Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:12]=1)[C:7]([NH:9][CH2:10][CH3:11])=[O:8].[Cu](C#N)[C:14]#[N:15]>>[C:14]([C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:12]=1)[C:7]([NH:9][CH2:10][CH3:11])=[O:8])#[N:15]
Reactant: N#C[Cu]C#N
Reactant: CCNC(=O)c1cncc(Br)c1
Product: CCNC(=O)c1cncc(C#N)c1
Yield: 31.8 %

Procedure:
By the reaction in the same manner as in Example 42-ii) using 5-bromo-N-ethylnicotinamide (580 mg) and copper cyanide (350 mg), the title compound (141 mg) was obtained as colorless powder crystals.
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[N+:9]([C:12]1[CH:13]=[C:14](B(O)O)[CH:15]=[CH:16][CH:17]=1)([O-:11])=[O:10]>>[N+:9]([C:12]1[CH:17]=[C:16]([C:2]2[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=2)[CH:15]=[CH:14][CH:13]=1)([O-:11])=[O:10]
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Reactant: Nc1ccc(I)cn1
Product: Nc1ccc(-c2cccc([N+](=O)[O-])c2)cn1
Yield: 59.7 %

Procedure:
Using the same procedureas for Example A43, 5-iodo-2-aminopyridine (0.31 g, 1.4 mmol) and 3-nitrophenylboronic acid (0.28 g, 1.7 mmol) were combined to yield 5-(3-nitrophenyl)pyridin-2-amine (0.18 g, 60%) as a white solid. 1H NMR (DMSO-d6): δ 8.37 (d, J=2.4 Hz, 1H), 8.34 (t, J=2.0 Hz, 1H), 8.11-8.04 (m, 2H), 7.83 (dd, J=8.0 Hz, 2.4 Hz, 1H), 7.68 (t, J=8.0 Hz, 1H), 6.55 (dd, J=8.4 Hz, 0.8 Hz, 1H), 6.26 (s, 2H); Exact mass: 215.0, Found: 216.0 (M+1)+.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:8]=2[C:14]2[CH:19]=[CH:18][N:17]=[C:16]3[C:20]([C:24]([NH:26][CH:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)=[O:25])=[C:21]([CH3:23])[NH:22][C:15]=23)[CH2:4][CH2:3]1.[C:33](Cl)(=[O:35])[CH3:34]>>[C:33]([N:30]1[CH2:29][CH2:28][CH:27]([NH:26][C:24]([C:20]2[C:16]3=[N:17][CH:18]=[CH:19][C:14]([C:8]4[CH:9]=[C:10]([CH3:13])[CH:11]=[CH:12][C:7]=4[O:6][CH2:5][CH:2]4[CH2:4][CH2:3]4)=[C:15]3[NH:22][C:21]=2[CH3:23])=[O:25])[CH2:32][CH2:31]1)(=[O:35])[CH3:34]
Reactant: Cc1ccc(OCC2CC2)c(-c2ccnc3c(C(=O)NC4CCNCC4)c(C)[nH]c23)c1
Reactant: CC(=O)Cl
Agent: Cl
Product: CC(=O)N1CCC(NC(=O)c2c(C)[nH]c3c(-c4cc(C)ccc4OCC4CC4)ccnc23)CC1

Procedure:
Starting from 7-[2-(cyclopropylmethoxy)-5-methylphenyl]-2-methyl-N-(piperidin-4-yl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f18) and commercially available acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][NH:7]2.Cl[C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:25][CH3:26])=[C:20]([O:23][CH3:24])[CH:21]=2)[N:16]=[CH:15][N:14]=1>>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][N:7]2[C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:25][CH3:26])=[C:20]([O:23][CH3:24])[CH:21]=2)[N:16]=[CH:15][N:14]=1
Reactant: Brc1cccc2c1CCCN2
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Product: COc1cc2ncnc(N3CCCc4c(Br)cccc43)c2cc1OC
Yield: 4 %

