Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:8]1[NH:9][C:10](=[O:18])[C:11]([C:16]#[N:17])=[C:12](SC)[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>C(#N)C>[CH2:1]([C:8]1[NH:9][C:10](=[O:18])[C:11]([C:16]#[N:17])=[C:12]([N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CSc1nc(Cc2ccccc2)[nH]c(=O)c1C#N
Reactant: C1CCNCC1
Solvent: CC#N
Product: N#Cc1c(N2CCCCC2)nc(Cc2ccccc2)[nH]c1=O

Procedure:
43 mg (0.17 mmol) of 2-benzyl-4-(methylsulphanyl)-6-oxo-1,6-dihydropyrimidine-5-carbonitrile are suspended in 0.3 ml of acetonitrile and stirred with 42.7 mg (0.50 mmol) of piperidine at 85° C. for 16 h. The resulting crude product is then purified by preparative HPLC. 11 mg (22% of theory) of the title compound are obtained.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)=[CH:16][CH:15]=2)=[O:13])(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:27]([O-:29])=[O:28].[CH3:30][C:31]1([CH3:37])[CH2:35][CH2:34][CH2:33][CH:32]1[NH2:36]>CN(C=O)C>[CH3:30][C:31]1([CH3:37])[CH2:35][CH2:34][CH2:33][CH:32]1[NH:36][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)=[CH:16][CH:15]=2)=[O:13])(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:27]([O-:29])=[O:28]
Reactant: O=C(NS(=O)(=O)c1ccc(Cl)c([N+](=O)[O-])c1)c1ccc(-c2ccc(F)cc2)cc1
Reactant: CC1(C)CCCC1N
Solvent: CN(C)C=O
Product: CC1(C)CCCC1Nc1ccc(S(=O)(=O)NC(=O)c2ccc(-c3ccc(F)cc3)cc2)cc1[N+](=O)[O-]
Reaction time: 16 h

Procedure:
A solution of Example 1D (50 mg, 0.12 mmol) and 2,2-dimethylcyclopentylamine (65 mg, 0.58 mmol) in DMF (2.0 mL) was heated to 120° C. in a sealed vial with shaking for 16 hours. The mixture was concentrated, dissolved in 1:1/DMSO:methanol (1.0 mL) and purified by reverse phase preparative HPLC using 0.1% TFA in H2O/CH3CN to provide the desired product. MS (APCI(+)) m/e 529 (M+NH4)+; 1H NMR (500 MHz, DMSO-d6) δ 12.45 (br s, 1H), 8.69 (d, 1H), 8.49 (d, 1H), 7.99 (dd, 1H), 7.97 (d, 2H), 7.80 (2d, 4H), 7.39 (d, 1H), 7.33 (t, 2H), 3.88 (ddd, 1H), 2.28-2.25 (m, 1H), 1.75-1.55 (m, 5H), 1.07 (s, 3H), 1.02 (s, 3H).
Reaction SMILES: [Cl:1][C:2]([Cl:11])([CH2:6][CH:7]([Cl:10])[C:8]#[N:9])[C:3](Cl)=[O:4].[ClH:12]>>[Cl:1][C:2]1([Cl:11])[CH2:6][C:7]([Cl:10])=[C:8]([Cl:12])[NH:9][C:3]1=[O:4]
Reactant: Cl
Reactant: N#CC(Cl)CC(Cl)(Cl)C(=O)Cl
Product: O=C1NC(Cl)=C(Cl)CC1(Cl)Cl

