Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[N:10]([O:11][CH:12]([C:14]3[C:19]([Cl:20])=[CH:18][CH:17]=[C:16]([F:21])[C:15]=3[Cl:22])[CH3:13])[CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1.[CH3:23][N:24]([CH3:39])[CH2:25][CH2:26][NH:27][C:28]([C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][CH:35]=1)=[O:29]>>[Cl:22][C:15]1[C:16]([F:21])=[CH:17][CH:18]=[C:19]([Cl:20])[C:14]=1[CH:12]([O:11][N:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([C:34]3[CH:35]=[C:30]([CH:31]=[CH:32][CH:33]=3)[C:28]([NH:27][CH2:26][CH2:25][N:24]([CH3:39])[CH3:23])=[O:29])[CH:3]=2)[CH:8]=[CH:9]1)[CH3:13]
Reactant: CN(C)CCNC(=O)c1cccc(B(O)O)c1
Reactant: CC(On1ccc2ncc(Br)cc21)c1c(Cl)ccc(F)c1Cl
Product: CC(On1ccc2ncc(-c3cccc(C(=O)NCCN(C)C)c3)cc21)c1c(Cl)ccc(F)c1Cl

Procedure:
The entitled compound was prepared from 6-bromo-1-[1-(2,6-dichloro-3-fluorophenyl)ethoxy]-1H-pyrrolo[3,2-b]pyridine and (3-{[2-(dimethylamino)ethyl]carbamoyl}phenyl)boronic acid according to the procedure described in example 4.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][C:9]2[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:16])=[O:7])=[CH:4][CH:3]=1.[OH-].[Na+].[CH3:21][O:22][C:23](=[O:32])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]Br.[I-].[Na+]>CN(C)C=O>[CH3:21][O:22][C:23](=[O:32])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][N:8]([C:9]1[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:16])[C:6](=[O:7])[C:5]1[CH:17]=[CH:18][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: COC(=O)CCCCCCCBr
Reactant: Cc1cccc(C)c1NC(=O)c1ccc(Cl)cc1
Agent: [I-]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: COC(=O)CCCCCCCN(C(=O)c1ccc(Cl)cc1)c1c(C)cccc1C

Procedure:
As described in example 1(a), the reaction is carried out with 11 g (42 mmol) of 4-chloro-N-(2.6-dimethylphenyl)-benzamide, 1.8 g (75 mmol) of sodium hydroxide, 12 g (50 mmol) of 8-bromocaprylic acid methyl ester, 100 cc. of dimethylformamide and 1.2 g (8 mmol) of sodium iodide. Reaction time: 4 hours, reaction temperature: 110°-120° C. The crude product is used in the next reaction step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[S:8][C:9]([C:12]([O:14]CC)=[O:13])=[CH:10][N:11]=2)=[CH:4][CH:3]=1.[Li+].[OH-].Cl>C1COCC1>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[S:8][C:9]([C:12]([OH:14])=[O:13])=[CH:10][N:11]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cnc(Oc2ccc(Cl)cc2)s1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1cnc(Oc2ccc(Cl)cc2)s1
Temperature: 25 °C

Procedure:
A solution of ethyl 2-(4-chlorophenoxy)-5-thiazolecarboxylate from above in 1:1 1N LiOH:THF (150 mL) was heated at 50° C. for 1 hr. It was then cooled to r.t. and the THF was stripped off in vacuo. The resulting aqueous solution was poured into 1:1 conc. HCl:ice (200 mL), the precipitate was collected, taken up in ethylacetate (250 mL), dried with MgSO4 and concentrated to afford 2-(4-chlorophenoxy)-5-thiazolecarboxylic acid (7.49 g, 89% over the two steps) as an off-white solid.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.N1C=CN=C1.[C:13]([Si:17]([CH3:20])([CH3:19])Cl)([CH3:16])([CH3:15])[CH3:14]>C(Cl)Cl>[C:13]([Si:17]([CH3:20])([CH3:19])[O:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1)([CH3:16])([CH3:15])[CH3:14]
Reactant: OC1CCNCC1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC1CCNCC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 173.2 %

