Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2-].[Na+].[CH3:3][CH:4]1[CH:9]([CH2:10][OH:11])[CH2:8][CH:7]=[CH:6][CH2:5]1.Br[CH2:13][CH:14]1[CH2:16][CH2:15]1>O1CCCC1>[CH:14]1([CH2:13][O:11][CH2:10][CH:9]2[CH:4]([CH3:3])[CH2:5][CH:6]=[CH:7][CH2:8]2)[CH2:16][CH2:15]1
Reactant: BrCC1CC1
Reactant: CC1CC=CCC1CO
Agent: [NH2-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1CC=CCC1COCC1CC1
Temperature: 65 °C

Procedure:
A reaction flask was charged with tetrahydrofuran (THF, 500 mL) and sodium amide (NaNH2, 100 g, 2.6 mol) and heated to reflux (˜65° C.). (6-Methyl-cyclohex-3-enyl)-methanol (300 g, 2.3 mol) was fed in. The reaction mixture was aged for a half-hour. Bromomethyl-cyclopropane (526 g, 3.9 mol) was then fed for over 2 hours at the reflux temperature. The reaction was monitored by gas chromatography. A sample the reaction mixture was quenched in isopropyl alcohol, water, and toluene. After the feed of bromomethyl-cyclopropane was completed, the reaction was aged for a total of 6 hours. The reaction mixture was then cooled to 10° C. and quenched with isopropyl alcohol (100 mL), water (1 L), and toluene (500 mL). On the work-up, the reaction mixture was acidified with HCl (300 mL) and washed with sodium carbonate solution (5%, 500 mL) in a separatory funnel followed with warm H2O until the pH was neutral. Distillation of the resulting mixture provided the product 4-cyclopropylmethoxymethyl-5-methyl-cyclohexene.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=2[NH:18][C:19]([C:21]2[CH:26]=[CH:25][C:24]([S:27]([CH3:38])(=[N:29][C:30]([CH:32]3[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)=[O:31])=[O:28])=[CH:23][CH:22]=2)=[O:20])=[O:10])=[N:6][CH:7]=1.[CH2:39](I)[CH3:40]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=2[NH:18][C:19]([C:21]2[CH:22]=[CH:23][C:24]([S:27]([CH3:38])(=[N:29][C:30]([CH:32]3[CH2:37][CH2:36][N:35]([CH2:39][CH3:40])[CH2:34][CH2:33]3)=[O:31])=[O:28])=[CH:25][CH:26]=2)=[O:20])=[O:10])=[N:6][CH:7]=1
Reactant: CS(=O)(=NC(=O)C1CCNCC1)c1ccc(C(=O)Nc2ccc(Cl)cc2C(=O)Nc2ccc(Cl)cn2)cc1
Reactant: CCI
Product: CCN1CCC(C(=O)N=S(C)(=O)c2ccc(C(=O)Nc3ccc(Cl)cc3C(=O)Nc3ccc(Cl)cn3)cc2)CC1
Yield: 71 %

Procedure:
Product of Example 25 was ethylated using standard N-alkylating procedure with ethyl iodide to give titled compound in 71% yield.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3](B(O)O)=[CH:2]1.[N:9]1([CH2:14][C:15]2[CH:16]=[CH:17][C:18](Br)=[N:19][CH:20]=2)[CH:13]=[CH:12][N:11]=[CH:10]1>>[O:1]1[CH:5]=[CH:4][C:3]([C:18]2[CH:17]=[CH:16][C:15]([CH2:14][N:9]3[CH:13]=[CH:12][N:11]=[CH:10]3)=[CH:20][N:19]=2)=[CH:2]1
Reactant: OB(O)c1ccoc1
Reactant: Brc1ccc(Cn2ccnc2)cn1
Product: c1cn(Cc2ccc(-c3ccoc3)nc2)cn1