Procedure:
The cyclization reaction may be conveniently conducted in a batch reaction or in a continuous fashion in a coil reactor. In a typical reaction, 2,2,4-trichloro-4-cyanobutanoyl chloride is diluted with the desired solvent in a closed pressure vessel, and the vessel is pressurized with anhydrous HCl to the desired pressure. The reaction mixture is stirred at the appropriate temperature until the reaction is completed, usually from about one to about three hours. The reaction vessel is vented and the product, 3,3,5,6-tetrachloro-3,4-dihydropyridin-2-one, can be isolated by conventional procedures. For example, evaporation of the solvent provides a crude solid product which can be slurried with an aliphatic hydrocarbon, such as hexane, and which can then be isolated by filtration. Product so obtained is sufficiently pure after drying to be used in the subsequent aromatization. Alternatively, the crude reaction mixture can be used directly, immediately after venting and removal of the HCl.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C@@H:9]([C:10]#[CH:11])[CH2:8][CH2:7][C@H:6]1[C:12]#[N:13])=[O:4].[CH3:14][O:15][CH2:16][C:17]1([NH2:22])[CH2:21][CH2:20][CH2:19][CH2:18]1>C(#N)C>[C:10]([C@@H:9]1[N:5]([C:3](=[O:4])[CH2:2][NH:22][C:17]2([CH2:16][O:15][CH3:14])[CH2:21][CH2:20][CH2:19][CH2:18]2)[C@H:6]([C:12]#[N:13])[CH2:7][CH2:8]1)#[CH:11]
Reactant: COCC1(N)CCCC1
Reactant: C#C[C@H]1CC[C@@H](C#N)N1C(=O)CCl
Solvent: CC#N
Product: C#C[C@H]1CC[C@@H](C#N)N1C(=O)CNC1(COC)CCCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of (2S,5R)-1-(chloroacetyl)-5-ethynylpyrrolidine-2-carbonitrile (0.018 g, 0.09 mmol, Example 8D) in acetonitrile (1 mL) at room temperature was added 1-methoxymethyl-cyclopentylamine (17 mg, 0.13 mmol). The reaction mixture was stirred at room temperature for 18 hours, concentrated under reduced pressure and purified by flash chromatography with 3% methanol:dichloromethane to provide the titled compound. MS (ESI) m/z 290 (M+H)+; 1H NMR (CD3OD) δ 4.84 (m, 2H), 3.48 (m, 2H), 3.41 (s, 3H), 3.31 (m, 2H), 2.43 (d, 1H), 2.30-2.48 (m, 4H), 1.72-1.96 (m, 8H).
Reaction SMILES: [NH2:1][C:2]1[C:44]([NH2:45])=[CH:43][CH:42]=[CH:41][C:3]=1[C:4]([NH:6][C:7]1[CH:38]=[CH:37][C:10]([C:11]([N:13]([CH3:36])[C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=2[O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([N:29]2[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]2)=[O:28])=[O:12])=[CH:9][C:8]=1[O:39][CH3:40])=[O:5].[C:46](OC)(OC)(OC)[O:47][CH3:48]>C(O)(=O)C>[CH3:46][O:47][C:48]1[NH:45][C:44]2[CH:43]=[CH:42][CH:41]=[C:3]([C:4]([NH:6][C:7]3[CH:38]=[CH:37][C:10]([C:11]([N:13]([CH3:36])[C:14]4[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=4[O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([N:29]4[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]4)=[O:28])=[O:12])=[CH:9][C:8]=3[O:39][CH3:40])=[O:5])[C:2]=2[N:1]=1
Reactant: COC(OC)(OC)OC
Reactant: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)N2CCN(C)CC2)ccc1NC(=O)c1cccc(N)c1N
Solvent: CC(=O)O
Product: COc1nc2c(C(=O)Nc3ccc(C(=O)N(C)c4ccc(C)cc4OCCCCCC(=O)N4CCN(C)CC4)cc3OC)cccc2[nH]1
Reaction time: 72 h
Yield: 80.3 %

Procedure:
To a solution of 4-(2,3-diaminobenzoyl)amino-3-methoxy-N-methyl-N-[4-methyl-2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]benzamide (200 mg) in acetic acid (1 ml) was added tetramethyl orthocarbonate (66 mg) at ambient temperature and the solution was allowed to stand at the same temperature for 3 days. After being concentrated in vacuo, the residue was diluted with chloroform and saturated sodium bicarbonate aqueous solution. The organic layer was separated and washed with water and brine. The solution was dried over magnesium sulfate and the solvent was evaporated in vacuo. The residue was purified by preparative thin-layer chromatography (chloroform-methanol=10:1) to give 4-(2-methoxy-1H-benzimidazol-4-yl)carbonylamino-3-methoxy-N-methyl-N-[4-methyl-2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]benzamide (171 mg) as a powder.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]([CH3:16])([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11].[I-:17].[Na+]>CC(C)=O>[I:17][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]([CH3:16])([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: [I-]
Reactant: CCOC(=O)C(C)(C)OCCCCCCBr
Agent: [Na+]
Solvent: CC(C)=O
Product: CCOC(=O)C(C)(C)OCCCCCCI
Yield: 102.6 %