Procedure:
To a solution of 4-hydroxypiperidine (2.00 g, 9.89 mmoles) in CH2Cl2 (30 mL) is added 1H-imidazole (2.69 g, 39.55 mmoles) followed by t-butyldimethylchlorosilane (3.58 g, 23.73 mmoles) and the reaction mixture is stirred at room temperature. After 12 hours, the reaction mixture is washed with water, saturated solution of NaHCO3, and brine. The organic layers are combined and dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue is purified by flash chromatography (silica gel) over a gradient using 100% CH2Cl2 to 10% 7N ammonia in MeOH/90% CH2Cl2 to afford the title compound (3.69 g, 86.3%). Mass spectrum (m/z): 216.2 (M+1).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH2:11][C:10]2([C:17]3[CH:18]=[CH:19][C:20]([O:22][CH3:23])=[CH:21][C:16]=3[O:15][CH2:14]2)[CH:9]1[C:24]#[N:25])C1C=CC=CC=1.[H][H]>C(O)C.[Ni]>[CH3:23][O:22][C:20]1[CH:19]=[CH:18][C:17]2[C:10]3([CH2:14][O:15][C:16]=2[CH:21]=1)[CH2:11][CH2:12][CH2:13][NH:8][CH:9]3[CH2:24][NH2:25]
Reactant: [H][H]
Reactant: COc1ccc2c(c1)OCC21CCCN(Cc2ccccc2)C1C#N
Agent: [Ni]
Solvent: CCO
Product: COc1ccc2c(c1)OCC21CCCNC1CN

Procedure:
A mixture of 1 mmol of 1′-benzyl-6-methoxyspiro[1-benzofuran-3,3′-piperidine]-2′-carbonitrile and 50 mg of Raney-Nickel (activated by washing with water till pH 7 and washing with ethanol) in 5 ml of ethanol is hydrogenated for 12 hours under 500 psi hydrogen. The reaction mixture is filtered over Hyflo and the filtrate is evaporated. From the residue the title compound is identified by means of flash chromatography (SiO2 60F) on the basis of the Rf value.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[C:6]([CH3:16])[CH:7]=[C:8]([C:13](O)=O)[CH:9]=2)[N:4]=1.[C:17]1([NH2:24])[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[NH2:23]>P(Cl)(Cl)(Cl)=O>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[C:6]([CH3:16])[CH:7]=[C:8]([C:13]3[NH:23][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=4[N:24]=3)[CH:9]=2)[N:4]=1
Reactant: Nc1ccccc1N
Reactant: COc1ccc2cc(C(=O)O)cc(C)c2n1
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc2cc(-c3nc4ccccc4[nH]3)cc(C)c2n1

Procedure:
2-Methoxy-8-methylquinoline-6-carboxylic acid (1.09 g) was added in portions to a stirred mixture of o-phenylene diamine (0.54 g) and phosphorus oxychloride (20 cm3) at room temperature (20° ). The mixture was heated under reflux for 4 hours and then solvent was evaporated in vacuo. Ice (20 g) was added to the residue which was then basified to pH 9 with aqueous 2.5M sodium hydroxide and filtered to yield a solid which was chromatographed on silica (Merck "MK 60.9385" [Trade Mark]) eluting with methanol:dichloromethane, 1:100 by volume. Combination and evaporation of appropriate fractions gave the title compound which was characterised spectroscopically and used directly in Example 2 without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:12]([CH:17]1CP(C2C=CC=CC=2)C(C2C=CC=CC=2)(C2C=CC=CC=2)C1=C)([O:14][CH2:15][CH3:16])=[O:13]>C(Cl)Cl>[N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[CH:17][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: C=C1C(C(=O)OCC)CP(c2ccccc2)C1(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: CCOC(=O)C=Cc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 89.8 %

