Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]([CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH3:3].[CH:9](=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>C(Cl)Cl.CC(O)=O>[CH2:9]([NH:1][C@H:2]([CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH3:3])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=Cc1ccccc1
Reactant: CCCCC[C@H](C)N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCCCC[C@H](C)NCc1ccccc1
Temperature: 0 °C
Reaction time: 28 h

Procedure:
A sample of 0.15 mL (1 mmol) of (S)-(+)-2-aminoheptane ((S)-44) 0.1 mL (1 mmol) of benzaldehyde and 0.1 mL of HOAc were combined in 10 mL of CH2Cl2 and cooled to 0° C., then added 650 mg (3 mmol) of sodium triacetoxyborohydride in one portion. The reaction mixture was stirred under argon at room temperature for 28 hours. The mixture was diluted with 10 mL of dichloromethane, cooled in an ice bath and 20 mL of 5% NaOH (in water) was added. Fractions were separated, organics were dried (Na2SO4) and evaporated to 154 mg (70%). 1H NMR (CDCl3) 600.88 (m, 3H), 1.08 (d, 3H J=6.6 Hz), 1.19-1.37 (m, 6H), 1.41-1.67 (m, 2H), 3.62-3.77 (m, 1H), 3.75 (p, 2H, J=12 Hz), 7.17-7.41 (m, 5H); MS (APCI+) m/z (rel): 206 (100); [α]D=+7.8° (c=1.0, MeOH).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[N:14]=[C:13]([N:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]3=[O:21])[CH:12]=[CH:11][CH:10]=2)O1.Br[C:24]1[CH:29]=[CH:28][C:27]([C@@H:30]([N:32]2[CH2:37][CH2:36][C@:35]([CH2:44][C:45]([OH:48])([CH3:47])[CH3:46])([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[O:34][C:33]2=[O:49])[CH3:31])=[CH:26][CH:25]=1>>[OH:48][C:45]([CH3:46])([CH3:47])[CH2:44][C@@:35]1([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[O:34][C:33](=[O:49])[N:32]([C@H:30]([C:27]2[CH:26]=[CH:25][C:24]([C:9]3[CH:10]=[CH:11][CH:12]=[C:13]([N:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]4=[O:21])[N:14]=3)=[CH:29][CH:28]=2)[CH3:31])[CH2:37][CH2:36]1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: CC1(C)OB(c2cccc(-n3ccccc3=O)n2)OC1(C)C
Product: C[C@@H](c1ccc(-c2cccc(-n3ccccc3=O)n2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from 1-[6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]pyridin-2(1H)-one (purchased from CombiPhos Catalysts Inc., Princeton, N.J., USA) and (S)-3-[(S)-1-(4-bromophenyl)ethyl]-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one following a procedure analogous to that described in Example 35. LC (method 5): tR=1.53 min; Mass spectrum (ESI+): m/z=466, 524 [M+H]+; 1H NMR (CD3OD) δ 0.94 (s, 3H), 1.26 (s, 3H), 1.57 (d, 3H), 2.16 (s, 2H), 2.25 (m, 1H), 2.47 (m, 2H), 3.04 (m, 1H), 5.59 (q, 1H), 6.54 (t, 1H), 6.64 (d, 1H), 7.08 (d, 2H), 7.25-7.40 (5H), 7.63 (m, 1H), 7.66 (m, 1H), 7.85-8.00 (5H).
Reaction SMILES: [Br:1][C:2]1[C:6]2[C:7]([Cl:12])=[N:8][CH:9]=[C:10]([CH3:11])[C:5]=2[S:4][CH:3]=1.C1C(=O)N([Br:20])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[C:6]2[C:7]([Cl:12])=[N:8][CH:9]=[C:10]([CH2:11][Br:20])[C:5]=2[S:4][CH:3]=1
Reactant: Cc1cnc(Cl)c2c(Br)csc12
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1ncc(CBr)c2scc(Br)c12
Temperature: 25 °C

