Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([Mg]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:10][N:11]([CH3:27])[C:12]1([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=2)[CH2:17][CH2:16][CH:15]([CH:18]=[O:19])[CH2:14][CH2:13]1.[Cl-].[NH4+]>O1CCCC1>[CH3:10][N:11]([CH3:27])[C:12]1([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=2)[CH2:17][CH2:16][CH:15]([CH:18]([OH:19])[CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:14][CH2:13]1
Reactant: CN(C)C1(c2cccc(F)c2)CCC(C=O)CC1
Reactant: Cl[Mg]Cc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CN(C)C1(c2cccc(F)c2)CCC(C(O)Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A 2 M solution of benzylmagnesium chloride in tetrahydrofuran (6.00 ml, 12 mmol) was added dropwise to a solution of 4-dimethylamino-4-(3-fluorophenyl)cyclohexanecarbaldehyde (1.49 g, 5.97 mmol) in anhydrous tetrahydrofuran (30 ml), while cooling with ice. The mixture was stirred at room temperature for 2 d and saturated ammonium chloride solution (30 ml) was then added, while cooling with ice. The tetrahydrofuran was removed i. vac. and the residue was brought to pH 8 with 4 M sodium hydroxide solution. The aqueous suspension was extracted with diethyl ether (3×30 ml). The combined organic phases were dried with sodium sulfate and concentrated i. vac. The crude product (2.18 g) was purified by flash chromatography with methylene chloride/methanol [95:5+1% NH3 (32% in H2O)]. The impure polar diastereoisomer (500 mg) was purified again by flash chromatography with methylene chloride/methanol [95:5+1% NH3 (32% in H2O)].
Reaction SMILES: [CH3:1][SH-:2][C:3](=[N:5][OH:6])[CH3:4].[CH3:7][N:8]([S:12][N:13]([CH3:15])[CH3:14])[C:9](F)=[O:10].C(N(CC)CC)C>O1CCCC1>[CH3:7][N:8]([S:12][N:13]([CH3:15])[CH3:14])[C:9]([O:6][N:5]=[C:3]([S:2][CH3:1])[CH3:4])=[O:10]
Reactant: C[SH-]C(C)=NO
Reactant: CN(C)SN(C)C(=O)F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CSC(C)=NOC(=O)N(C)SN(C)C
Reaction time: 8 h
Yield: 13.5 %

Procedure:
A mixture of 5.25 g (0.05 mole) of S-methyl-N-hydroxythioacetimidate, 7.9 g of N-methyl-N-(dimethylaminosulfenyl)carbamoyl fluoride, and 5.1 g of triethylamine in 75 ml of tetrahydrofuran was stirred and heated at 40°-60° C. for 3 hrs. and then at 25° C. for 8 hrs. The solvent was removed in vacuo, and the residue was taken up in chloroform. This solution was extracted with water and 10% potassium carbonate, dried (MgSO4) and then was concentrated in vacuo. The crude syrupy residue obtained was purified by column chromatography on silica gel to give 1.6 g of S-methyl N-[N'-methyl-N'-(dimethylaminosulfenyl)-carbamoyloxy]thioacetimidate, a yellow syrup.
Reaction SMILES: C1(C)C=CC(S([O-])(=O)=O)=CC=1.[CH3:12][N+:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[S:15][C:14]=1SC.C([NH:26][NH2:27])=O>O>[CH3:12][N:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[S:15][C:14]1=[N:26][NH2:27]
Reactant: NNC=O
Reactant: CSc1sc2ccccc2[n+]1C
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: O
Product: Cn1c(=NN)sc2ccccc21

Procedure:
Into a flask equipped with a reflux condenser and magnetic stirrer is charged 50 ml water. Then 28.1 g (0.076 moles) 3-methyl-2-methylthiobenzothiazolium p-toluene sulfonate is dissolved with slight heating. A solution of 9.1 g (0.15 moles) formylhydrazine in 25 ml of water then is added and the mixture is heated at reflux for 15 minutes. The cooled suspension is made acidic until a clear solution results, then made basic. The product precipitates and is filtered, giving 9.1 g (66%), m.p. 134° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:9])[CH2:7][NH2:8])([CH3:4])([CH3:3])[CH3:2].[CH3:10][C:11]1([CH2:17][CH:18]=O)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1>C(Cl)Cl>[C:1]([O:5][C:6](=[O:9])[CH2:7]/[N:8]=[CH:18]/[CH2:17][C:11]1([CH3:10])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1(CC=O)CCCCC1
Reactant: CC(C)(C)OC(=O)CN
Solvent: ClCCl
Product: CC1(C/C=N/CC(=O)OC(C)(C)C)CCCCC1
Yield: 93.8 %