Procedure:
Synthesized using 3-furanylboronic acid (188 mg, 1.68 mmol) and 1a (200 mg, 0.84 mmol) according to Method C. Brown solid. Yield: 144 mg, 0.61 mmol, 73%. 1H NMR (CDCl3, 500 MHz): OH (ppm): 5.13 (s, 2H), 6.87 (dd, J=1.9, 0.9 Hz, 1H), 6.90 (t, J=1.3 Hz, 1H), 7.10 (s, 1H), 7.41 (dd, J=8.2, 2.2 Hz, 1H), 7.43 (dd, J=8.2, 1.3 Hz, 1H), 7.49 (t, J=1.6 Hz, 1H), 7.56 (brs, 1H), 8.02 (dd, J=0.7 Hz, J=1.4 Hz, 1H); 13C NMR (CDCl3, 125 MHz): 00 (ppm)=48.1, 108.5, 118.9, 120.1, 126.5, 129.5, 130.3, 135.6, 137.3, 141.5, 144.0, 148.6, 152.1; MS (ESI): m/z=226.15 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[NH:13][C:12]3[C:14]([OH:21])=[CH:15][CH:16]=[C:17]([C:18]([OH:20])=[O:19])[C:11]=3[N:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].O=S(Cl)Cl.[CH3:26]O>>[CH3:26][O:19][C:18]([C:17]1[C:11]2[N:10]=[C:9]([C:4]3[CH:5]=[CH:6][C:7]([F:8])=[C:2]([Cl:1])[CH:3]=3)[NH:13][C:12]=2[C:14]([OH:21])=[CH:15][CH:16]=1)=[O:20]
Reactant: O=C(O)c1ccc(O)c2[nH]c(-c3ccc(F)c(Cl)c3)nc12
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(O)c2[nH]c(-c3ccc(F)c(Cl)c3)nc12
Temperature: 25 °C
Yield: 81 %

Procedure:
2-(3-chloro-4-fluoro-phenyl)-7-hydroxy-1H-benzoimidazole-4-carboxylic acid (800 mg, 2.64 mmol) obtained in step 3 was dissolved in methanol, SOCl2 (1.93 ml, 26.41 mmol) was added dropwise thereto and refluxed for 15 hours. The resulting solution was cooled to room temperature, concentrated under a reduced pressure to remove methanol, and the residue was neutralized with NaHCO3. Then, the neutralized residue was extracted with ethyl acetate and concentrated under a reduced pressure to obtain a residue which was purified by silica gel chromatography to obtain the title compound (690 mg, 2.15 mmol) in a yield of 81%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](F)[CH:5]=[CH:4][C:3]=1[S:9]([C@H:12]1[CH2:16][N:15]([C:17]2[N:21]([CH:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[N:20]=[C:19]([CH3:28])[CH:18]=2)[C@H:14]([C:29]([NH:31][C:32]2([C:35]#[N:36])[CH2:34][CH2:33]2)=[O:30])[CH2:13]1)(=[O:11])=[O:10].[CH3:37][O:38][CH2:39][CH2:40][OH:41]>>[C:35]([C:32]1([NH:31][C:29]([C@@H:14]2[CH2:13][C@@H:12]([S:9]([C:3]3[CH:4]=[CH:5][C:6]([O:41][CH2:40][CH2:39][O:38][CH3:37])=[CH:7][C:2]=3[Cl:1])(=[O:11])=[O:10])[CH2:16][N:15]2[C:17]2[N:21]([CH:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[N:20]=[C:19]([CH3:28])[CH:18]=2)=[O:30])[CH2:34][CH2:33]1)#[N:36]
Reactant: Cc1cc(N2C[C@H](S(=O)(=O)c3ccc(F)cc3Cl)C[C@H]2C(=O)NC2(C#N)CC2)n(C2CCOCC2)n1
Reactant: COCCO
Product: COCCOc1ccc(S(=O)(=O)[C@@H]2C[C@@H](C(=O)NC3(C#N)CC3)N(c3cc(C)nn3C3CCOCC3)C2)c(Cl)c1

Procedure:
In analogy to the procedure described in example 392, (2S,4R)-4-(2-chloro-4-fluorophenylsulfonyl)-N-(1-cyanocyclopropyl)-1-(3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-5-yl)pyrrolidine-2-carboxamide (example 464d) was reacted with 2-methoxyethanol (CAS Reg. No. 109-86-4) to give the title compound as colorless oil. MS (ESI): m/z=592.2 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C@:8]2([CH3:17])[C@@H:14]([F:15])[CH2:13][O:12][CH2:11][C:10]([NH2:16])=[N:9]2)[CH:7]=1.[O:19]1[CH2:23][CH2:22][C:21](=O)[CH2:20]1>>[F:15][C@H:14]1[CH2:13][O:12][CH2:11][C:10]([NH2:16])=[N:9][C@@:8]1([C:6]1[CH:7]=[C:2]([NH:1][CH:21]2[CH2:22][CH2:23][O:19][CH2:20]2)[CH:3]=[CH:4][C:5]=1[F:18])[CH3:17]
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)COC[C@@H]1F
Reactant: O=C1CCOC1
Product: C[C@]1(c2cc(NC3CCOC3)ccc2F)N=C(N)COC[C@@H]1F
Yield: 44.7 %