Procedure:
A solution of Example 277C (1 g, 3.81 mmol) in CCl4 (30 mL) was treated with NBS (0.755 g, 4.24 mmol) and benzoyl peroxide (0.093 g, 0.38 mmol), heated to reflux for 24 hours, cooled to room temperature, and filtered. The filtrate was concentrated to provide 3-bromo-7-(bromomethyl)-4-chlorothieno[3,2-c]pyridine, which was used directly. MS (ESI(+)) m/e 339.5, 341.6, 343.4 (M+H)+. The crude product was dissolved in DMF (7.5 mL), treated with sodium acetate (1.6 g, 19.5 mmol), heated to 100° C. overnight, and partitioned between water and ethyl acetate. The organic extract was washed with brine, dried (Na2SO4), filtered, and concentrated. The residue was purified by silica gel chromatography with 10% ethyl acetate/hexanes to provide 0.65 g (53% yield) of the desired product. MS (ESI(+)) m/e 319.7, 321.7, 323.7 (M+H)+.
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:14]([OH:16])=O)[CH3:13])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].C(N(CC)CC)C.C(Cl)(=O)OCC(C)C.Cl.[CH2:33]([O:35][C:36](=[O:44])[CH2:37][NH:38][CH:39]1[CH2:43][CH2:42][CH2:41][CH2:40]1)[CH3:34]>O1CCCC1.C(Cl)(Cl)Cl>[CH2:33]([O:35][C:36](=[O:44])[CH2:37][N:38]([C:14](=[O:16])[C@H:12]([CH3:13])[NH:11][C:1]([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2])[CH:39]1[CH2:43][CH2:42][CH2:41][CH2:40]1)[CH3:34]
Reactant: CCOC(=O)CNC1CCCC1
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: CCOC(=O)CN(C(=O)[C@H](C)NC(=O)OCc1ccccc1)C1CCCC1
Temperature: -10 °C
Reaction time: 8 h
Yield: 60.7 %

Procedure:
N-Carbobenzoxy-L-alanine (11.4 g) and triethylamine (6.7 ml) are dissolved in 100 ml of tetrahydrofuran and under stirring at -10° C., 6.5 ml of isobutyl chlorocarbonate is added in small portions. Then, at -10° C. to -5° C., a solution of N-cyclopentylglycine ethyl ester hydrochloride (10 g) and triethylamine (6.7 ml) in chloroform (100 ml) is added and the mixture is allowed to stand at room temperature overnight. The reaction mixture is filtered and the filtrate is concentrated. To the residue is added 300 ml of water, followed by extraction with 200 ml of ethyl acetate. The ethyl acetate layer is washed with 5% hydrochloric acid, aqueous sodium hydrogen carbonate and water in that order and dried over sodium sulfate. Removal of the solvent by distillation gives an oil, which is separated and purified by column chromatography using 150 g of silica gel. The fractions eluted with toluene-ethyl acetate (5:1) are collected to give 11 g of N-carbobenzoxy-L-alanyl-N-cyclopentylglycine ethyl ester as an oil. This product (10 g) is dissolved in 100 ml of ethanol, then 16 ml of 2N sodium hydroxide is added, and the mixture is stirred at room temperature for 5 hours. The reaction mixture is concentrated and the concentrate is diluted with 100 ml of water and acidified with 10% hydrochloric acid, whereupon an oil separates out. This oil is extracted with 300 ml of ethyl acetate and the extract is washed with water, dried and concentrated to give 8 g of N-carbobenzoxy-L-alanyl-N-cyclopentylglycine as colorless oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:18]2[CH:23]=[CH:22][C:21]([O:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=3)=[C:20]([O:32][CH3:33])[CH:19]=2)=[C:4]2[N:9]([C:10]=1[CH:11]1[CH2:16][CH2:15][CH2:14][NH:13][CH2:12]1)[N:8]=[CH:7][N:6]=[C:5]2[NH2:17].C(N(CC)CC)C.[C:41](Cl)(=[O:44])[CH:42]=[CH2:43]>C(Cl)Cl>[NH2:17][C:5]1[C:4]2=[C:3]([C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=4)=[C:20]([O:32][CH3:33])[CH:19]=3)[C:2]([Cl:1])=[C:10]([CH:11]3[CH2:16][CH2:15][CH2:14][N:13]([C:41](=[O:44])[CH:42]=[CH2:43])[CH2:12]3)[N:9]2[N:8]=[CH:7][N:6]=1
Reactant: COc1cc(-c2c(Cl)c(C3CCCNC3)n3ncnc(N)c23)ccc1Oc1cccc(Cl)c1
Reactant: C=CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CC(=O)N1CCCC(c2c(Cl)c(-c3ccc(Oc4cccc(Cl)c4)c(OC)c3)c3c(N)ncnn23)C1
Temperature: -10 °C