Procedure:
Step E In a manner similar to the method described in Example 1a, glycine tert-butyl ester (1.87 g, 14.3 mmol) was reacted with (1-methyl-cyclohexyl)-acetaldehyde (2.9 g, 14.3 mmol) in CH2Cl2 at room temperature for 18 h to give [2-(1-methyl-cyclohexyl)-eth-(E)-ylideneamino]-acetic acid tert-butyl ester as a colorless oil (3.4 g, 95%).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[N:6]=[CH:5][CH:4]=1.[CH:17]([OH:20])([CH3:19])[CH3:18]>NC1C=C(O)C=CC=1>[ClH:2].[CH3:14][O:13][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][C:9]=1[O:15][CH3:16])[N:6]=[CH:5][CH:4]=[C:3]2[NH:6][C:5]1[CH:4]=[CH:3][CH:19]=[C:17]([OH:20])[CH:18]=1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: CC(C)O
Agent: Cl
Agent: Nc1cccc(O)c1
Product: COc1cc2nccc(Nc3cccc(O)c3)c2cc1OC
Yield: 47 %

Procedure:
A mixture of 4-chloro-6,7-dimethoxyquinoline hydrochloride (540 mg, 2.08 mmol), (prepared as described for the starting material in Example 2), in 3-aminophenol (1 ml) and isopropanol (15 ml) was heated at reflux for 2 hours. The mixture was allowed to cool and the solid product was collected by filtration, washed with acetone and dried to give 6,7-dimethoxy-4-(3-hydroxyanilino)quinoline hydrochloride (336 mg, 47%).
Reaction SMILES: [CH:1]1([C:7]([C:9]2[N:10]([CH3:14])[CH:11]=[CH:12][CH:13]=2)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:15][S:16](O)(=[O:18])=[O:17]>>[CH:1]1([C:7]([C:9]2[N:10]([CH3:14])[C:11]([S:16]([Cl:15])(=[O:18])=[O:17])=[CH:12][CH:13]=2)=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Cn1cccc1C(=O)C1CCCCC1
Reactant: O=S(=O)(O)Cl
Product: Cn1c(C(=O)C2CCCCC2)ccc1S(=O)(=O)Cl
Temperature: 60 °C
Yield: 79.6 %

Procedure:
To a solution of compound 25b (1.0 g, 5.2 mmol) was added portionwise chlorosulfonic acid (5 mL, 75 mmol) at 0° C., heated to 60° C. for 2 h, poured carefully into ice-water and extracted with CHCl3. The organic phase was dried (MgSO4), evaporated and purified by CC to give compound 25c (1.2 g, 80%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)[CH3:2].Br[CH2:12][Si:13]1(C2C=CC=CC=2)[CH2:18][CH2:17][CH:16]([CH2:19][CH2:20][CH2:21][CH:22]=[CH2:23])[CH2:15][CH2:14]1>>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:12][Si@H:13]2[CH2:14][CH2:15][C@H:16]([CH2:19][CH2:20][CH2:21][CH:22]=[CH2:23])[CH2:17][CH2:18]2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOc1ccc(O)cc1
Reactant: C=CCCCC1CC[Si](CBr)(c2ccccc2)CC1
Product: C=CCCC[C@H]1CC[Si@H](COc2ccc(OCC)cc2)CC1