Procedure:
In an analogous manner as described for example 1 the reductive amination of (5R,6R)-5-(5-amino-2-fluoro-phenyl)-6-fluoro-5-methyl-2,5,6,7-tetrahydro-1,4-oxazepin-3-ylamine (intermediate A10B) (20 mg, 78.4 μmol) and dihydrofuran-3(2H)-one (3-oxotetrahydrofuran) (CAS [22929-52-8]) (7.42 mg, 6.67 μl, 86.2 μmol) yielded the title compound (11.4 mg, 44.7%) as a colorless solid. MS (ISP): m/z=326.3 [M+H]+.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6].Br[C:8]1[CH:13]=[CH:12][C:11]([C:14]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[C:27]([CH3:28])=[CH:26][C:25]([CH:29]4[CH2:31][CH2:30]4)=[CH:24][N:23]=3)[CH2:18][CH2:17]2)=[O:15])=[C:10]([S:32]([CH3:35])(=[O:34])=[O:33])[CH:9]=1>>[CH:29]1([C:25]2[CH:26]=[C:27]([CH3:28])[C:22]([N:19]3[CH2:20][CH2:21][N:16]([C:14]([C:11]4[CH:12]=[CH:13][C:8]([N:1]5[CH2:5][CH2:4][CH2:3][C:2]5=[O:6])=[CH:9][C:10]=4[S:32]([CH3:35])(=[O:34])=[O:33])=[O:15])[CH2:17][CH2:18]3)=[N:23][CH:24]=2)[CH2:30][CH2:31]1
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(Br)cc2S(C)(=O)=O)CC1
Reactant: O=C1CCCN1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3CCCC3=O)cc2S(C)(=O)=O)CC1
Yield: 84.6 %

Procedure:
Using pyrrolidin-2-one (47 mg) and (4-bromo-2-methanesulfonylphenyl)[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (239 mg) described in Preparation Example 126 and by the reaction and treatment in the same manner as in Example 1, the title compound (204 mg) was obtained.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[N:13]=[C:12](N)[C:11]([N+:15]([O-:17])=[O:16])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.N1C=CC=CC=1.N([O-])=O.[Na+].[FH:28]>>[F:28][C:12]1[N:13]=[C:8]([N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)[CH:9]=[CH:10][C:11]=1[N+:15]([O-:17])=[O:16]
Reactant: CN1CCN(c2ccc([N+](=O)[O-])c(N)n2)CC1
Reactant: F
Agent: O=N[O-]
Agent: [Na+]
Solvent: c1ccncc1
Product: CN1CCN(c2ccc([N+](=O)[O-])c(F)n2)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 6-(4-methylpiperazin-1-yl)-3-nitropyridin-2-amine (1.2 g, 5.0 mmol) in hydrogen fluoride.pyridine (15 mL) is cooled to 0° C. in an ice-water bath. Sodium nitrite (0.36 g, 5.2 mmol) is added in a single portion, and the mixture is stirred for 30 minutes at 0° C. The bath is removed and the mixture is heated for 15 minutes in an oil bath on a 70° C. hot plate. After cooling to room temperature, the reaction mixture is poured onto ice (50 g), neutralized with saturated aqueous sodium hydrogen carbonate solution, and basified with 10 N sodium hydroxide solution. The mixture is extracted 3× with dichloromethane, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Eighty-percent of the crude residue is purified by reverse-phase HPLC to give 1-(6-fluoro-5-nitropyridin-2-yl)-4-methylpiperazine.trifluoroacetic acid salt (0.40 g, 29%).
Reaction SMILES: [C:1]1([CH3:14])[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[O:11][N:10]=[C:9]([CH:12]=[O:13])[CH:8]=2)[CH:2]=1.[CH3:15][Mg]Br.C(OCC)C>C1COCC1>[CH3:14][C:1]1[CH:2]=[C:3]([C:7]2[O:11][N:10]=[C:9]([CH:12]([OH:13])[CH3:15])[CH:8]=2)[CH:4]=[CH:5][CH:6]=1
Reactant: Cc1cccc(-c2cc(C=O)no2)c1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1cccc(-c2cc(C(C)O)no2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 103.2 %