Procedure:
The compound (27.6 mg, 0.057 mmol) prepared in Example 31 was taken up in 1 mL DCM (dry) under argon and triethylamine (23.8 μl, 0.171 mmole) was added. The reaction was cooled to −10° C. and the acryloyl chloride (4.17 μl, 0.051 mmole) was added via syringe slowly. The reaction quenched with methanol and solvent removed under vacuum. The title compound (10.5 mg) having the following data was isolated by prep-HPLC.
Reaction SMILES: [O:1]([CH2:8][C:9]#[C:10]/[CH:11]=[CH:12]\[C:13]#[C:14][Si](C)(C)C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.O[Li].O>C1COCC1.CCOCC>[O:1]([CH2:8][C:9]#[C:10][CH:11]=[CH:12][C:13]#[CH:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)C#C/C=C\C#CCOc1ccccc1
Agent: [Li]O
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: C#CC=CC#CCOc1ccccc1
Reaction time: 4 h
Yield: 93.9 %

Procedure:
To a solution of the product of step (b) (5.0 g, 19.7 mmol) in 20 mL THF was added 5 mL of water and LiOH-H2O (5.6 g, 133 mmol). The solution was stirred for 4 h, diluted with ether and washed with water. The aqueous layer extracted with ether and then ethyl acetate. The organic fractions were combined, dried (MgSO4) and concentrated. The residue was chromatographed over silica (30:1 hexane/ethyl acetate) to give 3.37 g of (94%) of 7-phenoxy-3-heptene-1,5-diyne.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6]([CH:11]([O:20]C(=O)C(Cl)(Cl)Cl)[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)=[C:5]([N+:27]([O-])=[O:28])[CH:4]=1.[CH3:30][O:31][C:32]1[C:37]([O:38][CH3:39])=[CH:36][C:35]([CH:40]([O:47]C(=O)C(Cl)(Cl)Cl)[C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[C:34]([N+:54]([O-])=[O:55])[CH:33]=1>C(#N)C>[CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6]([C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)=[O:20])=[C:5]([N:27]=[O:28])[CH:4]=1.[CH3:30][O:31][C:32]1[C:37]([O:38][CH3:39])=[CH:36][C:35]([C:40]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[O:47])=[C:34]([N:54]=[O:55])[CH:33]=1
Reactant: COc1cc(C(OC(=O)C(Cl)(Cl)Cl)c2ccccc2)c([N+](=O)[O-])cc1OC
Reactant: COc1cccc(C(OC(=O)C(Cl)(Cl)Cl)c2cc(OC)c(OC)cc2[N+](=O)[O-])c1
Solvent: CC#N
Product: COc1cc(N=O)c(C(=O)c2ccccc2)cc1OC
Product: COc1cccc(C(=O)c2cc(OC)c(OC)cc2N=O)c1