Procedure:
The general procedure of Example 9 was repeated using 4-ethoxyphenol and 4-bromomethyl1 -(4-pentenyl)-4-phenyl-4-silacyclohexane, thereby obtaining the intended compound.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]3[C:14]([C:15]4[CH:20]=[CH:19][CH:18]=[C:17]([N:21]5[CH2:29][C:28]6[C:23](=[CH:24][C:25]([O:30][CH3:31])=[CH:26][CH:27]=6)[C:22]5=[O:32])[C:16]=4[CH3:33])=[CH:13][N:12]=[C:11]([C:34]([NH2:36])=[O:35])[C:7]=3[NH:8]2)=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:42]([O:44]CC)=[CH2:43])CCC.C(N(CC)CC)C.C(OCC)(=O)C.CCCCCC>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:42]([C:2]1[CH:10]=[C:9]2[C:5]([C:6]3[C:14]([C:15]4[CH:20]=[CH:19][CH:18]=[C:17]([N:21]5[CH2:29][C:28]6[C:23](=[CH:24][C:25]([O:30][CH3:31])=[CH:26][CH:27]=6)[C:22]5=[O:32])[C:16]=4[CH3:33])=[CH:13][N:12]=[C:11]([C:34]([NH2:36])=[O:35])[C:7]=3[NH:8]2)=[CH:4][CH:3]=1)(=[O:44])[CH3:43]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: COc1ccc2c(c1)C(=O)N(c1cccc(-c3cnc(C(N)=O)c4[nH]c5cc(Br)ccc5c34)c1C)C2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COc1ccc2c(c1)C(=O)N(c1cccc(-c3cnc(C(N)=O)c4[nH]c5cc(C(C)=O)ccc5c34)c1C)C2
Temperature: 125 °C
Reaction time: 1 h
Yield: 60.7 %

Procedure:
A mixture of 7-bromo-4-(3-(6-methoxy-1-oxoisoindolin-2-yl)-2-methylphenyl)-9H-pyrido[3,4-b]indole-1-carboxamide (0.198 g, 0.366 mmol), tributyl(1-ethoxyvinyl)stannane (0.301 mL, 0.914 mmol), bis(triphenylphosphine)palladium(II) chloride (0.039 g, 0.055 mmol), triethylamine (0.071 mL, 0.512 mmol) in 1,4-Dioxane (12 mL) was heated at 125° C. for 16 hr. Upon cooling to room temperature, the reaction mixture was filtered through CELITE®, and the filtrate was concentrated under vacuum. The residue was diluted with THF (40 mL) and stirred with 1 N HCl solution (10 mL) at 50° C. for 1 hr. The solution was concentrated under vacuum, basified with 1 N NaOH solution, and extracted with ethyl acetate (3×40 mL). The combined extract was dried over anhydrous MgSO4. The desired product (0.112 g, 0.222 mmol, 60.7% yield) was isolated as a pale yellow solid by ISCO (40 g silica gel, solid loading, 50-90% ethyl acetate/hexane).
Reaction SMILES: Cl[C:2](Cl)(Cl)[C:3](=N)[O:4][C@H:5]1[O:22][C@H:21]([CH2:23][O:24][C:25](=[O:27])[CH3:26])[C@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:6]1[O:7][C:8](=[O:10])[CH3:9].OC1C=[CH:38][C:35]([CH:36]=[O:37])=[CH:34][CH:33]=1.B(F)(F)F.CCOCC.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:8]([O:7][C@@H:6]1[C@@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@@H:21]([CH2:23][O:24][C:25](=[O:27])[CH3:26])[O:22][CH:5]1[O:4][C:3]1[CH:33]=[CH:34][C:35]([CH:36]=[O:37])=[CH:38][CH:2]=1)(=[O:10])[CH3:9]
Reactant: CC(=O)OC[C@H]1O[C@H](OC(=N)C(Cl)(Cl)Cl)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Reactant: O=Cc1ccc(O)cc1
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: ClCCl
Product: CC(=O)OC[C@H]1OC(Oc2ccc(C=O)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: -20 °C
Reaction time: 4 h
Yield: 42 %