Procedure:
To 76 ml of a solution of 12.16 g of ethyl 2-(6-bromohexyloxy)-2-methylpropionate in acetone, 18.52 g of sodium iodide was added, and heated to reflux for 18 hours. The reaction solution was cooled, filtered to remove insolubles and washed with acetone. The filtrate was concentrated and, after addition of water, extracted with ethyl acetate. The organic layer was washed with water and brine sequentially, dried over anhydrous magnesium sulfate and concentrated to provide 14.46 g of the objective compound as red-yellow oil.
Reaction SMILES: C[O-].[Na+].[CH3:4][CH:5]([SH:7])[CH3:6].[N+:8]([C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[CH2:14]Cl)([O-:10])=[O:9]>CO>[N+:8]([C:11]1[CH:18]=[CH:17][CH:16]=[C:13]([CH2:14][S:7][CH:5]([CH3:6])[CH3:4])[CH:12]=1)([O-:10])=[O:9]
Reactant: CC(C)S
Reactant: O=[N+]([O-])c1cccc(CCl)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC(C)SCc1cccc([N+](=O)[O-])c1
Temperature: -15 °C
Reaction time: 2 h

Procedure:
A solution of sodium methoxide (15.5 mL, 25 wt % in methanol) was diluted with methanol (85 mL) and treated with 2-propanethiol (6.3 mL) at room temperature for 60 minutes, cooled to −15° C., treated with 3-nitrobenzylchloride (10 g) in 3 portions, kept for 2 hours at −15° C., then the temperature was increased to room temperature. The reaction mixture was concentrated in vacuo, treated with diethyl ether (300 mL), washed with water (2×100 mL) and brine (100 mL), dried with sodium sulfate and evaporated to dryness. The title compound (12.3 g) was thus obtained and used without further purification.
Reaction SMILES: [OH:1][C:2]1[C:7](=[O:8])[CH:6]=[CH:5][O:4][CH:3]=1.[OH-].[Na+].[CH:11](=[O:13])[CH3:12].Cl>O>[OH:13][CH:11]([C:3]1[O:4][CH:5]=[CH:6][C:7](=[O:8])[C:2]=1[OH:1])[CH3:12]
Reactant: CC=O
Reactant: O=c1ccocc1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(O)c1occc(=O)c1O
Reaction time: 8 h

Procedure:
3-Hydroxy-pyran-4(1H)-one (5.6 g, 50 mmol, 1 eq.) was added to 50 ml water and the pH of the solution was adjusted to 10.5 using 50% aqueous sodium hydroxide. Acetaldehyde (2.64 g, 60 mmol, 1.25 eq.) dissolved in 20 ml water was slowly added dropwise over 1 hour and the solution allowed to stir overnight. The reaction mixture was acidified to pH 1 with 37% w/v hydrochloric acid and concentrated in vacuo to dryness. The residue was extracted with 2×70 ml of isopropanol at 90° C. The isopropanol extracts were combined and concentrated to yield after recrystallisation from toluene, the pure product (3.7 g, 47.4%) as a pale yellow crystalline solid. m.p. 131-132° C. [lit. 130-131° C. (Ichimoto, 1970)].
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@@H:16]2[C@@H:21]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[C@H:20]([CH:29]=O)[CH2:19][CH2:18][O:17]2)[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[OH:33][CH:34]1[C:38]2([CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)[CH2:37][O:36][C:35]1([CH3:45])[CH3:44]>>[F:32][C:2]([F:1])([F:31])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@@H:16]2[C@@H:21]([C:22]3[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=3)[C@H:20]([CH2:29][N:41]3[CH2:42][CH2:43][C:38]4([CH2:37][O:36][C:35]([CH3:45])([CH3:44])[CH:34]4[OH:33])[CH2:39][CH2:40]3)[CH2:19][CH2:18][O:17]2)[CH3:14])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: CC1(C)OCC2(CCNCC2)C1O
Reactant: C[C@@H](O[C@H]1OCC[C@@H](C=O)[C@@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: C[C@@H](O[C@H]1OCC[C@@H](CN2CCC3(CC2)COC(C)(C)C3O)[C@@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
This product was prepared according to the procedure described in Example 6 using (2R,3R,4R)-2-[(1R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy]-3-(4-fluorophenyl)-tetrahydropyran-4-carbaldehyde (Description 11) and 4-hydroxy-3,3-dimethyl-2-oxa-8-azaspiro[4.5]decane (Description 21).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[C:5]([O:16][CH2:17][O:18][CH3:19])=[C:6]([CH2:14][OH:15])[CH:7]=[C:8]([O:10][CH2:11][O:12][CH3:13])[CH:9]=1.[CH3:20]I>CN(C=O)C>[Br:3][C:4]1[CH:9]=[C:8]([O:10][CH2:11][O:12][CH3:13])[CH:7]=[C:6]([CH2:14][O:15][CH3:20])[C:5]=1[O:16][CH2:17][O:18][CH3:19]
Reactant: COCOc1cc(Br)c(OCOC)c(CO)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCOc1cc(Br)c(OCOC)c(COC)c1
Yield: 88 %