Procedure:
Irradiation of 0.2% solutions of α-(3-methoxyphenyl)-4,5-dimethoxy-2-nitrobenzyltrichloroacetate (38) and α-phenyl-4,5-dimethoxy-2-nitrobenzyltrichloroacetate (39) in acetonitrile resulted in nearly quantitative conversions into the expected photoproducts, 4,5-dimethoxy-3′-methoxy-2-nitrosobenzophenone (50) and 4,5-dimethoxy-2-nitrosobenzophenone (51), respectively, after less than 4 minutes. Irradiations at lower concentrations, monitored by UV, resulted in even faster photoreactions. When a 0.004% solution of α-phenyl-4,5-dimethoxy-2-nitrobenzyltrichloroacetate (39) was irradiated, there was a quantitative conversion into the photoproduct after 30 seconds. The two esters appeared to have a similar rate of photoconversion but the photolysis of α-phenyl-4,5-dimethoxy-2-nitrobenzyltrichloroacetate (39), quantum yield φ˜0.14, was cleaner with less amount of polar secondary photoproducts. These properties, coupled with the reduced inner filter effect and absorption maximum at 345 nm, make compound 39 a prime candidate for use in the microarray format.
Reaction SMILES: FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.C(N(C(C)C)CC)(C)C.O[CH:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28](=[O:35])[C:27]1([CH3:37])[CH3:36].[NH:38]1[CH:42]=[CH:41][N:40]=[CH:39]1>ClCCl.C([O-])(O)=O.[Na+].C(OCC)(=O)C>[N:38]1([CH:26]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:28](=[O:35])[C:27]2([CH3:37])[CH3:36])[CH:42]=[CH:41][N:40]=[CH:39]1
Reactant: CC1(C)C(=O)c2ccccc2C1O
Reactant: c1c[nH]cn1
Agent: O=C([O-])O
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC1(C)C(=O)c2ccccc2C1n1ccnc1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a solution of trifluoromethansulfonic anhydride (1.13 mL, 6.75 mmol) in dichloromethane (10 mL) at −78° C. is added, via cannula, a solution of diisopropylethylamine (1.8 mL, 10.1 mmol) and 3-hydroxy-2,2-dimethyl-indan-1-one, prepared as described in Example 20, (400 mg, 2.25 mmol) in dichloromethane (5 mL). The reaction is stirred at −78° C. for 10 minutes and then is placed at −10° C. for 10 minutes. The reaction is then re-cooled to −78° C. and a solution of imidazole (920 mg, 13.5 mmol) in dichloromethane (12 mL) is added via cannula. The reaction is then placed at room temperature for 1 hour, at which time it is diluted with saturated aqueous NaHCO3 and ethyl acetate. The layers are separated and the aqueous layer is extracted two times with ethyl acetate. The combined organic layers are dried with MgSO4, filtered, and concentrated. The resulting residue is purified by silica gel flash chromatography (ethyl acetate-dichloromethane, 1:3 to 1:0), to afford 3-imidazol-1-yl-2,2-dimethyl-indan-1-one; MS: (ESI) m/z 227 (M+H)+; 1H NMR: (400 MHz, CDCl3) δ ppm 0.80 (s, 3 H), 1.41 (s, 3 H), 5.52 (s, 1 H), 6.73 (s, 1 H), 7.12 (s, 1 H), 7.51 (d, J=7.6 Hz, 1 H), 7.56 (s, 1 H), 7.62 (t, J=7.5 Hz, 1 H), 7.70-7.80 (m, 1 H), 7.91 (d, J=7.6 Hz, 1 H).
Reaction SMILES: N.CC(O)C.ClC(C1C=CC(Cl)=CC=1)(C1N(C)C=NC=1)[C:8]1[CH:9]=[CH:10][C:11]2[N:17](C)[C:16](=[O:19])[CH2:15][N:14]=[C:13](C3C=CC=C(Cl)C=3)[C:12]=2[CH:27]=1>C1COCC1>[N:17]1[C:16](=[O:19])[CH:15]=[N:14][CH:13]=[C:12]2[CH:27]=[CH:8][CH:9]=[CH:10][C:11]=12
Reactant: CN1C(=O)CN=C(c2cccc(Cl)c2)c2cc(C(Cl)(c3ccc(Cl)cc3)c3cncn3C)ccc21
Agent: N
Solvent: CC(C)O
Solvent: C1CCOC1
Product: O=c1cncc2ccccc2n1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 151.7 %