Procedure:
2,3,4,6-Tetra-O-acetyl-α-D-galactopyranosyl 2,2,2-trichloroacetimidate 1 (9.85 g, 20 mmol) and 4-hydroxybenzaldehyde (3.66 g, 30 mmol) were dissolved in CH2Cl2 (100 mL) and then the reaction mixture was cooled to −20° C. Boron trifluoride diethyl etherate (46%, 16 mL, 60 mmol) was added dropwise at this temperature. The reaction mixture was stirred at −20° C. for 4 h and was monitored by TLC. Saturated NaHCO3 aqueous solution (150 mL) was added to the mixture. The aqueous layer was separated and extracted with CH2Cl2 (2×150 mL). The organic layers were combined, dried over MgSO4 and concentrated. Purification by silica gel column chromatography yielded 2 (3.8 g, 42%) as a white solid.
Reaction SMILES: [O:1]=[C:2]1[N:14]2[C:5](=[N:6][C:7]3[C:12]([CH2:13]2)=[CH:11][CH:10]=[CH:9][CH:8]=3)[S:4][C:3]1=[CH:15][C:16]([OH:18])=O.C(N(CC)CC)C.[C:26]([NH:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([CH3:29])([CH3:28])[CH3:27].O=C1N(N(N2CCOC2=O)P(Cl)(N)=O)CCO1.Cl>ClCCl>[C:26]([N:30]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:16](=[O:18])[CH:15]=[C:3]1[S:4][C:5]2=[N:6][C:7]3[C:12]([CH2:13][N:14]2[C:2]1=[O:1])=[CH:11][CH:10]=[CH:9][CH:8]=3)([CH3:29])([CH3:27])[CH3:28]
Reactant: O=C(O)C=c1sc2n(c1=O)Cc1ccccc1N=2
Reactant: CC(C)(C)NCc1ccccc1
Agent: Cl
Agent: NP(=O)(Cl)N(N1CCOC1=O)N1CCOC1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)N(Cc1ccccc1)C(=O)C=c1sc2n(c1=O)Cc1ccccc1N=2
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of (3-oxo-5H-thiazolo[2,3-b]quinazolin-2(3H)-ylidene)acetic acid (1.3 g, 5 mmols), triethylamine (1.5 ml, 0.01 mol), and N-(tert-butyl)benzylamine (0.93 ml, 5 mmols) in 10 ml dichloromethane, was cooled to 10° C. Then, 1.27 g (5 mmols) of N,N-bis(2-oxo-3-oxazolidinyl)phosphorodiamidic chloride was added, and the reaction mixture was stirred at room temperature for 20 hours. Following acidification with dilute hydrochloric acid, the reaction mixture was filtered and the organic layer was washed with water, dried over anhydrous magnesium sulfate, and evaporated to dryness under reduced pressure leaving an orange-yellow solid which was recrystallized from anhydrous ethanol. Yield--0.71 g. Mp 195°-197° C.
Reaction SMILES: C(Cl)CCl.C(N(CC)CC)C.[C:12]12([OH:22])[CH2:21][CH:16]3[CH2:17][CH:18]([CH2:20][CH:14]([CH2:15]3)[CH2:13]1)[CH2:19]2.[C:23]([NH:30][C@H:31]([C:39](O)=[O:40])[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24]>CN(C1C=CN=CC=1)C.ClCCl>[C:12]12([O:22][C:39](=[O:40])[C@H:31]([CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[NH:30][C:23]([O:25][C:26]([CH3:29])([CH3:27])[CH3:28])=[O:24])[CH2:19][CH:18]3[CH2:17][CH:16]([CH2:15][CH:14]([CH2:20]3)[CH2:13]1)[CH2:21]2
Reactant: OC12CC3CC(CC(C3)C1)C2
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)OC12CC3CC(CC(C3)C1)C2
Reaction time: 8 h

Procedure:
1192 mg (6.2 mmol) of EDC, 578 μl (4.1 mmol) of triethylamine, 345 mg (2.8 mmol) of DMAP, and 316 mg (2.1 mmol) of 1-adamantanol were added at RT to a solution of 500 mg (1.89 mmol) of N-Boc-L-phenylalanine in 25 ml dichlormethane. The reaction composition was stirred overnight, then diluted with 50 ml Dichlormethane and successively washed in a solution of 10% of aqueous citric acid, water, and saturated saline. The organic phase was dried over magnesium sulphate and then evaporated, and the residue purified with preparative HPLC. The yield was 336 mg (43% o. th.) of the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][C:13]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)=[CH:12][N:11]3[CH:22]=2)=[CH:4][CH:3]=1.[CH:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][C:24]=1[C:33]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[C:40](B(O)O)=[C:39]2[C:34]=1[CH:35]=[CH:36][CH:37]=[CH:38]2.C(=O)([O-])[O-].[Na+].[Na+]>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.COCCOC>[CH:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][C:24]=1[C:33]1[C:34]2[C:39](=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:40]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[N:9]=[C:10]4[CH:15]=[CH:14][C:13]([C:16]5[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=5)=[CH:12][N:11]4[CH:22]=3)=[CH:4][CH:3]=2)=[C:41]2[C:46]=1[CH:45]=[CH:44][CH:43]=[CH:42]2
Reactant: Brc1ccc(-c2cn3cc(-c4ccccc4)ccc3n2)cc1
Reactant: OB(O)c1c2ccccc2c(-c2ccc3ccccc3c2)c2ccccc12
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: c1ccc(-c2ccc3nc(-c4ccc(-c5c6ccccc6c(-c6ccc7ccccc7c6)c6ccccc56)cc4)cn3c2)cc1
Yield: 77.8 %