Procedure:
Utilizing a procedure analogous to that described in Example 1, this product was prepared in 4% yield from 5-bromo-1,2,3,4-tetrahydroquinoline and 4-chloro-6,7-dimethoxy-quinazoline. (film; LC-MS: 399 (MH+)).
Reaction SMILES: [C:1]1([CH3:32])[CH:6]=[CH:5][C:4]([S:7]([N:10]2[CH2:19][CH:18]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[C:21]=3[CH2:30]O)[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1>S(=O)(=O)(O)O>[CH3:29][O:28][C:22]1[C:23]([O:26][CH3:27])=[CH:24][CH:25]=[C:20]2[C:21]=1[CH2:30][C:16]1[C:17]3[CH:18]2[CH2:19][N:10]([S:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:32])=[CH:2][CH:3]=2)(=[O:8])=[O:9])[CH2:11][C:12]=3[CH:13]=[CH:14][CH:15]=1
Reactant: COc1ccc(C2CN(S(=O)(=O)c3ccc(C)cc3)Cc3ccccc32)c(CO)c1OC
Agent: O=S(=O)(O)O
Product: COc1ccc2c(c1OC)Cc1cccc3c1C2CN(S(=O)(=O)c1ccc(C)cc1)C3
Temperature: -5 °C
Reaction time: 1 h
Yield: 82.7 %

Procedure:
Powdered compound 13 (427 mg, 0.98 mmol) was added in several portions to 50 mL of cold concentrated sulfuric acid (50 mL) at -40° C. under nitrogen with vigorous mechanical stirring. After the addition, the reaction mixture was warmed to -5° C. over 2 h and then poured onto crushed ice (450 g) and left stirring for 1 h. The product was extracted with dichloromethane (2×150 mL), washed with water (2×150 mL ), dried (MgSO4), filtered and evaporated to afford an oil that on trituration with ether at 0° C. yielded compound 14 (353 mg, 82%) as a white solid that was used for the next step without further purification. An analytical sample was prepared by centrifugal rotary chromatography using 50% ethyl acetate-hexane as the eluent followed by recrystallization from EtOAc/Hexane: mp 204-206° C.; 1H NMR (CDCl3) δ2.40 (s, 3H, CH3), 2.80 (m, 1H, H-1a), 3.50 (dd, 1H, J=4.5, 17.5 Hz, H-1b), 3.70 (dd, 1H, J=7, 14 Hz, H-3a), 3.828 (s, 3H, OCH3), 3.832 (s, 3H, OCH3), 3.9 (m, 1H, H-11b), 4.31 (d, 1H, J=17.6 Hz, H-7a), 4.74 (ddd, 1H, J=1.7, 6.0, 11.2 Hz, H-7b), 4.76 (d, 1H, J=14.8 Hz, H-3b), 6.77 (d, 1H, J=8.3 Hz, ArH), 6.87 (d, 1H, J=8.4 Hz, ArH), 6.94 (d, 1H, J=7.6 Hz, ArH), 7.13 (t, 1H, J=7.5 Hz, Ar-H-5), 7.18 (d, 1H, J=7.2 Hz, ArH), 7.33 (d, 2H, J=8.1 Hz, ArH), 7.78 (d, 2H, J=8.2 Hz, ArH); MS (CI) m/z 436 (55), 198 (86), 157 (100); HRCIMS Calculated for C25H25NO4S: 436.1583; Found 436.1570; Anal. (C25H25NO4S) C, H, N.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[O:17]1[CH2:22][CH2:21]O[CH2:19][CH2:18]1>[Pd]>[O:17]1[CH:22]=[CH:21][C:19]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)=[CH:18]1
Reactant: O=[N+]([O-])c1ccc(Br)cc1
Reactant: C1COCCO1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: O=[N+]([O-])c1ccc(-c2ccoc2)cc1
Reaction time: 1.67 h