Procedure:
The title compound of Example 5.3 (739 mg, 3.9 mmol) was dissolved in THF (20 mL) under Argon and the flask was immersed in ice. Methyl magnesium bromide (1 M solution/diethyl ether 6.6 mL, 19.7 mmol) was added dropwise while the reaction was cooled in ice. After fifteen minutes at 0° C., the ice bath was removed and the reaction was allowed to stir at room temperature for two hours. Aqueous NH4Cl (saturated) was added to quench the reaction and an aqueous workup was done extracting with ethyl acetate three times. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (3% MeOH/DCM) to yield the title compound as a clear oil (818 mg, 100%).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8](=[O:20])[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([NH2:18])=[C:14]([F:19])[CH:13]=3)[O:11][C:6]=2[C:5]([F:21])=[C:4]([CH2:22][OH:23])[C:3]=1[F:24].Cl[C:26]([O:28][CH2:29][CH:30]=[CH2:31])=[O:27].O>N1C=CC=CC=1>[CH2:29]([O:28][C:26]([NH:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]2[O:11][C:6]3[C:5]([F:21])=[C:4]([CH2:22][OH:23])[C:3]([F:24])=[C:2]([NH2:1])[C:7]=3[C:8](=[O:20])[CH:9]=2)=[CH:13][C:14]=1[F:19])=[O:27])[CH:30]=[CH2:31]
Reactant: C=CCOC(=O)Cl
Reactant: Nc1ccc(-c2cc(=O)c3c(N)c(F)c(CO)c(F)c3o2)cc1F
Solvent: O
Solvent: c1ccncc1
Product: C=CCOC(=O)Nc1ccc(-c2cc(=O)c3c(N)c(F)c(CO)c(F)c3o2)cc1F
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 82.3 %

Procedure:
6.72 mg (20.0 mmol) of Compound 118 obtained in Example 118 was dissolved in 200 mL of pyridine, 10.6 mL (100 mmol) of allyl chloroformate was added dropwise under ice-cooling, and the mixture was stirred at room temperature for 1.5 hours. Water was added to the reaction solution and the precipitated crystals were collected by filtration. The crystals were dissolved in 500 mL of ethanol, 18 mL of a 2N aqueous solution of sodium hydroxide was added, and the mixture was stirred at room temperature for 1.5 hours. Water was added to the reaction solution and the precipitated crystals were collected by filtration, to give 6.92 g of Compound P (yield: 82%).
Reaction SMILES: [CH3:1][CH:2]1[C:6](=[O:7])[CH:5]=[C:4]([CH3:8])[O:3]1.[Si:9](OS(C(F)(F)F)(=O)=O)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]>C(Cl)Cl>[CH3:13][C:12]([Si:9]([CH3:11])([CH3:10])[O:7][C:6]1[CH:5]=[C:4]([CH3:8])[O:3][C:2]=1[CH3:1])([CH3:15])[CH3:14]
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: CC1=CC(=O)C(C)O1
Solvent: ClCCl
Product: Cc1cc(O[Si](C)(C)C(C)(C)C)c(C)o1
Reaction time: 1 h
Yield: 89.3 %

Procedure:
2,5-Dimethyl-3(3H)-furanone (2.00 g, 17.8 mmol) was dissolved in methylene chloride (180 mL). TEA (7.43 mL, 53.5 mmol) was added followed by TBSOTf (4.92 mL, 21.4 mmol) at 25° C. After 1 h, the reaction was concentrated in vacuo and the resulting slurry was run through a silica gel column conditioned with 3% TEA in hexanes. The product was eluted with 3% TEA/hexanes to give 3.6 g (89%) of compound 222A as an orange oil which was used directly in subsequent reactions.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:13][CH3:14])[C:4]1[CH:5]=[N:6][CH:7]=[C:8]([C:10]([CH3:12])=[CH2:11])[CH:9]=1.C1C=C(Cl)C=C(C(OO)=[O:23])C=1>C(Cl)Cl>[CH3:1][O:2][CH:3]([O:13][CH3:14])[C:4]1[CH:5]=[N+:6]([O-:23])[CH:7]=[C:8]([C:10]([CH3:12])=[CH2:11])[CH:9]=1
Reactant: C=C(C)c1cncc(C(OC)OC)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: C=C(C)c1cc(C(OC)OC)c[n+]([O-])c1
Reaction time: 2 h
Yield: 108.6 %