Procedure:
Dissolving 4.0 g (11 mmol) of 2-(4-bromo-phenyl)-6-phenyl-imidazo [1,2-a] pyridine, 4.0 g (11 mmol) of 10-naphthalen-2-yl-anthracene-9-boronic acid and 0.27 g of tetrakis (triphenylphosphine) palladium into 40 milliliter of 1,2-dimethoxyethane, adding 18 milliliter of 2.0M sodium carbonate aqueous solution, the resultant suspension was refluxed under heating for 7 hours. After completion of the reaction, separation with filtration was carried out and resultant crystals were washed with water and methanol, thereby obtaining 4.9 g of yellowish white solids (yield: 76%). As a result of mass spectrum (MS) analysis, it was recognized that m/e=572 for molecular weight of 572.23 and the yellowish white solids were identified as the aimed substance.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:18]=[CH:17][C:8]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].C(OC(=O)C)(=O)C.[N+:26]([O-])([OH:28])=[O:27].NC(N)=O.C(C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(O)(=O)C>[C:1]([NH:4][C:5]1[CH:18]=[CH:17][C:8]([C:9]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:10])=[CH:7][C:6]=1[N+:26]([O-:28])=[O:27])(=[O:3])[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: CC(=O)Nc1ccc(C(=O)c2ccccc2)cc1
Agent: NC(N)=O
Agent: O=C(c1ccccc1)c1ccccc1
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc(C(=O)c2ccccc2)cc1[N+](=O)[O-]
Temperature: 50 °C
Yield: 62.5 %

Procedure:
Twenty-three grams (0.1 m.) of 4-acetamidobenzophenone, 50 ml. of acetic anhydride and 20 ml. of acetic acid were stirred together. A solution of 90 percent nitric acid (15 ml.), 10 ml. of acetic acid and 0.2 g. of urea was added dropwise to the benzophenone mixture. The reaction mixture was maintained at a temperature of about 50° C. during the nitration. The mixture was stirred at ambient temperature whereupon the mixture became very thick. The thick slurry was poured over ice and the insoluble product was filtered to yield 17.7 g. (62.5 percent yield) of 4-acetamido-3-nitrobenzophenone.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[Cl:10][C:11]1[CH:12]=[C:13]([CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[NH2:14]>>[Cl:10][C:11]1[CH:12]=[C:13]([NH:14][C:2]2[N:7]=[C:6]([NH:14][C:13]3[CH:15]=[CH:16][C:17]([O:18][CH3:19])=[C:11]([Cl:10])[CH:12]=3)[C:5]([F:9])=[CH:4][N:3]=2)[CH:15]=[CH:16][C:17]=1[O:18][CH3:19]
Reactant: COc1ccc(N)cc1Cl
Reactant: Fc1cnc(Cl)nc1Cl
Product: COc1ccc(Nc2ncc(F)c(Nc3ccc(OC)c(Cl)c3)n2)cc1Cl

Procedure:
In a like manner to the preparation of N2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloro-5-fluoropyrimidine and 3-chloro-4-methoxyaniline were reacted to provide N2,N4-Bis(3-chloro-4-methoxyphenyl)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): δ 9.90 (bs, 1H), 9.68 (bs, 1H), 8.16 (d, 1H, J=4.8 Hz), 7.72 (d, 1H, J=2.4 Hz), 7.65 (d, 1H, J=2.1 Hz), 7.58 (dd, 1H, J=2.4 and 9.0 Hz), 7.38 (dd, 1H, J=2.7 and 9.3 Hz), 7.12 (d, 1H, J=8.7 Hz), 7.12 (d, 1H, J=8.7 Hz), 7.05 (d, 1H, J=8.7 Hz), 3.83 (s, 3H), 3.79 (s, 3H); LCMS: purity: 99%; MS (m/e): 410 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][C:10]3[CH:12]=[C:13]([CH2:16][OH:17])[CH:14]=[CH:15][C:9]=3[CH2:8][CH2:7][C:6]=2[CH:18]=1.[OH:19]CC1C=CC2C=CC3C=CC=CC=3SC=2C=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:19])[C:10]3[CH:12]=[C:13]([CH2:16][OH:17])[CH:14]=[CH:15][C:9]=3[CH2:8][CH2:7][C:6]=2[CH:18]=1
Reactant: OCc1ccc2c(c1)Sc1ccccc1C=C2
Reactant: OCc1ccc2c(c1)Sc1ccc(F)cc1CC2
Product: O=S1c2ccc(F)cc2CCc2ccc(CO)cc21