Procedure:
Add sodium hydride (0.430 g of 60% in oil, 10.75 mmol) to DMF (100 mL) at −5° C. Add (3-bromo-2,5-bis-methoxymethoxy-phenyl)-methanol (3.00 g, 9.77 mmol) in DMF (20 mL) in portions and stir the resulting solution at −5° C. for 1 hour. Add methyl iodide (0.67 mL, 10.75 mmol) and stir the reaction for 1 hour. Pour the reaction into ice-H2O (200 mL) and extract with EtOAc (2×50 mL). Combine the extracts and wash with H2O (2×100 mL) and brine (50 mL) then dry (MgSO4), filter and concentrate. Purify the residue by silica gel chromatography eluting with Hex:EtOAc (80:20) to provide the subtitled product (2.76 g, 88%) as an oil. 1H NMR (CDCl3) δ 3.41 (s, 3H), 3.47 (s, 3H), 3.62 (s, 3H), 4.54 (s, 2H), 5.03 (s, 2H), 5.13 (s, 2H), 7.06 (d, J=2.9 Hz, 1H), 7.20 (d, J=2.9 Hz, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]([CH:11]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:12][S:13]([C:16]([CH3:21])([CH3:20])[C:17](Cl)=[O:18])(=[O:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:29]1([NH2:32])[CH2:31][CH2:30]1>N1C=CC=CC=1>[CH:29]1([NH:32][C:17]([C:16]([S:13]([CH2:12][CH:11]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])(=[O:15])=[O:14])([CH3:21])[CH3:20])=[O:18])[CH2:31][CH2:30]1
Reactant: CC(C)(C(=O)Cl)S(=O)(=O)CC(Cc1ccccc1)C(=O)OCc1ccccc1
Reactant: NC1CC1
Solvent: c1ccncc1
Product: CC(C)(C(=O)NC1CC1)S(=O)(=O)CC(Cc1ccccc1)C(=O)OCc1ccccc1
Yield: 86.6 %

Procedure:
A solution of 1.07 g (2.5 mmol) of (RS)-2-[[2-[(benzyloxy)carbonyl]-3-phenylpropyl]sulfonyl]-2-methylpropionyl chloride and 0.42 g (7.4 mmol) of cyclopropylamine in 20 ml of pyridine was stirred at room temperature for 2 hours. Thereafter, the reaction solution was evaporated under reduced pressure and the residue was chromatographed on 30 g of silica gel using a 99:1 mixture of methylene chloride and methanol as the eluent. There was obtained 0.96 g of benzyl rac-α-[[[1-(cyclopropylcarbamoyl)-1-methylethyl]sulfonyl]methyl]hydrocinnamate as a yellowish solid, MS: 444 (M)+.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([Br:12])[C:6]=1[CH2:7][C:8]([O:10][CH3:11])=[O:9].[C:13]([C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1)([OH:15])=[O:14].C([O-])([O-])=O.[Na+].[Na+]>CC#N.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>[Br:12][C:5]1[C:6]([CH2:7][C:8]([O:10][CH3:11])=[O:9])=[C:2]([C:19]2[CH:20]=[CH:21][C:16]([C:13]([OH:15])=[O:14])=[CH:17][CH:18]=2)[S:3][CH:4]=1
Reactant: COC(=O)Cc1c(Br)csc1Br
Reactant: O=C(O)c1ccc(B(O)O)cc1
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: CC#N
Product: COC(=O)Cc1c(Br)csc1-c1ccc(C(=O)O)cc1
Yield: 69.7 %

