48]([F:51])=CC=1.ClCC1(C(F)(F)F)C=CC(OCC2C=CC=CC=2)=CC1>>[F:51][CH2:48][C:30]1[CH:31]=[CH:32][C:27]([CH2:26][O:25][C:22]2[CH:23]=[CH:24][C:19]([CH2:18][S:15][C:12]3[CH:13]=[CH:14][C:6]([O:5][CH2:4][C:3]([OH:2])=[O:16])=[C:7]4[C:11]=3[CH2:10][CH2:9][CH2:8]4)=[CH:20][CH:21]=2)=[CH:28][CH:29]=1
Reactant: COC(=O)COc1ccc(S)c2c1CCC2
Reactant: Fc1ccc(CBr)cc1
Reactant: FC1(CCl)C=CC(OCc2ccccc2)=CC1
Agent: FC(F)(F)C1(CCl)C=CC(OCc2ccccc2)=CC1
Agent: OCc1ccc(O)cc1
Product: O=C(O)COc1ccc(SCc2ccc(OCc3ccc(CF)cc3)cc2)c2c1CCC2

Procedure:
The title compound was prepared in the manner analogous to Example 1F using 12C and 4-chloromethyl-(4-fluoro-benzyloxy-benzene), prepared from 4-hydroxymethyl-phenol and 1-bromomethyl-4-fluoro-benzene in a manner analagous to Examples 14A and 14B. MS m/z 453 (M+1).
Reaction SMILES: [O:1]1[CH2:13][CH:2]1[CH2:3][O:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[C:7]#[N:8].NCCCC[C:19]1[CH:27]=[C:23]([C:24]([NH2:26])=[O:25])[C:22]([OH:28])=[CH:21][CH:20]=1.[OH2:29]>CS(C)=O>[C:24]([C:23]1[CH:27]=[C:19]([CH:20]=[CH:21][C:22]=1[OH:28])[O:29][CH2:12][CH2:5][CH2:6][CH2:7][NH:8][CH2:13][CH:2]([OH:1])[CH2:3][O:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[C:7]#[N:8])(=[O:25])[NH2:26]
Reactant: NCCCCc1ccc(O)c(C(N)=O)c1
Reactant: N#Cc1ccccc1OCC1CO1
Reactant: O
Solvent: CS(C)=O
Product: N#Cc1ccccc1OCC(O)CNCCCCOc1ccc(O)c(C(N)=O)c1
Reaction time: 1 h

Procedure:
7.3 g of 2-(2,3-epoxypropoxy)benzonitrile are added to a solution of 6.7 g of 5-(4-aminobutyl)salicylamide in 60 ml of dimethyl sulphoxide and the mixture is stirred for 1 hour in a bath at 90°. The reaction mixture is poured into 300 ml of water and extracted twice with 200 ml of ethyl acetate each time. Working up analogously to Example 23 yields crude 1-[4-(3-carbamoyl-4-hydroxyphenoxy)butylamino]-3-(2-cyanophenoxy)propan-2-ol as a viscous oil, the IR- and 1H-NMR-spectra of which are in concordance with the assumed structure and the Rf-value of which is 0,51 according to thin-layer chromatography on silicagel using a mixture of ethylacetate-ethanol-conc. ammonia 24:12:4 as the eluent.
Reaction SMILES: [OH:1][CH:2]([C:4]1[O:5][C:6]([CH3:12])=[CH:7][C:8](=[O:11])[C:9]=1[OH:10])[CH3:3].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[OH:1][CH:2]([C:4]1[O:5][C:6]([CH3:12])=[CH:7][C:8](=[O:11])[C:9]=1[O:10][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:3]
Reactant: Cc1cc(=O)c(O)c(C(C)O)o1
Reactant: BrCc1ccccc1
Product: Cc1cc(=O)c(OCc2ccccc2)c(C(C)O)o1