Procedure:
NH3/2-propanol (40 ml) was added dropwise at 5° C. to a mixture of 7-[chloro(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-5-(3-chlorophenyl)-1,3-dihydro-1-methyl-2H-1,4-benzodiazepin-2-one (described in Example B10a) (0.0075 mol) in THF (40 ml). The mixture was stirred at 5° C. for 30 min, hydrolyzed and extracted with DCM. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated till dryness. The residue (4 g) was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH4OH 97.5/2.5/0.1 and 96/4/0.1; 15–40 μm). The pure fractions were collected and the solvent was evaporated. The residue was crystallized from acetonitrile and diethyl ether. The precipitate was filtered off and dried, yielding 1.8 g (48%) of 2H-1,4-benzodiazepin-2-one, 7-[amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-5-(3-chlorophenyl)-1,3-dihydro-1-methyl-2H-1,4-benzodiazepin-2-one, mp. 213° C.
Reaction SMILES: [C:1]1([C@H:7]([NH2:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:10][O:11][C:12](=[O:17])[CH2:13][C:14](=O)[CH3:15].[CH3:18][O:19][C:20](=[O:23])[C:21]#[CH:22]>CO>[CH3:18][O:19][C:20](=[O:23])[CH:21]=[CH:22][C:13](=[C:14]([NH:9][C@@H:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:8])[CH3:15])[C:12]([O:11][CH3:10])=[O:17]
Reactant: C#CC(=O)OC
Reactant: C[C@@H](N)c1ccccc1
Reactant: COC(=O)CC(C)=O
Solvent: CO
Product: COC(=O)C=CC(C(=O)OC)=C(C)N[C@H](C)c1ccccc1
Temperature: 25 °C
Yield: 73.9 %

Procedure:
A mixture of (R)-1-phenyl-ethylamine (3 g, 24.8 mmol) and 3-oxo-butyric acid methyl ester (3.2 mL, 29.7 mmol) in MeOH (100 mL) was refluxed for 3 h. Propynoic acid methyl ester (3.3 mL, 37.1 mmol) was added, and the resulting mixture was refluxed for 2 days. After cooling to r.t., the solvent was evaporated, and the crude oil was recrystallized from MeOH to give 5.56 g of the title compound as a pale orange solid. MS: (+) m/z 304.31 (M+1).
Reaction SMILES: [OH:1][C:2]1[C:3]([C:12](O)=O)=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[Cl:15][C:16]1[CH:21]=[CH:20][C:19](Br)=[CH:18][CH:17]=1.Br[C:24]1C=CC=CC=1>>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:12][C:3]2[C:2]([O:1][CH3:24])=[CH:11][C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=2)=[CH:18][CH:17]=1
Reactant: Clc1ccc(Br)cc1
Reactant: Brc1ccccc1
Reactant: O=C(O)c1cc2ccccc2cc1O
Product: COc1cc2ccccc2cc1Cc1ccc(Cl)cc1

Procedure:
Using 3-hydroxy-2-naphthoic acid as the starting material, and 4-chlorobromobenzene to replace bromobenzene, the procedures of Examples 3-7 were repeated to obtain the compound 2-(4-chlorobenzyl)-3-methoxynaphthalene.
Reaction SMILES: [OH-:1].[K+].[CH2:3]([O:10][C:11]1[CH:20]=[C:19]2[C:14]([CH:15]=[CH:16][C:17]([C:21]#N)=[CH:18]2)=[CH:13][CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C1(C)C=CC=CC=1.Cl.[OH2:31]>C(O)C>[CH2:3]([O:10][C:11]1[CH:20]=[C:19]2[C:14]([CH:15]=[CH:16][C:17]([C:21]([OH:31])=[O:1])=[CH:18]2)=[CH:13][CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: [OH-]
Reactant: N#Cc1ccc2ccc(OCc3ccccc3)cc2c1
Reactant: O
Agent: Cl
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: O=C(O)c1ccc2ccc(OCc3ccccc3)cc2c1
Temperature: 80 °C
Yield: 72 %