Procedure:
Pd(PPh3)4 (0.046 g, 0.4 mmol was added to a degassed solution of methyl (2,4-dibromothien-3-yl)acetate (2.51 g, 8 mmol) and 4-carboxybenzeneboronic acid (1.32 g, 8 mmol) in Na2CO3(40 mL, 0.4 M, 16 mmol) and CH3CN (40 mL). The mixture was heated to reflux overnight under argon for 16 h. The solution was filtered hot and the filtrate was concentrated to about half volume. The solution was extracted with CH2Cl2. The aqueous phase was acidified with concentrated HCl and the resulting solid was collected by vacuum filtration and washed with H2O to yield 4-(4-bromo-3-methoxycarbonylmethyl-thiophen-2-yl)-benzoic acid (1.98 g) which was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[CH2:9][S:10][C:11]#[N:12].[BrH:14].C(O)(=O)C.O>C(O)(=O)C>[Br:14][C:11]1[S:10][CH:9]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[N:12]=1
Reactant: Br
Reactant: N#CSCC(=O)c1ccccc1F
Solvent: O
Solvent: CC(=O)O
Product: Fc1ccccc1-c1csc(Br)n1
Temperature: 130 °C
Reaction time: 2 h
Yield: 61.4 %

Procedure:
To a solution of 2-(2-fluorophenyl)-2-oxoethyl thiocyanate (4.20 g, 21.5 mmol) in acetic acid (40 ml) was added a solution of 25% hydrogen bromide/acetic acid (40 ml), and the mixture was stirred at 130° C. for 2 hours. Water was poured into the reaction solution, and the mixture was extracted with chloroform. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to give the desired product (3.41 g, 61.4%) as an oil.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][C:6]1[O:10][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:8][C:7]=1[CH2:17][O:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21]O>C1(C)C=CC=CC=1>[Cl:3][CH2:21][C:20]1[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=1[O:18][CH2:17][C:7]1[N:8]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:10][C:6]=1[CH3:5]
Reactant: O=S(Cl)Cl
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccccc1CO
Solvent: Cc1ccccc1
Product: Cc1oc(-c2ccccc2)nc1COc1ccccc1CCl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Thionyl chloride (1.69 g) was added dropwise to a stirred suspension of 2-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl alcohol (4.00 g) in toluene (60 ml) at 0° C. After stirring at room temperature for 2 hours, the reaction mixture was concentrated. The residual crystals were dissolved in ethyl acetate and washed with aqueous sodium bicarbonate and water. The ethyl acetate layer was separated, dried (MgSO4), and concentrated to give 4-(2-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole as crystals. Recrystallization from ethyl acetate-hexane gave colorless needles (3.50 g, yield 82%). m.p. 103-104° C.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(O)(C)C>[Cl:1][C:2]1[N:11]=[C:10]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Clc1nc(Cl)c2ccccc2n1
Reactant: Nc1ccccc1
Solvent: CC(C)O
Product: Clc1nc(Nc2ccccc2)c2ccccc2n1