Procedure:
The title compound was prepared by the method outlined for 2-hydroxymethyl-3-benzyloxy-6-methyl-pyran-4(1 )-one, using 8.5 g (50 mmol, 1 eq.) of 2(1-hydroxyethyl)-3-hydroxy-6-methyl-pyran-4(1H)-one and 9.5 g benzyl bromide (55 mmol, 1.1 eq.) to yield the pure product 10.1 g (77.7%) after recrystallisation from CH2Cl2/Pet. ether 40/60, as a white crystalline solid. m.p 91-92° C.
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[S:10][C:11]([C:14]([OH:16])=O)=[CH:12][N:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[F:18][C:19]1([F:25])[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>ClCCl>[F:18][C:19]1([F:25])[CH2:24][CH2:23][N:22]([C:14]([C:11]2[S:10][C:9]([C:8]#[C:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[N:13][CH:12]=2)=[O:16])[CH2:21][CH2:20]1
Reactant: O=C(O)c1cnc(C#Cc2ccccc2)s1
Reactant: FC1(F)CCNCC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(c1cnc(C#Cc2ccccc2)s1)N1CCC(F)(F)CC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 92.8 %

Procedure:
In a small culture tube, 2-phenylethynyl-thiazole-5-carboxylic acid (28 mg, 0.12 mmol) [Intermediate 1], 4,4-difluoropiperidine hydrochloride (23 mg, 0.14 mmol) (Oakwood Products, Inc. (West Columbia, S.C., USA) and dichloromethane (1.5 mL) were added. To the mixture, PyBOP® (76 mg, 0.14 mmol) was added, followed by N,N-diisopropylethylamine (63 μL, 0.36 mmol), and the reaction was stirred at room temperature for about 17 hours. Afterwards, the crude reaction mixture was directly purified by Preparative TLC, eluting with 40% EtOAc in hexanes to give 37 mg (92%) of the titled compound, (4,4-difluoro-piperidin-1-yl)-(2-phenylethynyl-thiazol-5-yl)-methanone, as a white solid. 1H NMR (300 MHz, CDCl3) δ 7.99 (s, 1H), 7.66-7.59 (m, 2H), 7.49-7.37 (m, 3H), 3.92-3.82 (m, 4H), 2.18-2.01 (m, 4H). LC/MS (Method 3), RT=1.43 min. Calculated [M+H]+=333; Observed [M+H]+=333.
Reaction SMILES: [O:1]=[C:2]1[N:6]2[C:7]3[CH:22]=[CH:21][C:20](Cl)=[N:19][C:8]=3[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:18])=[N:10][CH2:11][C:5]2=[N:4][NH:3]1.[NH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1.O>C(O)(=O)C>[O:1]=[C:2]1[N:6]2[C:7]3[CH:22]=[CH:21][C:20]([N:24]4[CH2:28][CH2:27][CH2:26][CH2:25]4)=[N:19][C:8]=3[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:18])=[N:10][CH2:11][C:5]2=[N:4][NH:3]1
Reactant: C1CCNC1
Reactant: O=c1[nH]nc2n1-c1ccc(Cl)nc1C(c1ccccc1Cl)=NC2
Solvent: CC(=O)O
Solvent: O
Product: O=c1[nH]nc2n1-c1ccc(N3CCCC3)nc1C(c1ccccc1Cl)=NC2

Procedure:
20 grams of 1-keto-6-(o-chlorophenyl)-8-chloro-1,2-dihydro-4H-s-triazolo-(4,3-a)-pyrido-(2,3-f)-(1,4)-diazepine were boiled with 60 ml. of pyrrolidine for 1 hour under reflux. Then the mixture was poured into 1 liter of water and acidified with glacial acetic acid whereupon the reaction product crystallized out. This was dissolved in alcohol, the alcoholic solution concentrated to about 70 ml. and ether added. The crystallized material was recrystallized from methanol. M.P. 228°-230° C.; Yield 8 grams.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:10])[NH2:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1B(O)O)#[N:12].C(N(CC)CC)C>ClCCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:1]([O:5][C:6]([N:8]([CH3:10])[NH:9][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:11]#[N:12])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: N#Cc1ccccc1B(O)O
Reactant: CN(N)C(=O)OC(C)(C)C
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CN(Nc1ccccc1C#N)C(=O)OC(C)(C)C
Temperature: 60 °C
Yield: 29.3 %