Procedure:
Repeat the process of Example 2, substituting an equivalent quantity of 8-fluoro-3-hydroxymethyl-10,11-dihydrodibenzo[b,f]thiepin for the 3-hydroxymethyldibenzo[b,f]thiepin, to obtain the title product (m.p. 181°-183° C.).
Reaction SMILES: [NH:1]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C@H:2]([C:7]([CH:9]=[N+]=[N-])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[ClH:19]>CCOCC>[NH:1]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C@H:2]([C:7]([CH2:9][Cl:19])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)C=[N+]=[N-]
Reactant: Cl
Solvent: CCOCC
Product: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)CCl
Reaction time: 0.08 h

Procedure:
Boc-LeuCHN2 (4.40 g, 17.2 mmoles) was dissolved in 50 mL of ether and cooled to 0°; anhydrous 3.45N ethanolic:HCl (5.22 mL, 18.0 mmoles) was added. After about 5 minutes, the resulting solution was washed with cold water, saturated aqueous sodium chloride, and was dried over anhydrous sodium sulfate. Solvent was evaporated to yield crystalline Boc-LeuCH2Cl. Product was isolated and washed with petroleum ether to yield 0.84 g (mp 65°-66°) in a first crop and 1.94 g (mp 64°-65.5°) in a second crop isolated from cold petroleum ether.
Reaction SMILES: Br[C:2]1[N:10]=[CH:9][C:8]2[NH:7][C:6]3[N:11]=[CH:12][C:13]([C:15]4[CH:20]=[CH:19][C:18]([CH2:21][N:22]5[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]5)=[CH:17][CH:16]=4)=[CH:14][C:5]=3[C:4]=2[CH:3]=1.CC1(C)C(C)(C)OB([C:36]2[CH:37]=[N:38][O:39][CH:40]=2)O1>C([O-])(=O)C.[K+].C(#N)C.C(Cl)Cl.CO>[O:39]1[CH:40]=[C:36]([C:2]2[N:10]=[CH:9][C:8]3[NH:7][C:6]4[N:11]=[CH:12][C:13]([C:15]5[CH:20]=[CH:19][C:18]([CH2:21][N:22]6[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]6)=[CH:17][CH:16]=5)=[CH:14][C:5]=4[C:4]=3[CH:3]=2)[CH:37]=[N:38]1
Reactant: CC1(C)OB(c2cnoc2)OC1(C)C
Reactant: Brc1cc2c(cn1)[nH]c1ncc(-c3ccc(CN4CCCCC4)cc3)cc12
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Solvent: CC#N
Product: c1cc(-c2cnc3[nH]c4cnc(-c5cnoc5)cc4c3c2)ccc1CN1CCCCC1
Temperature: 85 °C
Yield: 13.6 %

Procedure:
A mixture of 6-bromo-3-(4-piperidin-1-ylmethylphenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole (130 mg, 0.18 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (140 mg, 0.74 mmol), 1,1′-[bis(diphenylphosphino)ferrocene]-dichloropalladium(II) (18 mg, 0.002 mmol) in 1N aqueous potassium acetate solution (0.62 mL) and acetonitrile (3 mL) was heated under microwave irradiation at 85° C. for 18 minutes. The cooled reaction mixture was diluted with DCM (20 mL) and methanol (2 mL) and washed with water (15 mL). The organic phase was separated, dried over sodium sulfate, filtered and evaporated in vacuo to afford a residue that was purified by preparative HPLC [0-30% MeCN in water (0.1% formic acid) over 30 min, 35 mL/min] to afford the title compound as a beige solid (10 mg, 10%). 1H NMR (DMSO-D6, 400 MHz): 12.32 (s, 1H), 9.47 (s, 1H), 9.18 (s, 1H), 8.95 (s, 1H), 8.94 (d, J=2.3 Hz, 1H), 8.89 (d, J=2.2 Hz, 1H), 8.68 (s, 1H), 7.76 (d, J=8.1 Hz, 2H), 7.45 (d, J=8.1 Hz, 2H), 3.50 (s, 2H), 2.37 (s, 4H), 1.52 (m, 4H), 1.41 (m, 2H). LCMS (Method D): RT=6.55 min, M+H+=410.
Reaction SMILES: [Mg].Br[C:3]1[CH:4]=[C:5]([O:9][CH3:10])[CH:6]=[CH:7][CH:8]=1.II.[C:13]1(=[O:19])[CH2:18][CH2:17][CH2:16][CH:15]=[CH:14]1.Cl>O1CCCC1.[Cu]Br>[CH3:10][O:9][C:5]1[CH:4]=[C:3]([CH:15]2[CH2:16][CH2:17][CH2:18][C:13](=[O:19])[CH2:14]2)[CH:8]=[CH:7][CH:6]=1
Reactant: COc1cccc(Br)c1
Reactant: O=C1C=CCCC1
Agent: [Cu]Br
Agent: Cl
Agent: II
Solvent: C1CCOC1
Product: COc1cccc(C2CCCC(=O)C2)c1
Yield: 47.6 %