Procedure:
200 mg 4-bromonitrobenzene, 110.8 mg furan-3-boric acid and 162 mg palladium/C are dissolved in 3 mL 1,4-dioxane. Then 965.3 mg caesium carbonate (dissolved in 586 μL water) are added. The reaction is completed in the microwave (110° C.) after 100 min. After aqueous working up the mixture is extracted with ethyl acetate and died on magnesium sulphate. The solvent is eliminated in vacuo. This crude product is used in the following reaction without further purification.
Reaction SMILES: C([O:8][C:9]1[CH:36]=[C:35]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:34]=[CH:33][C:10]=1[C:11]([NH:13][C:14]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:24]=[CH:23][C:15]=1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:12])C1C=CC=CC=1>CO.C(Cl)(Cl)Cl.[C].[Pd]>[OH:8][C:9]1[CH:36]=[C:35]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:34]=[CH:33][C:10]=1[C:11]([NH:13][C:14]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:24]=[CH:23][C:15]=1[C:16]([O:18][C:19]([CH3:22])([CH3:20])[CH3:21])=[O:17])=[O:12]
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1ccc(-c2ccccc2)cc1OCc1ccccc1
Agent: [Pd]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1ccc(-c2ccccc2)cc1O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution mixture of the obtained tert-butyl 2-(2-(benzyloxy)-4-phenylbenzamido)-4-phenylbenzoate (0.11 g) in methanol (4 mL) and chloroform (4 mL), 10% palladium-carbon (40 mg) was added, followed by stirring under a hydrogen atmosphere at room temperature for 5 hours and 30 minutes and then at 35° C. for 1 hour. To the reaction mixture, 10% palladium-carbon (40 mg) was added, followed by stirring under a hydrogen atmosphere at 35° C. for 2 hours. The insoluble substance was removed by filtration, and the solvent was evaporated under reduced pressure. Diisopropyl ether and hexane were added to the obtained residue, and the solid substance was collected by filtration to obtain tert-butyl 2-(2-hydroxy-4-phenylbenzamido)-4-phenylbenzoate.
Reaction SMILES: [C:1]([N:4]1[C@@H:10]([CH3:11])[C@H:9]([NH:12][C:13](=[O:25])[C@@H:14]([N:16](C)[C:17](=O)OC(C)(C)C)[CH3:15])[C:8](=[O:26])[N:7]([CH2:27][C:28]2[CH:33]=[C:32]([Br:34])[CH:31]=[CH:30][C:29]=2[O:35][CH3:36])[C:6]2[CH:37]=[CH:38][C:39]([C:41]#[N:42])=[CH:40][C:5]1=2)(=[O:3])[CH3:2].[ClH:43]>O1CCOCC1.CCOCC>[ClH:43].[C:1]([N:4]1[C@@H:10]([CH3:11])[C@H:9]([NH:12][C:13](=[O:25])[C@@H:14]([NH:16][CH3:17])[CH3:15])[C:8](=[O:26])[N:7]([CH2:27][C:28]2[CH:33]=[C:32]([Br:34])[CH:31]=[CH:30][C:29]=2[O:35][CH3:36])[C:6]2[CH:37]=[CH:38][C:39]([C:41]#[N:42])=[CH:40][C:5]1=2)(=[O:3])[CH3:2]
Reactant: COc1ccc(Br)cc1CN1C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)[C@H](C)N(C(C)=O)c2cc(C#N)ccc21
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: CN[C@@H](C)C(=O)N[C@@H]1C(=O)N(Cc2cc(Br)ccc2OC)c2ccc(C#N)cc2N(C(C)=O)[C@H]1C
Yield: 72 %

Procedure:
A rt solution of tert-butyl(S)-1-((3S,4S)-5-acetyl-1-(5-bromo-2-methoxybenzyl)-7-cyano-4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylamino)-1-oxopropan-2-yl(methyl)carbamate (35.5 mg, 55.2 μmol) in 4 M HCl in dioxane (276 μl) was stirred for 1 h. The reaction was diluted with Et2O and the solids were collected by vacuum filtration, taken up in MeCN—H2O, and lyophilized to provide (S)-N-((3S,4S)-5-acetyl-1-(5-bromo-2-methoxybenzyl)-7-cyano-4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl)-2-(methylamino)propanamide hydrochloride (23.0 mg, 72%) as a white solid. MS m/z 542/544 (MH)+.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7](O)=[O:8])=[CH:5][C:4]=1[CH3:12])#[N:2].C(Cl)(=O)C([Cl:16])=O>ClCCl.CN(C)C=O>[C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([Cl:16])=[O:8])=[CH:5][C:4]=1[CH3:12])#[N:2]
Reactant: Cc1cc(C(=O)O)ccc1C#N
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1cc(C(=O)Cl)ccc1C#N
Reaction time: 3 h