Procedure:
A mixture of N-methyl-hydrazinecarboxylic acid tert-butyl ester (Intermediate 1; 890 mg, 6.06 mmol), 2-cyanophenylboronic acid (CombiBlock; 1.00 g, 6.8 mmol), copper(II) acetate (1.25 g, 6.9 mmol) and triethylamine (2 mL, 14.4 mmol) in 1,2-dichloroethane (30 mL) was heated in an oil bath at 60° C. for 3 h. The mixture was allowed to cool, and it was then adsorbed onto silica gel and purified by chromatography using an ISCO 40 g column, eluting with 10-20% ethyl acetate/hexanes, to give N′-(2-cyano-phenyl)-N-methyl-hydrazinecarboxylic acid tert-butyl ester (439 mg, 29%) as a pale yellow oil.
Reaction SMILES: C[O:2][C:3]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[C:4]=1[CH2:5][NH:6][C:7]1[C:8]2[N:9]([C:13]([CH3:17])=[C:14]([CH3:16])[N:15]=2)[CH:10]=[CH:11][CH:12]=1.B(Br)(Br)Br.O>C(Cl)Cl>[OH:2][C:3]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[C:4]=1[CH2:5][NH:6][C:7]1[C:8]2[N:9]([C:13]([CH3:17])=[C:14]([CH3:16])[N:15]=2)[CH:10]=[CH:11][CH:12]=1
Reactant: COc1cccc(C)c1CNc1cccn2c(C)c(C)nc12
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: Cc1cccc(O)c1CNc1cccn2c(C)c(C)nc12
Temperature: -73 °C
Reaction time: 20 h
Yield: 57 %

Procedure:
8-(2-methoxy-6-methylbenzylamino)-2,3-dimethylimidazo[1,2-a]pyridine (0.14 g, 0.48 mmol) was solved in methylene chloride (9 ml) and the mixture was cooled to −73° C. Boron tribromide in methylene chloride (1M) (2.37 ml, 2.37 mmol) was added dropwise and the mixture was stirred for 20 h. in a nitrogen atmosphere and the temperature was allowed to raise to room temperature. The reaction mixture was cooled on ice and ice, water and methylene chloride were added. The organic layer was separated, washed with saturated sodium bicarbonate, dried and evaporated under reduced pressure to give 0.077 g (57%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([CH3:19])[N:8]2[CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:4][CH:3]=1.[Cl-].[Cl-].C([Al+2])C.[CH3:25][C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29]([C:36](Cl)=[O:37])=[CH:28][CH:27]=1>C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:36]([C:29]3[C:30]4[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=4)[C:26]([CH3:25])=[CH:27][CH:28]=3)=[O:37])=[C:7]([CH3:19])[N:8]2[CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(=O)Cl)c2ccccc12
Reactant: Cc1cc2ccc(Cl)cc2n1CCN1CCOCC1
Agent: CC[Al+2]
Agent: [Cl-]
Solvent: ClCCl
Product: Cc1ccc(C(=O)c2c(C)n(CCN3CCOCC3)c3cc(Cl)ccc23)c2ccccc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-(2-(6-chloro-2-methyl-1H-indol-1-yl)ethyl)morpholine (48 mg, 0.17 mmol) in 0.5 mL CH2Cl2 at 0° C. was added dropwise ethyl aluminum dichloride (0.14 mL, 0.26 mmol, 1.8 M in toluene). The reaction mixture was stirred at 0° C. for 30 min, then a solution of 4-methyl-1-naphthoyl chloride (43 mg, 0.21 mmol) in 0.5 mL CH2Cl2 was added and stirred at 0° C. for 1 h, then allowed to slowly warm to room temperature overnight. The reaction stirred at room temp for 3 d. The reaction mixture was then poured into ice cold 1M HCl and extracted three times with CH2Cl2. The combined organic extract was washed three times with a saturated solution of sodium bicarbonate, dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified via silica gel chromatography using a gradient from 0 to 5% MeOH in CH2Cl2 to give CBX004 (23 mg, 0.052 mmol). 1H NMR (500 MHz, CDCl3, δ): 2.46 (s, 3H), 2.48-2.59 (m, 4H), 2.71 (t, J=6.9 Hz, 2H), 2.80 (s, 3H), 3.71 (t, J=4.6 Hz, 4H), 4.20 (t, J=6.9 Hz, 2H), 7.02 (dd, J=8.6 Hz, 1.8 Hz, 1H), 7.25 (d, J=8.6 Hz, 1H), 7.33 (d, J=1.7 Hz, 1H), 7.37 (d, J=7.2 Hz, 1H), 7.44-7.53 (m, 2H), 7.58 (td, J=7.6 Hz, 1.1 Hz, 1H), 8.11 (d, J=8.4 Hz, 1H), 8.18 (d, J=8.4 Hz, 1H). 13C NMR (500 MHz, CDCl3, δ): 12.62, 19.93, 41.40, 54.10, 57.36, 66.88, 109.40, 115.34, 122.34, 122.49, 124.40, 125.72, 125.76, 126.03, 126.08, 126.21, 126.66, 128.25, 130.43, 132.91, 136.51, 137.22, 138.35, 146.00, 193.43. MS m/z 447.6 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([O:13][CH2:14][CH:15]=[C:16]([Cl:18])[Cl:17])[CH:10]=[C:9]([Cl:19])[C:3]=1[O:4][CH2:5][C:6](=O)[CH3:7].Cl.[CH2:21]([O:23][NH2:24])[CH3:22].Cl>N1C=CC=CC=1>[CH2:21]([O:23][N:24]=[C:6]([CH2:5][O:4][C:3]1[C:2]([Cl:1])=[CH:12][C:11]([O:13][CH2:14][CH:15]=[C:16]([Cl:18])[Cl:17])=[CH:10][C:9]=1[Cl:19])[CH3:7])[CH3:22]
Reactant: CCON
Reactant: CC(=O)COc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Agent: Cl
Solvent: c1ccncc1
Product: CCON=C(C)COc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 83.6 %