Procedure:
To a stirred solution of 3-(dimethoxymethyl)-5-(prop-1-en-2-yl)pyridine (178 mg, 0.92 mmol) in CH2Cl2 (10 mL) was added m-CPBA (227 mg, 1.0 mmol). The reaction mixture was stirred for 2 h and quenched with saturated aqueous NaHCO3. The layers were separated and the organic layer was washed with brine and dried over Na2SO4. The solvent was removed to provide 3-(dimethoxymethyl)-5-(prop-1-en-2-yl)pyridine 1-oxide (209 mg), which was converted to 3-formyl-5-(prop-1-en-2-yl)pyridine 1-oxide as described herein.
Reaction SMILES: [C:1]1([CH:7]2[C:12](=[O:13])[CH2:11][CH2:10][O:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:14](Cl)([N:16]=[C:17]=[O:18])=[O:15]>CCOC(C)=O>[C:1]1([CH:7]2[C:12]3[O:13][C:17](=[O:18])[NH:16][C:14](=[O:15])[C:11]=3[CH2:10][O:9][CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C=NC(=O)Cl
Reactant: O=C1CCOCC1c1ccccc1
Solvent: CCOC(C)=O
Product: O=c1[nH]c(=O)c2c(o1)C(c1ccccc1)COC2
Temperature: 58 °C
Reaction time: 1 h
Yield: 61.8 %

Procedure:
A mixture of 3-phenyldihydro-2H-pyran-4(3H)-one (Intermediate I(2)) (3 g, 17.02 mmol) and carbonisocyanatidic chloride (10.48 g, 29.8 mmol) in a sealed tube was heated to 58° C. and stirred for 1 h. The mixture was then brought to 130° C. and stirred for an additional 2 h. The reaction turned black during this time. After cooling to RT, the tar was taken up in EtOAc (100 mL). The resulting solution was washed with saturated aqueous sodium bicarbonate (2×50 mL), brine (50 mL), dried over MgSO4, filtered and concentrated in vacuo. Purification by flash chromatography (Silica, EtOAc/Hexanes) gave 8-phenyl-7,8-dihydropyrano[3,4-e][1,3]oxazine-2,4(3H,5H)-dione (2.58 g, 10.52 mmol, 61.8% yield) as a brown solid. LC-MS (M+H)+=246.0. 1H NMR (500 MHz, MeOD) δ ppm 7.34-7.41 (4H, m), 7.29-7.34 (1H, m), 4.42-4.63 (2H, m), 4.08-4.15 (1H, m), 3.94 (1H, dd, J=11.44, 4.12 Hz), 3.85 (1H, ddd, J=4.20, 2.44, 2.21 Hz).
Reaction SMILES: [SH:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.CN(C)C=O.[H-].[Na+].[NH2:14][C:15]1[CH:20]=[C:19](Cl)[CH:18]=[CH:17][C:16]=1[N+:22]([O-:24])=[O:23]>O>[NH2:14][C:15]1[CH:20]=[C:19]([S:1][C:2]2[NH:3][CH:4]=[CH:5][N:6]=2)[CH:18]=[CH:17][C:16]=1[N+:22]([O-:24])=[O:23]
Reactant: Sc1ncc[nH]1
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1cc(Sc2ncc[nH]2)ccc1[N+](=O)[O-]