Procedure:
Grignard reagent was prepared from magnesium (2.8 g) and 3-bromoanisole (22.0 g) in tetrahydrofuran (50 ml) in the presence of iodine, and a catalytic amount of copper (I) bromide (CuBr, 0.83 g) was added thereto. A tetrahydrofuran (10 ml) solution containing 2-cyclohexen-1-one (9.6 g) was also added dropwise while stirring on ice. After stirring at room temperature for 3 hours, hydrochloric acid was added, and extraction was performed with ethyl acetate. After drying with anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to produce a light yellow oily substance which was then separated and purified by silica gel column chromatography (n-hexane:ethyl acetate=5:1) to give 9.7 g of 3-(3-methoxyphenyl)cyclohexanone (47.6% yield).
Reaction SMILES: [C:1]1(=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[CH:3]=[CH:2]1.S(=O)(=O)(O)O.S(=O)(=O)=O.[N+:22]([O-])([OH:24])=[O:23]>O>[N+:22]([C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[C:4](=[O:11])[CH:3]=[CH:2][C:1]2=[O:12])([O-:24])=[O:23]
Reactant: O=C1C=CC(=O)c2ccccc21
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: O=S(=O)=O
Solvent: O
Product: O=C1C=CC(=O)c2c1cccc2[N+](=O)[O-]

Procedure:
In the same apparatus as in Example 1, 10.0 g of 1,4-naphthoquinone was added to 40 g of fuming sulfuric acid of a sulfur trioxide content of 20 percent maintained at 0° to 5°C, then added thereto 30 g of a mixed acid consisting of 70 percent by weight of sulfuric acid, 25 percent by weight of nitric acid and 5 percent by weight of water dropwise over 1 hour while maintaining the reaction temperature at 15° to 20°C. The reaction mixture was maintained at 15° to 20°C for additional 3 hours and then processed in the same manner as in Example 6 to obtain 11.0 g of crude 5-nitro-1,4-naphthoquinone of a melting point of 153°C. The crude product was purified in the same manner as in Example 6 to obtain the same result as in Example 1.
Reaction SMILES: [CH3:1][CH2:2][C:3]([O-])([CH3:5])[CH3:4].[K+]>[Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C.C1COCC1>[CH:2]1[C:3]2[C:5](=[CH:4][CH:3]=[CH:5][CH:4]=2)[CH:1]=[CH:2][CH:1]=1
Reactant: CCC(C)(C)[O-]
Agent: CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: c1ccc2ccccc2c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To the suspension of ethyl triphenyl phosphonium bromide (3.72 g, 10.0 mmol) in anhydrous THF (8 ml), a solution is added by drops of potassium tert-amylate (5.5 ml, 9.3 mmol, 1.7 M solution in toluene) using a syringe at room temperature. After 1 hour, the reaction mixture is cooled to a temperature of 0° C., a solution is added of aldehyde with formula 20 (1.68 g, 7.16 mmol), the cooling bath is removed, and mixing is carried out for 3 hours at room temperature. Then, the reaction mixture is diluted with cyclohexane (30 ml), the sediment is filtered off, and the solvent is evaporated at reduced pressure. The residue is chromatographed on silica gel (cyclohexane), obtaining a naphthalene derivative with formula 21 in the form of an oil as a mixture of isomers E:Z=1.82:1 (1.66 g, 94%).