Procedure:
To a mixture of 0.34 g of (2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenoxy)acetone and 10 ml of pyridine was added 0.11 g of O-ethylhydroxylamine hydrochloride. After stirring at room temperature for 24 hours, the reaction mixture was poured into diluted hydrochloric acid, and extracted twice with diethyl ether. The diethyl ether layers were combined, washed with water, dried over anhydrous magnesium sulfate, and concentrated to give a crude product. This crude product was subjected to silica gel chromatography, which afforded 0.32 g (yield, 81%) of (2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenoxy)acetone O-ethyloxime, m.p., 65.4° C.
Reaction SMILES: [CH2:1]([C:4]1[N:5]([CH2:17][CH2:18][C:19](OCC)=[O:20])[C:6]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:16]=1)[CH2:2][CH3:3].[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>>[N:24]1([C:19](=[O:20])[CH2:18][CH2:17][N:5]2[C:6]3[C:15]4[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=4[N:9]=[CH:8][C:7]=3[N:16]=[C:4]2[CH2:1][CH2:2][CH3:3])[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1
Reactant: C1COCCN1
Reactant: CCCc1nc2cnc3ccccc3c2n1CCC(=O)OCC
Product: CCCc1nc2cnc3ccccc3c2n1CCC(=O)N1CCOCC1
Temperature: 25 °C
Yield: 98.4 %

Procedure:
A solution of ethyl 3-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)propanoate (4.0 g, 15 mmol) in morpholine (20 mL, 0.2 mol) was heated at reflux for two days, allowed to cool to ambient temperature, and concentrated under reduced pressure to provide 5.2 g of 1-(3-morpholin-4-yl-3-oxopropyl)-2-propyl-1H-imidazo[4,5-c]quinoline.
Reaction SMILES: [C:1]([CH2:4][C:5](=[O:7])[CH3:6])(=[O:3])[CH3:2].C(N(CC)CC)C.[C:15]1([N:21]=[C:22]=[O:23])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O>C1C=CC=CC=1>[C:1]([CH:4]([C:5](=[O:7])[CH3:6])[C:22]([NH:21][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:23])(=[O:3])[CH3:2]
Reactant: CC(=O)CC(C)=O
Reactant: O=C=Nc1ccccc1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Solvent: O
Product: CC(=O)C(C(C)=O)C(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 63.9 %