Procedure:
The crude product of 4-cyano-3-methylbenzoic acid (1.0 g) was suspended in dichloromethane. To the mixture, oxalyl chloride (1.2 g) and an catalytic amount of N,N-dimethylformamide (2 to 3 drops) were added under ice cooling. After adjusting to room temperature, the reaction solution was stirred for three hours. The solvent was distilled off under reduced pressure to obtain 4-cyano-3-methylbenzoyl chloride as a crude product (1.0 g).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([O:9][C:10]2[CH:15]=[C:14]([F:16])[C:13]([NH:17][C:18]([NH:20][C:21]3[CH:34]=[CH:33][C:24]4[O:25][C:26]([F:32])([F:31])[O:27][C:28]([F:30])([F:29])[C:23]=4[CH:22]=3)=[O:19])=[C:12]([F:35])[CH:11]=2)[CH:6]=[CH:5][N:4]=1)#[N:2].C([O-])([O-])=[O:37].C([O-])([O-])=O.OO.OO.OO.[Na+].[Na+].[Na+].[Na+]>CC(C)=O.O>[F:35][C:12]1[CH:11]=[C:10]([CH:15]=[C:14]([F:16])[C:13]=1[NH:17][C:18]([NH:20][C:21]1[CH:34]=[CH:33][C:24]2[O:25][C:26]([F:31])([F:32])[O:27][C:28]([F:29])([F:30])[C:23]=2[CH:22]=1)=[O:19])[O:9][C:7]1[CH:6]=[CH:5][N:4]=[C:3]([C:1]([NH2:2])=[O:37])[CH:8]=1
Reactant: O=C([O-])[O-]
Reactant: N#Cc1cc(Oc2cc(F)c(NC(=O)Nc3ccc4c(c3)C(F)(F)OC(F)(F)O4)c(F)c2)ccn1
Agent: OO
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: NC(=O)c1cc(Oc2cc(F)c(NC(=O)Nc3ccc4c(c3)C(F)(F)OC(F)(F)O4)c(F)c2)ccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of N-{4-[(2-cyanopyridin-4-yl)oxy]-2,6-difluorophenyl}-N′-(2,2,4,4-tetra-fluoro-4H-1,3-benzodioxin-6-yl)urea (100 mg, 0.20 mmol) in acetone (2 ml) and water (1 ml) was treated with sodium percarbonate (contain 25% H2O2, 320 mg, 2.0 mmol), and the mixture was stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate (20 ml) and water (10 ml). The organic layer was washed with water (10 ml) and brine (5 ml), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was crystallized from methanol providing 42 mg (41%) of title compound as a white solid. 1H-NMR (DMSO-d6) δ 9.48 (s, 1H), 8.56 (d, J=6.0 Hz, 1H), 8.31 (s, 1H), 8.15 (s, 1H), 8.07 (d, J=2.2 Hz, 1H), 7.74 (s, 1H), 7.68 (dd, J=9.2, 2.7 Hz, 1H), 7.46 (d, J=2.3 Hz, 1H), 7.41 (d, J=9.3 Hz, 1H), 7.25 (m, 2H); MS GC-MS M+=515.0, RT=3.63 min.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[CH2:8][CH2:7][CH2:6][CH:5]([NH2:12])[C:4]=2[N:3]=1.[O:13]=[C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16](=[O:23])[N:15]1[CH2:24][CH2:25][CH2:26][CH:27]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[CH2:8][CH2:7][CH2:6][CH:5]([NH:12][CH2:27][CH2:26][CH2:25][CH2:24][N:15]3[C:16](=[O:23])[C:17]4[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:14]3=[O:13])[C:4]=2[N:3]=1
Reactant: O=CCCCN1C(=O)c2ccccc2C1=O
Reactant: Cc1ccc2c(n1)C(N)CCC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccc2c(n1)C(NCCCCN1C(=O)c3ccccc3C1=O)CCC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 79 %