Procedure:
4-Nitrobenzaldehyde (1 g) was dissolved in methylene chloride (20 ml), and the reaction system was cooled to 0° C. The solution was added with carboethoxy-methylenetriphenylphospholan (2.56 g) and stirred at 0° C. for 1 hour. The reaction system was concentrated under reduced pressure without any treatment, and the residue was purified by silica gel column chromatography (50 g, hexane:ethyl acetate=4:1) to obtain ethyl 3-(4-nitrophenyl)acrylate (1.27 g, 86%).
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].Cl.[CH2:7]1[CH2:11][O:10][C:9]2[CH:12]=[CH:13][C:14]3[CH2:15][CH2:16][C@@H:17]([CH2:19][CH2:20][NH2:21])[C:18]=3[C:8]1=2.C(N(CC)CC)C.O>CN(C)C=O>[CH2:7]1[CH2:11][O:10][C:9]2[CH:12]=[CH:13][C:14]3[CH2:15][CH2:16][C@@H:17]([CH2:19][CH2:20][NH:21][C:1](=[O:4])[CH2:2][CH3:3])[C:18]=3[C:8]1=2
Reactant: CCC(=O)Cl
Reactant: NCC[C@@H]1CCc2ccc3c(c21)CCO3
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CCC(=O)NCC[C@@H]1CCc2ccc3c(c21)CCO3
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.6 %

Procedure:
Propionyl chloride (2.57 g, 27.8 mmol.) was gradually added dropwise, under ice-cooling, to a solution of (S)-2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl) ethylamine hydrochloride (5.55 g, 23.1 mmol.) and triethylamine (4.7 g, 46.3 mmol.) in N,N-dimethylformamide (100 ml). The mixture was stirred for one hour at room temperature, which was then poured into water, followed by extracting the organic matter with ethyl acetate. The extract solution was washed with a saturated aqueous saline solution and water, which was then dried over anhydrous magnesium sulfate, followed by distilling off the solvent under reduced pressure. The residue was purified by means of silica gel column chromatography (ethyl acetate:methanol=98:2) to afford the title compound (yield 5.25 g, 88%).
Reaction SMILES: [CH3:1][CH:2]([NH:11][C:12]([CH:14]1[O:19][CH2:18][CH2:17][N:16]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:15]1)=O)[C:3](=O)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.FC(F)(F)C([O-])=O.[NH4+:34]>>[CH3:1][C:2]1[N:11]=[C:12]([CH:14]2[O:19][CH2:18][CH2:17][N:16]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:15]2)[NH:34][C:3]=1[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(NC(=O)C1CN(Cc2ccccc2)CCO1)C(=O)c1ccccc1
Reactant: [NH4+]
Agent: O=C([O-])C(F)(F)F
Product: Cc1nc(C2CN(Cc3ccccc3)CCO2)[nH]c1-c1ccccc1
Temperature: 150 °C
Reaction time: 0.75 h
Yield: 97.5 %

Procedure:
A mixture of N-(1-methyl-2-oxo-2-phenylethyl)-4-(phenylmethyl)-2-morpholinecarboxamide (1.3 g, 3.69 mmol) and ammonium trifluoroacetate (2.417 g, 18.44 mmol) was stirred for 0.75 hours at 150° C. The LCMS indicated that the starting material was consumed. The desired product was contained in the residue. Water (150 mL) was added to the residue, and the resulting mixture was extracted with EtOAc (3×100 mL). The organics were dried (Na2SO4), filtered, and evaporated to afford the title compound (1.2 g) as a brown oil. LC-MS (ES) m/z=334 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:11])[C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].Br[CH2:13][CH2:14]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[Cl:1][C:2]1[CH:9]=[C:6]([CH:7]=[O:8])[C:5]2[O:10][CH2:14][CH2:13][O:11][C:4]=2[CH:3]=1
Reactant: O=Cc1cc(Cl)cc(O)c1O
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1cc(Cl)cc2c1OCCO2
Temperature: 100 °C
Reaction time: 1 h
Yield: 94.3 %