Procedure:
KOH (406 mg, 7.3 mmol) is added to a suspension of 7-benzyloxy-2-naphthonitrile (626 mg; 2.42 mmol) in water, ethanol, and toluene (15 mL, 1:3:2). The reaction is heated to 80° C. for 72 hours. The reaction is allowed to cool, poured into 1M HCl and extracted three times with CH2Cl2. The combined organic layers are dried (Na2SO4), filtered and concentrated to dryness. The product is purified by column chromatography (step gradient, 5 to 10% methanol in CH2Cl2). The resulting material is crystallized from ethanol-water to give 7-benzyloxy-2-naphthoic acid (484 mg, 72%) as a white solid. HRMS (EI) calculated for C18H14O3: 278.0943, found 278.0947.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8]([N:10]=[C:11]=[S:12])=[O:9])[CH:5]=[CH:6][CH:7]=1.[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][C:24]=1[O:25][CH3:26])[N:21]=[CH:20][CH:19]=[C:18]2[O:27][C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[C:30]([CH3:35])[CH:29]=1.C1(C)C=CC=CC=1>C(O)C>[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][C:24]=1[O:25][CH3:26])[N:21]=[CH:20][CH:19]=[C:18]2[O:27][C:28]1[CH:34]=[CH:33][C:31]([NH:32][C:11]([NH:10][C:8](=[O:9])[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[CH:3]=2)=[S:12])=[C:30]([CH3:35])[CH:29]=1
Reactant: Cc1cccc(C(=O)N=C=S)c1
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3)c2cc1OC
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4cccc(C)c4)c(C)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 40 %

Procedure:
Commercially available 3-methyl-1-benzenecarbonyl isothiocyanate (50 μl) was dissolved in ethanol (1 ml) to prepare a solution. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-methylaniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (32 mg, yield 40%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10]2[CH:14]=[CH:13][S:12][CH:11]=2)=[CH:4][CH:3]=1.[CH2:16]([O:18][C:19]1[CH:20]=[C:21]([CH:24]=[C:25]([N+:28]([O-:30])=[O:29])[C:26]=1[OH:27])[CH:22]=O)[CH3:17].[NH2:31][C:32]([NH2:34])=[O:33].Cl>CCO.CCOC(C)=O>[CH2:16]([O:18][C:19]1[CH:20]=[C:21]([CH:22]2[C:9]([C:10]3[CH:14]=[CH:13][S:12][CH:11]=3)=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[NH:34][C:32](=[O:33])[NH:31]2)[CH:24]=[C:25]([N+:28]([O-:30])=[O:29])[C:26]=1[OH:27])[CH3:17]
Reactant: NC(N)=O
Reactant: O=C(Cc1ccsc1)c1ccc(F)cc1
Reactant: CCOc1cc(C=O)cc([N+](=O)[O-])c1O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOc1cc(C2NC(=O)NC(c3ccc(F)cc3)=C2c2ccsc2)cc([N+](=O)[O-])c1O
Yield: 26.8 %