Procedure:
To a solution of 2-methyl-5,6,7,8-tetrahydroquinolin-8-ylamine (237 mg, 1.46 mmol) in CH2Cl2 (20 mL) at room temperature under inert atmosphere was added 4-(1,3,-dioxo-1,3-dihydro-isoindol-2-yl)-butyraldehyde (159 mg, 0.731 mmol) followed by sodium triacetoxyborohydride (309 mg, 2.92 mmol). The reaction mixture was stirred at room temperature for 2 hours. Saturated sodium bicarbonate solution (10 mL) was added and the mixture was extracted with dichloromethane (3×20 mL). The combined organic extracts were washed with brine, dried (MgSO4), filtered and concentrated. The resultant material was purified by column chromatography on silica gel (10:1:0.5 CH2Cl2: MeOH: NH4OH) to provide the product as a yellow oil (210 mg, 79%): 1H NMR (CDCl3): δ 1.56-1.83 (m, 6H), 1.90-2.04 (m, 2H), 2.04-2.18 (m, 2H), 2.47 (s, 3H), 2.64-2.80 (m, 4H), 3.70-3.76 (m, 3H), 6.90 (d, 1H, J=7.8 Hz), 7.24 (d, 1H, J=7.8 Hz), 7.69-7.73 (m, 2H), 7.81-7.85 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([Cl:10])[C:8]=1[Cl:9])[NH2:5].[C:11](=O)([O-])[O-].[K+].[K+].IC>C(#N)C>[CH3:11][NH:5][C:4]1[CH:3]=[C:2]([Cl:1])[C:8]([Cl:9])=[C:7]([Cl:10])[CH:6]=1
Reactant: O=C([O-])[O-]
Reactant: Nc1cc(Cl)c(Cl)c(Cl)c1
Agent: [K+]
Solvent: CI
Solvent: CC#N
Product: CNc1cc(Cl)c(Cl)c(Cl)c1
Temperature: 40 °C
Reaction time: 72 h
Yield: 41.9 %

Procedure:
To a 100 ml three neck round bottom flask was added 3,4,5-trichloroaniline (1.96 g), potassium carbonate (1.66 g), acetonitrile (25 mL) and iodomethane (1.42 g). The reaction mixture was stirred at 40° C. for 3 days under nitrogen in the dark. The reaction mixture was then quenched with ethyl acetate (50 ml) and filtered. The residue was washed with ethyl acetate (3×20 ml). The filtrate and the washings were combined and washed with water (3×30 ml). The organic layer was then filtered through anhydrous MgSO4 and evaporated under reduced pressure. The residue was dissolved in a minimum amount of ethyl acetate/hexane 1:12 and the solution was placed on a wet column of silica gel (80 g) and eluted with ethyl acetate/hexane 300 ml (1:12), 500 ml (1:8) to afford 0.88 g of N-methyl-3,4,5-trichloraniline (42%) as a white solid. The product was used directly for the condensation without characterization. To a 100 ml three neck round bottom flask was added anhydrous DMSO (5 ml), N-methyl-3,4,5-trichloroaniline (0.88 g) crude compound 117 (0.20 g) and anhydrous potassium carbonate (0.56 g). The reaction mixture was stirred at 45° C. for 24 h and then quenched with distilled water (15 ml). The resulting suspension was stirred at room temperature for 4 h and filtered. The residue was extracted with MeOH (100 ml) several times and the extracts which showed a major spot of the product on TLC were pooled and mixed with silica gel (2 g). The mixture was evaporated under reduced pressure and dried in vacuo. The residue was ground into fine powder and poured on top of a dry column of silica gel (40 g). The column was eluted with 3% MeOH in CHCl3. Fractions corresponding to a single spot of the product were pooled and evaporated. The residue was washed with ether and air dried to afford 0.06 g (16% for two steps) of compound 432 as a light yellow solid.
Reaction SMILES: [C:1]1(=[O:13])[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH:6]=[CH:5][CH:4]=[C:3]3[CH2:2]1.[C:14](OCC)(=[O:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16].[O-]CC.[Na+]>C(O)C>[C:14]([CH:2]1[C:3]2[C:12]3[C:7]([CH:6]=[CH:5][CH:4]=2)=[CH:8][CH:9]=[CH:10][C:11]=3[C:1]1=[O:13])([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:20]
Reactant: CCOC(=O)C(=O)OCC
Reactant: O=C1Cc2cccc3cccc1c23
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(=O)C1C(=O)c2cccc3cccc1c23