Procedure:
A solution of 2.0 g. 2-mercaptoimidazole in 25 ml. dimethylformamide is treated with 0.85 g. of 57% sodium hydride (in oil suspension). 3.0 G. of 2-amino-4-chloro-1-nitrobenzene is added and the mixture heated overnight at 150°-155°C. The mixture is diluted with water, filtered and the crude product washed with chloroform, recrystallized from aqueous methanol to yield 2-amino-4-(imidazol-2-ylthio)-1-nitrobenzene.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)[C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14](=[O:19])[CH:13]=[C:12]3[Br:20])=[CH:4][CH:3]=1.CN(C)C=O.[H-].[Na+].Br[CH2:36][C:37]([NH2:39])=[O:38]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)[C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]([CH2:36][C:37]([NH2:39])=[O:38])[C:14](=[O:19])[CH:13]=[C:12]3[Br:20])=[CH:6][CH:7]=1
Reactant: NC(=O)CBr
Reactant: O=c1cc(Br)c2cc(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)ccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: NC(=O)Cn1c(=O)cc(Br)c2cc(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)ccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Into a 25-mL round-bottom flask, was placed 6-[bis(4-chlorophenyl)methyl]-4-bromo-1,2-dihydroquinolin-2-one (300 mg, 0.65 mmol, 1.00 equip), N,N-dimethylformamide (10 mg, 0.14 mmol, 0.21 equip) and sodium hydride (52.3 mg, 1.31 mmol, 2.00 equip, 60%). To the resulting mixture was then added 2-bromoacetamide (108 mg, 0.78 mmol, 1.20 equip). The resulting solution was stirred for 2 h at room temperature. The reaction was then quenched by the addition of water (200 mL). The resulting solution was extracted with ethyl acetate (3×100 mL) and the organic layers combined and dried over sodium sulfate. The solids were filtered out. The filtrate was concentrated under vacuum. The residue was applied onto a silica gel column with DCM: MeOH (20:1) to yield 2-[6-[bis(4-chlorophenyl)methyl]-4-bromo-2-oxo-1,2-dihydroquinolin-1-yl]acetamide as a white solid. LCMS (ES, m/z) 517 [M+H]+
Reaction SMILES: [C:1]1([CH2:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:11][C:12]1[CH:13]=[C:14]([CH:19]([CH3:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:15]=[CH:16][C:17]=1O>N1C=CC=CC=1>[CH2:7]([C:8]1[O:9][C:17]2[CH:16]=[CH:15][C:14]([CH:19]([CH3:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:13][C:12]=2[N:11]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)C(C)c1ccc(O)c(N)c1
Reactant: O=C(Cl)Cc1ccccc1
Solvent: c1ccncc1
Product: CCOC(=O)C(C)c1ccc2oc(Cc3ccccc3)nc2c1
Temperature: 100 °C

Procedure:
Phenyl acetyl chloride (2.2 ml.) was added to a stirred solution of ethyl 2-(3-amino-4-hydroxyphenyl)propionate (3.15g.) in anhydrous pyridine (50 ml.) and the solution was heated at 100° C for two hours. Excess pyridine was removed by distillation and the residue heated until the temperature of the distillate immediately above the reaction mixture was 200° C. The resultant dark brown gum was dissolved in ether (75 ml.) and then washed with water (3 × 50 ml.) The ether solution was extracted with 1N sodium hydroxide (50 ml.), washed with water (2 × 50 ml.) and evaporated to give ethyl 2-(2-benzyl-5-benzoxazolyl)propionate as a light brown mobile gum, which was shown to be pure by thin layer chromatography. Similarly the following esters were prepared and characterised:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[N:16]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[NH:18][CH:17]=1.O>CN(C=O)C>[N:16]1([C:2]2[N:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[N:3]=2)[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[N:18]=[CH:17]1
Reactant: c1ccc2[nH]cnc2c1
Reactant: Clc1cc(Cl)nc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Clc1cc(Cl)nc(-n2cnc3ccccc32)n1
Temperature: -5 °C
Reaction time: 0.5 h
Yield: 32.2 %

Procedure:
30.5 g (167 mmol) of 2,4,6-trichloropyrimidine dissolved in DMF (300 ml) was cooled to −5° C., added with potassium carbonate (40 g) and benzimidazole (17.7 g, 150 mmol) and stirred for 30 minutes. The reaction mixture was further stirred at room temperature overnight. The reaction mixture was added with water (500 ml) and the precipitated crystals were collection by filtration. The obtained crude crystals were purified by silica gel chromatography to obtain 12.8 g (yield: 32%) of 2-(benzimidazol-1-yl)-4,6-dichloropyrimidine with melting point of 173° C. -175° C. as colorless crystals.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH:4]=[O:5].[CH3:13][O-:14].[Na+]>CO>[CH3:13][O:14][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: C[O-]
Reactant: O=Cc1cc([N+](=O)[O-])ccc1Cl
Agent: [Na+]
Solvent: CO
Product: COc1ccc([N+](=O)[O-])cc1C=O
Temperature: 25 °C