Procedure:
A mixture of 1-(4-fluorophenyl)-2-(thiophen-3-yl)ethanone (Intermediate 54) (100 mg, 0.45 mmol), 3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (87 mg, 0.41 mmol), urea (74 mg, 1.24 mmol), concentrated HCl (0.04 mL, 0.41 mmol) in EtOH (5 mL) was refluxed overnight. Followed standard aqueous/EtOAc workup procedure, then purified by preparative HPLC to give Compound 109 (50 mg, yield 27%). 1H NMR (DMSO-d6 400 MHz): δ 10.30 (s, 1H), 8.77 (s, 1H), 7.58 (s, 1H), 7.49 (s, 1H), 7.34-7.30 (m, 2H), 7.27 (s, 1H), 7.23-7.18 (m, 3H), 6.88 (s, 1H), 6.27 (d, J=5.2 Hz, 1H), 5.21 (d, J=2.8 Hz, 1H), 4.13-4.06 (m, 2H), 1.36 (t, J=6.8 Hz, 3H); MS (ESI): m/z 456.0 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:23]2[C:31](=[O:32])[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24]2=[O:33])=[CH:4][C:5]([S:9]([N:12]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[CH2:16][CH2:15][CH2:14][CH2:13]2)(=[O:11])=[O:10])=[C:6]([OH:8])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43]>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[C:3]([N:23]2[C:24](=[O:33])[C:25]3[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:31]2=[O:32])=[CH:4][C:5]([S:9]([N:12]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[CH2:16][CH2:15][CH2:14][CH2:13]2)(=[O:10])=[O:11])=[C:6]([CH:7]=1)[O:8][CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43]
Reactant: CCOC(=O)CBr
Reactant: O=C1c2ccccc2C(=O)N1c1cc(S(=O)(=O)N2CCCCc3ccccc32)c(O)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cc(Cl)c(N2C(=O)c3ccccc3C2=O)cc1S(=O)(=O)N1CCCCc2ccccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 5-chloro-2-(2,3,4,5-tetrahydro-1H-1-benzoazepin-1-yl-sulfonyl)-4-(1,3-dioxo-1,3-dihydroisoindol-2-yl)phenol (0.26 g) and potassium carbonate (0.11 g) in N,N-dimethylformamide (3 mL) was added ethyl bromoacetate (0.078 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate, and the resulting mixture was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=9/1−1/9) to give ethyl 2-[5-chloro-2-(2,3,4,5-tetrahydro-1H-1-benzoazepin-1-yl-sulfonyl)-4-(1,3-dioxo-1,3-dihydroisoindol-2-yl)phenoxy]acetate (0.29 g). To this material were added tetrahydrofuran (10 mL), methanol (5 mL), water (5 mL) and lithium hydroxide monohydrate (0.21 g), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into 1 mol/L hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was dissolved in tetrahydrofuran (5 mL). To the solution was added 1,1′-carbonyldiimidazole (0.16 g), and the mixture was stirred at room temperature for 30 minutes. To the reaction mixture was added methylamine (40% methanol solution, 2.5 mL), and the mixture was stirred at room temperature for 5 hours, and then stirred at 50° C. for 1 hour. The reaction mixture was poured into 2 mol/L hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=1/1−ethyl acetate) to give the title compound (0.14 g).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4](Cl)[N:3]=1.CO[NH:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[OH-].[Na+].[CH2:24]([OH:28])CCC>>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([NH:14][CH2:15][C:16]2[CH:17]=[CH:18][C:19]([O:28][CH3:24])=[CH:20][CH:21]=2)[N:3]=1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Reactant: CCCCO
Reactant: CONCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc(CNc2nc(Cl)nc3nc[nH]c23)cc1
Temperature: 120 °C
Reaction time: 0.17 h

Procedure:
The 2,6-dichloropurine (4.06 g, 21.5 mmol) was suspended in n-butanol (150 ml) and the 4 methoxybenzylamine was added (3.4 ml, 26 mmol). The solution turned clear and then cloudy a few minutes later. The solution was heated at 120° C. for 2 hr and then cooled. The n-butanol was evaporated followed by suspension of the residue in water and diethyl ether mixture. A solution of 2N NaOH (1.3 ml, 26 mmol) was added and the solution stirred for 10 min before filtration. The filtered precipitate was washed with water and a small portion of ether and then dried under vacuum. The residual liquor was left overnight and more crystals were collected the next day and washed with diethyl ether.