Procedure:
A solution of 2,4-dichloro-quinazoline (15 g) N,N-diisopropyl-ethylamine (24.9 ml) and aniline (7.5 ml) in isopropanol (75 ml) is heated to reflux for 45 min. The cold reaction mixture is filtered and the filtrate is concentrated in vacuo. The residue is crystallized from diethylether-toluene (1:1) to give 2-chloro-4-phenylamino-quinazoline, m.p. 194-196° C.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=O.[Cl:12][C:13]1[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([Cl:24])[C:14]=1[C:15]([NH:17][NH2:18])=[O:16]>>[I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([N:17]([C:15](=[O:16])[C:14]1[C:19]([Cl:24])=[CH:20][C:21]([Cl:23])=[CH:22][C:13]=1[Cl:12])[NH2:18])=[O:7]
Reactant: NNC(=O)c1c(Cl)cc(Cl)cc1Cl
Reactant: Cc1ccc(C(=O)O)cc1I
Product: Cc1ccc(C(=O)N(N)C(=O)c2c(Cl)cc(Cl)cc2Cl)cc1I

Procedure:
N-(3-iodo-4-methylbenzoyl)-2,4,6-trichlorobenzohydrazide was prepared by the reaction of 3-iodo-4-methylbenzoic acid with 2,4,6-trichlorobenzohydrazide. The coupling was performed in a manner similar to that described in Reference Example 3.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([C:7]2[CH:8]=[CH:9][C:10]3[O:14][CH:13]=[C:12]([C:15]4[CH:16]=[N:17][NH:18][CH:19]=4)[C:11]=3[CH:20]=2)=[N:5][N:6]=1.[F:21][C:22]([F:32])([F:31])[C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[CH2:25]Br>>[CH3:1][C:2]1[O:3][C:4]([C:7]2[CH:8]=[CH:9][C:10]3[O:14][CH:13]=[C:12]([C:15]4[CH:19]=[N:18][N:17]([CH2:25][C:24]5[CH:27]=[CH:28][CH:29]=[CH:30][C:23]=5[C:22]([F:21])([F:31])[F:32])[CH:16]=4)[C:11]=3[CH:20]=2)=[N:5][N:6]=1
Reactant: FC(F)(F)c1ccccc1CBr
Reactant: Cc1nnc(-c2ccc3occ(-c4cn[nH]c4)c3c2)o1
Product: Cc1nnc(-c2ccc3occ(-c4cnn(Cc5ccccc5C(F)(F)F)c4)c3c2)o1
Yield: 92 %

Procedure:
In the same manner as in Example 1 and using 2-methyl-5-[3-(1H-pyrazol-4-yl)-1-benzofuran-5-yl]-1,3,4-oxadiazole instead of 5-(benzothiazol-6-yl)-1,3,4-oxadiazole-2-thiol and using 2-(trifluoromethyl)benzyl bromide instead of 3-(trifluoromethyl)benzyl chloride, the title compound (yield 92%) was obtained as colorless crystals.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:17]=[C:16]([NH:18][CH2:19][C@H:20]3[O:25][CH2:24][CH2:23][N:22]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:21]3)[C:15]3[C:10](=[N:11][CH:12]=[CH:13][N:14]=3)[CH:9]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:40][CH2:41][CH2:42][OH:43].O>CN(C=O)C>[OH:43][CH2:42][CH2:41][CH2:40][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:17]=[C:16]([NH:18][CH2:19][C@H:20]3[O:25][CH2:24][CH2:23][N:22]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:21]3)[C:15]3[C:10](=[N:11][CH:12]=[CH:13][N:14]=3)[CH:9]=2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](CNc2nc(-c3ccc(O)cc3)cc3nccnc23)C1
Reactant: OCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCO[C@H](CNc2nc(-c3ccc(OCCCO)cc3)cc3nccnc23)C1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
To a solution of (R)-tert-butyl 2-((7-(4-hydroxyphenyl)pyrido[4,3-b]pyrazin-5-ylamino)methyl)morpholine-4-carboxylate (115 mg, 0.26 mmol) in DMF (5 mL) was added Cs2CO3 (128 mg, 0.39 mmol) and 3-bromopropan-1-ol (55 mg, 0.39 mmol). The reaction was stirred at 80° C. for 0.5 hours. TLC and LC-Ms showed the reaction had completed and the reaction was poured into water, extracted with EA, washed with water and brine, dried and concentrated, purified on TLC (CH2Cl2:MeOH=30:1) to give yellow solid. MS (m/z): 496 (M+H)+
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:29]=[CH:28][C:7]([CH2:8][O:9][C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[N:14]([CH2:20][CH:21]([OH:26])[C:22]([F:25])([F:24])[F:23])[C:13]3=[O:27])=[CH:6][CH:5]=1.I[CH3:31].O>O1CCCC1>[F:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][O:9][C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[N:14]([CH2:20][CH:21]([O:26][CH3:31])[C:22]([F:24])([F:25])[F:23])[C:13]3=[O:27])=[CH:28][CH:29]=1
Reactant: CI
Reactant: O=C1c2ccc(OCc3ccc(F)cc3)cc2C(=O)N1CC(O)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(CN1C(=O)c2ccc(OCc3ccc(F)cc3)cc2C1=O)C(F)(F)F
Reaction time: 14 h
Yield: 33.6 %