Procedure:
A mixture of acetylacetone (5 g) and triethylamine (5.2 g) in dry benzene (50 ml) was treated with phenyl isocyanate (6 g) in dry benzene (25 ml). The mixture was stirred for 3 hr at room temperature. Water (50 ml) was then added, the mixture shaken and the water layer separated. The benzene solution was extracted with two further portions (25 ml) of water and the combined aqueous extracts acidified with dilute hydrochloric acid. The product precipitated and was collected by filtration, washed with water and dried. Diacetyl acetanilide (7.0 g, 73%) was obtained as a colourless solid, m.p. 119-121° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9](O)[C:10]1[CH:11]=[N:12][CH:13]=[N:14][CH:15]=1.CN(C)C=O.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([SH:29])=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>S(Cl)(Cl)=O.C(OCC)C>[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([S:29][CH:9]([C:3]2[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=2[F:1])[C:10]2[CH:11]=[N:12][CH:13]=[N:14][CH:15]=2)=[CH:25][CH:24]=1
Reactant: OC(c1cncnc1)c1cc(F)ccc1F
Reactant: Sc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: CCOCC
Product: Fc1ccc(F)c(C(Sc2ccc(Cl)cc2)c2cncnc2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 115.8 %

Procedure:
The 5-[(2,5-difluorophenyl)-hydroxymethyl]pyrimidine (111 mg, 0.5 mmol) obtained in Referential Example 12 was dissolved in thionyl chloride (1.0 ml). A catalytic amount of dimethylformamide was added and the resulting mixture was stirred for 16 hours. The reaction mixture was concentrated under reduced pressure. To the residue was added dioxane, and the resulting mixture was concentrated further. The residue was dissolved in dimethylformamide (5 ml), followed by the addition of 4-chlorobenzenethiol (108 mg, 0.75 mmol) and potassium carbonate (414 mg, 3.0 mmol) under a nitrogen atmosphere. The resulting mixture was stirred at 50° C. for 1 hour. After the reaction mixture was cooled to room temperature, diethyl ether (50 ml) was added thereto. The resulting mixture was washed with water and brine. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography (hexane:ethyl acetate=4:1) to give a mixture (202 mg) of the title compound and an unidentified compound as an oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[O:21][C:20](=[S:22])[NH:19][N:18]=1.[OH-].[Na+].I[CH3:26]>CO>[Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[O:21][C:20]([S:22][CH3:26])=[N:19][N:18]=1
Reactant: CI
Reactant: Cc1ccc(Cl)c(Nc2ccccc2-c2n[nH]c(=S)o2)c1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CSc1nnc(-c2ccccc2Nc2c(Cl)ccc(C)c2Cl)o1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 86.1 %

Procedure:
To a room temperature suspension of 5-[2-[(2,6-dichloro-3-methylphenyl)amino]phenyl]-1,3,4-oxadiazole-2(3H)-thione (1.706 g, 4.85 mmoles) in 70 ml of methanol is added dropwise 5.0 ml of 1.0N sodium hydroxide. The clear pale yellow solution is stirred at room temperature for 10 minutes. Iodomethane (320.0 μl, 5.13 mmoles) is added dropwise, and stirring is continued for six hours. The white solid is collected by filtration and dried in vacuo overnight at 60° C. to provide 1.530 g (86%) of 2,6-dichloro-3-methyl-N-[2-[5-(methylthio)-1,3,4-oxadiazol-2-yl]phenyl]benzenamine, mp 170°-171° C.
Reaction SMILES: O1CCCC1.[F:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:8]=1[C:9](Cl)=[O:10].[F:17][C:18]([F:32])([F:31])[O:19][C:20]1[CH:30]=[CH:29][C:23]([O:24][CH2:25][CH2:26][CH2:27][NH2:28])=[CH:22][CH:21]=1>C(N(CC)CC)C>[F:17][C:18]([F:31])([F:32])[O:19][C:20]1[CH:30]=[CH:29][C:23]([O:24][CH2:25][CH2:26][CH2:27][NH:28][C:9](=[O:10])[C:8]2[C:7]([F:6])=[CH:15][CH:14]=[CH:13][C:12]=2[F:16])=[CH:22][CH:21]=1
Reactant: NCCCOc1ccc(OC(F)(F)F)cc1
Reactant: O=C(Cl)c1c(F)cccc1F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(NCCCOc1ccc(OC(F)(F)F)cc1)c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A tetrahydrofuran (5 ml) solution of 2,6-difluorobenzoyl chloride (0.88 g) was added dropwise under ice-cooling and stirring to a tetrahydrofuran (20 ml) solution of 3-(4-trifluoromethoxyphenoxy)propylamine (1.18 g) and triethylamine (0.50 g) and the mixture was further stirred at room temperature for one hour.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][CH:10]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:12]=2)=[C:4]([F:18])[CH:3]=1.[O:19]1[CH2:23][CH2:22]OC1=O.CN1C=CN=C1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:22][CH2:23][OH:19])[CH:10]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:12]=2)=[C:4]([F:18])[CH:3]=1
Reactant: O=C1OCCO1
Reactant: CCOC(=O)c1c[nH]c(-c2ccc(Br)cc2F)n1
Agent: Cn1ccnc1
Product: CCOC(=O)c1cn(CCO)c(-c2ccc(Br)cc2F)n1