Procedure:
5-Chloro-2,3-dihydroxybenzaldehyde (6.0 g, 34.7 mmol) was dissolved in DMF (100 mL) and to the solution were added 1,2-dibromoethane (8.0 g, 42.5 mmol) and potassium carbonate (10.0 g, 70 mmol). The mixture was stirred at 100° C. for one hour, cooled to room temperature and then diluted with water (200 mL). After extraction twice with ethyl acetate (200 mL) the combined organic solutions were washed with brine and then dried over Na2SO4. The solvent was removed by evaporation and the solid residue treated with methanol. After filtration and drying there was obtained 6.5 g (94%) of 7-chloro-2,3-dihydro-1,4-benzodioxine-5-carbaldehyde. 1H NMR (300 MHz, CDCl3): 4.3-4.4 (m, 4H), 7.1 (d, 1H), 7.3 (d, 1H), 10.3 (s, 1H).
Reaction SMILES: [C:1]([NH2:9])(=[S:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[CH2:10]([O:12][C:13](=[O:22])[CH:14](Cl)[C:15](=O)[C:16]([F:19])([F:18])[F:17])[CH3:11].CCN(CC)CC>C(O)C>[CH2:10]([O:12][C:13]([C:14]1[S:8][C:1]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=2)=[N:9][C:15]=1[C:16]([F:17])([F:18])[F:19])=[O:22])[CH3:11]
Reactant: NC(=S)c1cccnc1
Reactant: CCOC(=O)C(Cl)C(=O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)c1sc(-c2cccnc2)nc1C(F)(F)F
Temperature: 150 °C

Procedure:
To a 20 mL microwave tube was added thionicotinamide (0.552 g, 4.0 mmol), ethanol (15 mL) and 2-chloro-4,4,4-trifluoro-3-oxo-butyric acid ethyl ester (1.75 g, 8 mmol). The tube was capped and heated in a microwave at 150° C. for 10 min. The reaction mixture was cooled to ambient temperature and Et3N (1.7 mL, 12 mmol) was added. The tube was capped and heated in a microwave at 130° C. for 1 min. After cooling to ambient temperature the solvent was evaporated and the crude reaction mixture was directly subjected to silica gel chromatography (0 to 100% ethyl acetate/hexanes) to give the desired product as an orange oil which subsequently solidified (0.885 g, 73%): IR (KBr) 2988, 1737, 1712 cm−1; 1H NMR (300 MHz, CDCl3) δ 9.21 (dd, J=2.5, 0.8 Hz, 1H), 8.77 (dd, J=5.0, 1.7 Hz, 1H), 8.33 (dt, J=8.0, 2.2 Hz, 1H), 7.47 (ddd, J=11.8, 4.7, 0.8 Hz, 1H), 4.45 (q, J=14.3, 7.1 Hz, 2H), 1.44 (t, J=7.1 Hz, 3H); ESIMS m/z 303 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:8]([CH2:19][NH2:20])=[CH:7]2.Cl[C:22]1[N:30]=[CH:29][N:28]=[C:27]2[C:23]=1[NH:24][CH:25]=[N:26]2.CCN(C(C)C)C(C)C>C(O)CCC>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:8]([CH2:19][NH:20][C:22]1[N:30]=[CH:29][N:28]=[C:27]3[C:23]=1[N:24]=[CH:25][NH:26]3)=[CH:7]2
Reactant: Clc1ncnc2nc[nH]c12
Reactant: NCc1cc2cccc(Cl)c2nc1Oc1ccccc1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Clc1cccc2cc(CNc3ncnc4[nH]cnc34)c(Oc3ccccc3)nc12