Procedure:
Acenaphthen-1-one (JACS, 62, 432, 1940) (4.1 g) is reacted with diethyl oxalate (4.2 g) in anhydrous ethanol (280 ml) containing sodium ethoxide (from 0.66 g of sodium) at room temperature for 2 hours. The precipitate is filtered and washed with hexane, then is dissolved in water. The aqueous solution is acidified to pH 4 with citric acid and the precipitate is filtered and washed with water. Crystallization from chloroform-hexane gives 2-ethoxalylacenaphthen-1-one, m.p. 101°-103° C. (5.1 g), which is reacted with methylhydrazide (1.3 g) in acetic acid (110 ml) at 60° C. for 4 hours. After cooling the reaction mixture is diluted with ice water and extracted with ethyl acetate.
Reaction SMILES: [C:1](Cl)(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[C:21]([O:25][C:26](=[O:52])/[CH:27]=[CH:28]/[C:29]1[CH:34]=[CH:33][C:32]([C:35]2[CH:40]=[CH:39][C:38]([OH:41])=[C:37]([C:42]34[CH2:51][CH:46]5[CH2:47][CH:48]([CH2:50][CH:44]([CH2:45]5)[CH2:43]3)[CH2:49]4)[CH:36]=2)=[CH:31][CH:30]=1)([CH3:24])([CH3:23])[CH3:22].CCOC(C)=O>N1C=CC=CC=1>[C:42]12([C:37]3[CH:36]=[C:35]([C:32]4[CH:33]=[CH:34][C:29]([CH:28]=[CH:27][C:26]([O:25][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:52])=[CH:30][CH:31]=4)[CH:40]=[CH:39][C:38]=3[O:41][C:1](=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]/[CH2:11][CH:12]=[CH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:43][CH:44]3[CH2:50][CH:48]([CH2:47][CH:46]([CH2:45]3)[CH2:51]1)[CH2:49]2
Reactant: CC(C)(C)OC(=O)/C=C/c1ccc(-c2ccc(O)c(C34CC5CC(CC(C5)C3)C4)c2)cc1
Reactant: CCCCC/C=C\C/C=C\CCCCCCCC(=O)Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCCCCC=CC/C=C/CCCCCCCC(=O)Oc1ccc(-c2ccc(C=CC(=O)OC(C)(C)C)cc2)cc1C12CC3CC(CC(C3)C1)C2
Temperature: 50 °C
Reaction time: 8 h
Yield: 65 %

Procedure:
Linoleoyl chloride (208 mg, 0.696 mmol) was added to a solution of (E)-3-(3′-adamantan-1-yl-4′-hydroxybiphenyl-4-yl)-acrylic acid tert-butyl ester (200 mg, 0.464 mmol) in pyridine (2.2 ml). The resulting mixture was heated to 50° C. for 1 h, and then stirred at RT overnight. After addition of EtOAc, the organic phase was washed twice with 1N HCl, water, dried over Na2SO4, filtered and removed under reduced pressure. (E)-Octadeca-9,12-dienoic acid 3-adamantan-1-yl-4′-(2-tert-butoxycarbonylvinyl)biphenyl-4-yl ester was obtained as a colourless oil after purification on silica gel (EtOAc/hexane 5:95) in 65% yield (210 mg).
Reaction SMILES: [CH3:1][N:2]([CH3:24])[C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[C:8]2[S:13]([NH:16][C:17]1[N:18]=[N:19][C:20](Cl)=[CH:21][CH:22]=1)(=[O:15])=[O:14].[CH3:25][O-:26].[Na+]>CN1CCCC1=O.CO>[CH3:1][N:2]([CH3:24])[C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[C:8]2[S:13]([NH:16][C:17]1[N:18]=[N:19][C:20]([O:26][CH3:25])=[CH:21][CH:22]=1)(=[O:15])=[O:14]
Reactant: C[O-]
Reactant: CN(C)c1cccc2c(S(=O)(=O)Nc3ccc(Cl)nn3)cccc12
Agent: [Na+]
Solvent: CO
Solvent: CN1CCCC1=O
Product: COc1ccc(NS(=O)(=O)c2cccc3c(N(C)C)cccc23)nn1