Procedure:
Ethyl 2-(4-bromo-2-fluorophenyl)-1H-imidazole-4-carboxylate 26 and 1,3-dioxolan-2-one and N-methylimidazole were reacted to give 27.
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].[NH:4]1[CH:8]=[CH:7][N:6]=[C:5]1[CH:9]=O>>[CH2:1]([NH:3][CH2:9][C:5]1[NH:4][CH:8]=[CH:7][N:6]=1)[CH3:2]
Reactant: O=Cc1ncc[nH]1
Reactant: CCN
Product: CCNCc1ncc[nH]1

Procedure:
prepared by reaction of ethylamine with 1H-imidazole-2-carbaldehyde
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:13]([F:16])([F:15])[F:14])=[N:4][NH:5][C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:24][C:25]([N:27]1[CH2:32][CH2:31][N:30]([C:33]2[CH:38]=[CH:37][C:36]([Br:39])=[C:35]([O:40][CH3:41])[CH:34]=2)[CH2:29][CH2:28]1)=[O:26].CN(C=O)C>CCCCCC.C(OCC)(=O)C>[Br:39][C:36]1[CH:37]=[CH:38][C:33]([N:30]2[CH2:31][CH2:32][N:27]([C:25](=[O:26])[CH2:24][N:5]3[C:6]([C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=4)=[C:2]([Cl:1])[C:3]([C:13]([F:14])([F:16])[F:15])=[N:4]3)[CH2:28][CH2:29]2)=[CH:34][C:35]=1[O:40][CH3:41]
Reactant: COc1cc(N2CCN(C(=O)CCl)CC2)ccc1Br
Reactant: FC(F)(F)c1n[nH]c(-c2ccccc2)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: COc1cc(N2CCN(C(=O)Cn3nc(C(F)(F)F)c(Cl)c3-c3ccccc3)CC2)ccc1Br

Procedure:
Protocol T was followed using 4-Chloro-5-phenyl-3-trifluoromethyl-1H-pyrazole, K2CO3, 2-Chloro-1-[4-(4-bromo-3-methoxy-phenyl)-piperazin-1-yl]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate=2/3:Rf=0.58) afforded the title compound as a white solid. 1H NMR (400 MHz, CDCl3): 7.81–7.86 (m, 1H), 7.36–7.44 (m, 4H), 6.42–6.48 (d, 1H), 6.34–6.38 (dd, 2H), 5.2 (s, 2H), 3.88 (s, 3H), 3.62–3.82 (m, 4H), 3.12–3.22 (m, 4H).
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][CH3:3].[CH2:5]([O:12][C:13]1[C:18](=[O:19])[CH:17]=[CH:16]O[C:14]=1[CH3:20])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[OH-].[Na+]>CO>[CH2:5]([O:12][C:13]1[C:18](=[O:19])[CH:17]=[CH:16][N:4]([CH2:1][CH2:2][CH3:3])[C:14]=1[CH3:20])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: CCCN
Reactant: Cc1occc(=O)c1OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCn1ccc(=O)c(OCc2ccccc2)c1C

Procedure:
The starting material can be prepared as follows: 20.64 ml of n-propylamine are added to a solution of 43.24 g of 3-benzyloxy-2-methyl-4H-pyran-4-one in 1000 ml of methanol, followed by the addition of 12.0 g of sodium hydroxide in 100 ml of methanol. The reaction mixture is refluxed for 3 hours, then concentrated by evaporation. The residue is taken up in methylene chloride and the organic solution is washed with water. The phases are clarified by addition of a saturated solution of sodium chloride in water, and the organic extract is dried over sodium sulfate and concentrated by evaporation under reduced pressure. The residue is dried under a high vacuum, giving 3-benzyloxy-2-methyl-1-n-propyl-4(1H)-pyridinone as an oily product.