Procedure:
Prepared according to Procedure H using (8-chloro-2-phenoxyquinolin-3-yl)-methanamine (0.110 g, 0.360 mmol), 6-chloropurine (0.072 g, 0.46 mmol, 1.2 eq) and DIEA (0.72 mmol, 2.0 eq) in n-butanol (3 mL). N-((8-chloro-2-phenoxyquinolin-3-yl)methyl)-9H-purin-6-amine [PI3Kδ IC50=125 nM] was obtained after purification as a white solid. 1H-NMR (MeOD) δ ppm 8.18-8.24 (s, 1 H), 8.14-8.20 (s, 1 H), 7.85-7.91 (d, J=7.58, 1 H), 7.72-7.79 (d, J=7.34, 1 H), 7.47-7.55 (m, 3 H), 7.42-7.47 (m, 3 H), 7.35-7.42 (m, 1 H), 4.01-4.14 (m, 2 H), Mass Spectrum (ESI) m/e=403 (M+1)
Reaction SMILES: [CH2:1]([O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]2[C@H:11]3[C@H:21]([CH2:22][CH2:23][C@:6]12[CH3:7])[C@:19]1([CH3:20])[C@H:14]([CH2:15][C:16](=[O:24])[CH2:17][CH2:18]1)[CH2:13][CH2:12]3)[C:2]#[CH:3].[Li][CH3:26]>C(Cl)Cl>[OH:24][C@:16]1([CH3:26])[CH2:17][CH2:18][C@@:19]2([CH3:20])[C@@H:14]([CH2:13][CH2:12][C@@H:11]3[C@@H:21]2[CH2:22][CH2:23][C@@:6]2([CH3:7])[C@H:8]3[CH2:9][CH2:10][C@@H:5]2[O:4][CH2:1][C:2]#[CH:3])[CH2:15]1
Reactant: [Li]C
Reactant: C#CCO[C@H]1CC[C@H]2[C@@H]3CC[C@H]4CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Solvent: ClCCl
Product: C#CCO[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@](C)(O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 16.6 %

Procedure:
A solution of 17β-(2-propynyloxy)-5α-androstan-3-one (230 mg, 0.7 mmol) in dry TBF (20 mL) was treated with MeLi (5 mL, 1M in THF, 5 mmol) at -70° C. After stirring the mixture at -70° C. for 0.5 hr, the cooling bath was removed and it was warmed to 10° C. The mixture was then quenched with NH4Cl solution (5 mL). The solvents were removed and the residue was extracted with EtOAc. The organic layer was washed with water, and brine. After drying over anhyd. MgSO4 the solution was filtered and evaporated to yield the crude product. This crude product was then dissolved in a small amount of CH2Cl2 and poured on a column of silica gel. Elution with toluene:acetone mixture (98:2) gave 3α-hydroxy-3β-methyl-17β-(2-propynyloxy)-5α-androstane (40 mg); TLC Rf (toluene:acetone 95:5)=0.31; and then 3β-hydroxy-3α-methyl-17β-(2-propynyloxy)-5α-androstane (70 mg) as a colorless solid; TLC Rf (hexane:acetone 7:3)=0.27.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:12][C@H:13]2[CH2:18][CH2:17][C@H:16]([CH:19]([CH3:21])[CH3:20])[CH2:15][CH2:14]2)=[N:4][C:5]([CH3:11])=[C:6]([N+:8]([O-])=O)[CH:7]=1.[Cl-].[NH4+]>CCO.O.[Fe]>[Br:1][C:2]1[CH:7]=[C:6]([NH2:8])[C:5]([CH3:11])=[N:4][C:3]=1[O:12][C@H:13]1[CH2:14][CH2:15][C@H:16]([CH:19]([CH3:20])[CH3:21])[CH2:17][CH2:18]1
Reactant: Cc1nc(O[C@H]2CC[C@H](C(C)C)CC2)c(Br)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Cc1nc(O[C@H]2CC[C@H](C(C)C)CC2)c(Br)cc1N