Procedure:
A mixture of 2.5 grams (13.5 mmol) of 2-chloro-5-nitrobenzaldehyde (Aldrich Chem. Co.) in 250 mL of CH3OH was treated with 2.92 grams (54.1 mmol) of sodium methoxide, refluxed for 16 hours and allowed to cool to room temperature. After removal of the solvent in vacuo, the residue was suspended in water, treated with 2N HCl (adjusting to pH <5) and extracted into methylene chloride. After drying over MgSO4 , the solvent was removed in vacuo to give a yellow solid, 2.02 grams (83%).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[N:8]([CH2:11][CH2:12][OH:13])[CH:9]=[N:10][C:6]=2[CH:5]=[CH:4][C:3]=1[F:14].CC(O)=[O:17]>CC(O)C.OS(O)(=O)=O.O>[Cl:1][C:2]1[C:7]2[N:8]([CH2:11][C:12]([OH:17])=[O:13])[CH:9]=[N:10][C:6]=2[CH:5]=[CH:4][C:3]=1[F:14]
Reactant: OCCn1cnc2ccc(F)c(Cl)c21
Reactant: CC(=O)O
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Solvent: O
Product: O=C(O)Cn1cnc2ccc(F)c(Cl)c21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-(7-Chloro-6-fluoro-1H-benzimidazol-1-yl)ethanol (550 mg, 2.57 mmol) is dissolved in AcOH (20.0 mL). Jones reagenta (3.31 mL, 3.00 mmol, 0.907 M) is added drop wise, and the solution is stirred for 1 hour at room temperature. The solution is diluted with iPrOH (50.0 mL), and the solvents are evaporated. 6N NaOH is added to the solution until the pH is 11. The aqueous phase is washed with EtOAc (50.0 mL), and the organic phase is extracted 3 times with water (3×50.0 mL). The combined aqueous phases are acidified with 12N HCl until the pH is 3. The aqueous phase is then extracted 4 times with EtOAc (4×50.0 mL). The combined organic phases are dried with MgSO4, filtered and concentrated. The product is sufficiently pure by 1H NMR (236 mg, 40%). 1H NMR (400 MHz, DMSO-D6) δ ppm 5.18 (s, 2H) 7.24 (dd, J=10.16, 8.79 Hz, 1H) 7.64 (dd, J=8.79, 4.49 Hz, 1H) 8.13-8.30 (m, 1H). a Jones reagent is prepared by mixing 997 mg of CrO3 in 1.00 mL of H2SO4 and 10.0 mL of water.
Reaction SMILES: [CH2:1]([NH:3][C:4]([C:6]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[CH:13][CH:12]=2)=[C:9]([C:24]2[CH:29]=[C:28]([CH:30]([CH3:32])[CH3:31])[C:27]([O:33]CC3C=CC=CC=3)=[CH:26][C:25]=2[O:41]CC2C=CC=CC=2)[O:8][N:7]=1)=[O:5])[CH3:2].CO>C(Cl)Cl>[CH2:1]([NH:3][C:4]([C:6]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[CH:13][CH:12]=2)=[C:9]([C:24]2[CH:29]=[C:28]([CH:30]([CH3:31])[CH3:32])[C:27]([OH:33])=[CH:26][C:25]=2[OH:41])[O:8][N:7]=1)=[O:5])[CH3:2]
Reactant: CCNC(=O)c1noc(-c2cc(C(C)C)c(OCc3ccccc3)cc2OCc2ccccc2)c1-c1ccc(CN2CCOCC2)cc1
Solvent: CO
Solvent: ClCCl
Product: CCNC(=O)c1noc(-c2cc(C(C)C)c(O)cc2O)c1-c1ccc(CN2CCOCC2)cc1
Reaction time: 0.5 h

Procedure:
5-(2,4-Bis-benzyloxy-5-isopropyl-phenyl)-4-(4-morpholin-4-ylmethyl-phenyl)-isoxazole-3-carboxylic acid ethylamide (1 eq) was dissolved in an. DCM and under a nitrogen atmosphere, was cooled to 0° C. 1MBCl3 in DCM was added drop wise and the solution was stirred under these conditions for 30 minutes. Methanol (2 ml) was added and the reaction mixture was concentrated in vacuo. Purification of the sample by preparative LC/MS gave 5-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(4-morpholin-4-ylmethyl-phenyl)-isoxazole-3-carboxylic acid ethylamide as a white solid.