Procedure:
To a suspension of sodium hydride (45 mg, 1.0 mmol) in tetrahydrofuran (8 mL) was added 5-(4-fluoro-benzyloxy)-2-(3,3,3-trifluoro-2-hydroxy-propyl)-isoindole-1,3-dione (360 mg, 0.9 mmol) at room temperature and then iodomethane (159 mg, 1.1 mmol) was added and then after 14 h, water was added. The mixture was then extracted with ethylacetate and the combined organic extracts washed with water, brine and then dried over sodium sulfate. Filtration and evaporation gave a residue which was purified by chromatography (SiO2, hexane-EtOAc 3:1) to afford the title compound (120 mg, 32%) as a white solid. MS: m/e=398.4 (M+H+).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][N:10]1[CH:14]=[C:13]([I:15])[N:12]=[C:11]1[CH2:16][CH3:17])(C)(C)C.[ClH:19].O1CCOCC1>C(Cl)Cl>[CH2:16]([C:11]1[N:10]([CH2:9][CH2:8][NH2:7])[CH:14]=[C:13]([I:15])[N:12]=1)[CH3:17].[ClH:19]
Reactant: CCc1nc(I)cn1CCNC(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCc1nc(I)cn1CCN
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To an ice-cooled solution of [2-(2-ethyl-4-iodo-imidazol-1-yl)-ethyl]carbamic acid tert-butyl ester (5.720 g; 15.662 mmol) in DCM (125 ml) was added slowly 4N HCl in dioxane (78 ml; 312 mmol). The resulting suspension was stirred at 0° C. for 15 min., then at rt for 1 h. The volatiles were removed under reduced pressure, then under HV. The product 2-(2-ethyl-4-iodo-imidazol-1-yl)-ethylamine was obtained as a pale beige solid (5.96 g; 100%; presence of 3 eq. of HCl). LC-MS: tR=0.14 min.; [M+H]+=266.24 g/mol.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([Br:31])=[CH:27][CH:26]=3)[N:13]([C:15]3[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=3)[CH:14]=2)=[CH:6][CH:5]=1.Br[CH2:34][C:35]([O:37][CH3:38])=[O:36]>>[CH3:1][O:2][C:3](=[O:32])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([Br:31])=[CH:27][CH:26]=3)[N:13]([C:15]3[CH:20]=[CH:19][C:18]([NH:21][CH2:34][C:35]([O:37][CH3:38])=[O:36])=[CH:17][CH:16]=3)[CH:14]=2)=[CH:6][CH:5]=1
Reactant: COC(=O)CBr
Reactant: COC(=O)c1ccc(-c2cn(-c3ccc([N+](=O)[O-])cc3)c(Cc3ccc(Br)cc3)n2)cc1
Product: COC(=O)CNc1ccc(-n2cc(-c3ccc(C(=O)OC)cc3)nc2Cc2ccc(Br)cc2)cc1

Procedure:
4-[2-(4-Bromo-benzyl)-1-(4-Nitro-phenyl)-1H-imidazol-4-yl]-benzoic acid methyl ester (9.8 g, 20 mmol) was reduced to amine and was reacted with methyl bromoacetate following general procedures D & E to give 4-{2-(4-Bromo-benzyl)-1-[4-(methoxycarbonylmethyl-amino)-phenyl]-1H-imidazol-4-yl}-benzoic acid methyl ester.