Procedure:
To a stirred solution of 3-bromo-2-(trans-4-isopropylcyclohexoxy)-6-methyl-5-nitro-pyridine (0.917 g, 2.00 mmol) in EtOH/H2O (24 mL/6 mL, 4/1 v/v), ammonium chloride (0.109 g, 2.00 mmol, 1.0 eq) and iron powder (0.452 g, 8.00 mmol, 4 eq) were added at room temperature under inert atmosphere (Ar). The reaction mixture was stirred under heating to reflux for 3 h. At this point in time, TLC indicated that the starting material was consumed. Therefore, the reaction mixture was allowed to reach room temperature and was filtered through a pad of celite. The filtrate was concentrated under reduced pressure and the residue partitioned between a 2 molar aqueous NaOH solution (20 mL) and ethyl acetate (30 mL). The phases were separated and the aqueous phase extracted with ethyl acetate (2×20 mL). The organic layer was washed with brine (40 mL), dried over anhydrous Na2SO4 and filtered. The solvent was removed in vacuo to afford the title compound (0.658 g, 100%) as an oil.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([S:13]([N:16]1[CH2:21][C:20](=[O:22])[N:19]([N:23]([CH3:36])[CH:24]3[CH2:29][CH2:28][N:27]([C:30]4[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=4)[CH2:26][CH2:25]3)[CH:18]([C:37](OC)=[O:38])[CH2:17]1)(=[O:15])=[O:14])[CH:7]=[CH:6]2.[BH4-].[Li+].Cl.CO>CO>[ClH:2].[Cl:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([S:13]([N:16]1[CH2:17][CH:18]([CH2:37][OH:38])[N:19]([N:23]([CH3:36])[CH:24]3[CH2:25][CH2:26][N:27]([C:30]4[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=4)[CH2:28][CH2:29]3)[C:20](=[O:22])[CH2:21]1)(=[O:14])=[O:15])[CH:7]=[CH:6]2
Reactant: COC(=O)C1CN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC(=O)N1N(C)C1CCN(c2ccncc2)CC1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Product: CN(C1CCN(c2ccncc2)CC1)N1C(=O)CN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1CO
Temperature: 0 °C
Yield: 83.9 %

Procedure:
A solution of methyl 4-[(6-chloro-2-naphthyl)sulfonyl)-1-[methyl[1-(4-pyridinyl)-4-piperidinyl]amino]-6-oxo-2-piperazinecarboxylate hydrochloride (0.3 g) in methanol (20 ml) was treated with 3 portions of lithium borohydride (1.14 g) with stirring at 0° C. After completion of the reaction, the reaction system was adjusted at pH 4 with a 10% hydrochloric acid/methanol solution, and then concentrated under reduced pressure. The residue was partitioned between methylene chloride and saturated aqueous sodium bicarbonate, and the organic phase was dried over magnesium sulfate, and then concentrated under reduced pressure. The residue was purified on a CHP-20 column (water→1% 1N hydrochloric acid-containing 30% aqueous solution of acetonitrile) to obtain the title compound (0.12 g) as a colorless powder.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[NH2:18])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=1)=[O:6].[CH3:19][C:20]1[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[C:21]=1[CH:22]=O>CO>[Cl:14][C:10]1[CH:9]=[C:8]([NH:7][C:5]([C:4]2[CH:15]=[CH:16][C:17]3[N:18]=[C:22]([C:21]4[C:24]([CH3:28])=[CH:25][CH:26]=[CH:27][C:20]=4[CH3:19])[NH:1][C:2]=3[CH:3]=2)=[O:6])[CH:13]=[CH:12][CH:11]=1
Reactant: Nc1ccc(C(=O)Nc2cccc(Cl)c2)cc1N
Reactant: Cc1cccc(C)c1C=O
Solvent: CO
Product: Cc1cccc(C)c1-c1nc2ccc(C(=O)Nc3cccc(Cl)c3)cc2[nH]1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 3,4-diamino-N-(3-chloro-phenyl)-benzamide (0.1 mL in 0.2 M DMSO solution), 2,6-dimethyl-benzaldehyde (0.1 mL in 0.2 M toluene solution) and YB(SO3CF3)3 (0.1 mL in 0.02M THF solution) was shaked at room temperature for 16 h. Then another 0.04 mL of 2,6-dimethyl benzaldehyde (0.2 M) toluene solution was added. The mixture was stirred in open air at ambient temperature overnight. The mixture was then diluted by MeOH and the whole was loaded onto a solid phase extraction (SPE) cartridge that contained strong cation exchange (SCX) (1 g media in 6 mL cartridge, United Chemical Technology). Wash-to-waste (5 mL MeOH) was followed by elute-to-collect (5 mL 20:2:1 ethyl acetate-MeOH-Et3N) and, after evaporation of volatiles, the crude was further purified by silica gel column chromatography to give of 2-(2,6-dimethyl-phenyl)-3H-benzoimidazole-5-carboxylic acid (3-chloro-phenyl)-amide as white powder: MS (m/z) 376 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=O)([O-:3])=[O:2].[C:12]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)(=[O:17])[CH2:13][C:14]([CH3:16])=[O:15].N1CCCCC1>C1C=CC=CC=1>[N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=[C:13]([C:14]([CH3:16])=[O:15])[C:12]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])([O-:3])=[O:2]
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Reactant: CC(=O)CC(=O)OCc1ccccc1
Solvent: C1CCNCC1
Solvent: c1ccccc1
Product: CC(=O)C(=Cc1ccccc1[N+](=O)[O-])C(=O)OCc1ccccc1
Yield: 107.9 %

Procedure:
A mixture of 2-nitrobenzaldehyde (3.023 g), benzyl acetoacetate (3.802 g) and piperidine (272.5 mg) in benzene (10 ml), was treated in a substantially similar manner that of Example 1-11) to give a brown oil (6.94 g) of benzyl 2-(2-nitrobenzylidene)acetoacetate, which was further treated with ethyl 3-amino-4,4-diethoxycrotonate (4.34 g) to give a dark brown oil (10.3 g). This oil was purified by column chromatography on silica-gel and the resultant oil (3.8 g) was crystallized to give crystals (1.65 g) of benzyl 2-methyl-4-(2-nitrophenyl)-5-ethoxycarbonyl-6-diethoxymethyl-1,4-dihydropyridine-3-carboxylate, m.p. 103° to 103.5° C. (recrystallized from a mixture of diisopropyl ether and n-hexane).
Reaction SMILES: C1(C=O)C2C(=CC3C(C=2)=CC=CC=3)C=CC=1.[Br:17][C:18]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[C:24]2[C:19]=1[CH:20]=[CH:21][CH:22]=[C:23]2[CH2:32][OH:33].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>>[Br:17][C:18]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[C:24]2[C:19]=1[CH:20]=[CH:21][CH:22]=[C:23]2[CH:32]=[O:33]
Reactant: OCc1cccc2c(Br)c3ccccc3cc12
Agent: O=[Cr](=O)([O-])Cl
Agent: O=Cc1cccc2cc3ccccc3cc12
Agent: c1cc[nH+]cc1
Product: O=Cc1cccc2c(Br)c3ccccc3cc12

Procedure:
Using the procedure outlined in 15D, oxidation of (10-bromo-1-anthracenyl)methanol (16A) with pyridinium chlorochromate (Aldrich) gave 10-bromo-1-anthracenecarbaldehyde mp 134.5°-135.5°, (PhCH3 /hexane), (C, H, Br).
Reaction SMILES: [CH2:1]([C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:15]=1[OH:25])[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:3]=1[OH:13].[C:26](O)(=[O:29])[CH:27]=[CH2:28].C(N(CC)CC)C.P(Cl)(Cl)(Cl)=O>C1(C)C=CC=CC=1>[C:26]([O:25][C:15]1[C:16]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:17][C:18]([CH3:20])=[CH:19][C:14]=1[CH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:3]=1[OH:13])(=[O:29])[CH:27]=[CH2:28]
Reactant: C=CC(=O)O
Reactant: Cc1cc(Cc2cc(C)cc(C(C)(C)C)c2O)c(O)c(C(C)(C)C)c1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: C=CC(=O)Oc1c(Cc2cc(C)cc(C(C)(C)C)c2O)cc(C)cc1C(C)(C)C
Reaction time: 1 h
Yield: 95 %

Procedure:
To a 2-liter four-necked flask equipped with a thermometer, stirring apparatus, condenser and dropping funnel were added 340.51 g (1.0 mole) of 2,2'-methylenebis(6-tert-butyl-4-methylphenol), 72.06 g (1.0 mole) of acrylic acid, 500 g of toluene and 209.47 g (2.07 moles) of triethylamine. After replacing the air in the container with nitrogen, 105.8 g (0.69 mole) of phosphorus oxychloride was added dropwise with stirring. After completion of the dropwise addition, the reaction solution was kept at 80° C. for 1 hour. Thereafter, the organic layer was washed with water until it became neutral, and toluene was removed under reduced pressure. The residue was then recrystallized from n-hexane to obtain 374.8 g of a white crystalline 2,2'-methylenebis(6-tert-butyl-4-methylphenol) monoacrylate having a melting point of 132° to 134° C. Yield, 95%.