Procedure:
5-Dimethylamino-N-(6-chloro-3-pyridazinyl)-1-naphthalenesulphonamide (0.36 g), was suspended in N-methylpyrrolidone (1 ml) and freshly prepared 1M sodium methoxide in methanol (3 ml) was added. The reaction mixture was heated to reflux for 4 hours, cooled and evaporated to dryness. The residue was purified by flash chromatography on silica gel (5 g) eluting with a methanol/dichloromethane gradient to give 5-dimethylamino-N-(6-methoxy-3-pyridazinyl)-1-naphthalenesulphonamide (0.14 g), m.p. 125°-127° C.; mass spectrum (+ve CI): 359 (M+H)+.
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.[CH2:7]([O:14][C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][CH:21]=1)[NH2:18])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C1C=CC=CC=1>[CH2:7]([O:14][C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][CH:21]=1)[NH:18][C:4](=[O:5])[CH2:3][C:2](=[O:6])[CH3:1])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: C=C1CC(=O)O1
Reactant: Nc1cccc(OCc2ccccc2)c1
Solvent: c1ccccc1
Product: CC(=O)CC(=O)Nc1cccc(OCc2ccccc2)c1
Temperature: 10 °C
Reaction time: 6 h
Yield: 84.8 %

Procedure:
84 g of diketene were added over 30 minutes to a mixture of 200 g of m-benzyloxy-aniline [Morton, J. Biol. Chem., (1949), p. 259] in 1 liter of benzene cooled to 10°C. and after stirring the mixture for 6 hours, the benzene was distilled off under reduced pressure. The residue was added to isopropyl ether and the mixture was vacuum filtered. The recovered precipitate was washed with isopropyl ether and dried to obtain 240 g of m-benzyloxy-acetylacetanilide melting at 80°C.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][C:3]=1[OH:9].[CH3:10][C:11]([CH3:16])=[CH:12][C:13](O)=[O:14]>>[Br:1][C:2]1[CH:8]=[C:7]2[C:5](=[CH:4][C:3]=1[OH:9])[O:6][C:11]([CH3:16])([CH3:10])[CH2:12][C:13]2=[O:14]
Reactant: CC(C)=CC(=O)O
Reactant: Oc1ccc(Br)c(O)c1
Product: CC1(C)CC(=O)c2cc(Br)c(O)cc2O1
Temperature: 90 °C
Reaction time: 0.25 h

Procedure:
A mixture of 4-bromoresorcinol (5.00 g, 26.5 mmol) and 3,3-dimethylacrylic acid (2.64 g, 26.5 mmol) were ground in a mortar. The mixture was then added portion-wise into polyphosphoric acid (8 g) at 90° C. After stirred at 90° C. for 15 min, the reaction mixture was cooled to room temperature and quenched with water. The mixture was then extracted with diethyl ether. The organic layer was separated, washed with water, brine, dried (MgSO4) and concentrated at reduced pressure to give a yellow residue. Purification by recrystallization (methanol and water) afforded the title compound as a yellow solid.
Reaction SMILES: Cl[CH:2]([NH:7][C:8](=[O:16])[C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1)[C:3]([F:6])([F:5])[F:4].[S-:17][C:18]#[N:19].[K+]>CC(C)=O>[CH3:15][C:12]1[CH:13]=[CH:14][C:9]([C:8]([NH:7][CH:2]([N:19]=[C:18]=[S:17])[C:3]([F:6])([F:5])[F:4])=[O:16])=[CH:10][CH:11]=1
Reactant: N#C[S-]
Reactant: Cc1ccc(C(=O)NC(Cl)C(F)(F)F)cc1
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1ccc(C(=O)NC(N=C=S)C(F)(F)F)cc1
Reaction time: 12 h
Yield: 61.1 %

Procedure:
A stirred solution of Example 1B (2.00 g, 8.00 mmol) in acetone (35 mL) at ambient temperature was treated with potassium thiocyanate (1.60 g, 16.0 mmol). The reaction mixture was stirred for 12 hours, concentrated, and the crude residue was purified by flash chromatography (elution with 40% ethyl acetate/hexanes) to provide 1.34 g of the desired product as an off-white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1N.[C-:10]#[N:11].[K+]>>[CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[C:10]#[N:11]
Reactant: [C-]#N
Reactant: Cc1cccc(C)c1N
Agent: [K+]
Product: Cc1cccc(C)c1C#N

Procedure:
The preparation of 2,6-dimethyl DL-phenylalanines is disclosed by R. R. Herr, T. Enkoji & J. P. Dailey, J. Amer. Chem. Soc., 79, 4229(1957). The method involves the conversion of 2,6-dimethyl aniline into its diazonium salt, followed by treatment with potassium cyanide and cuprous cyanide to produce 2,6-dimethylbenzonitrile. The benzonitrile is reduced with lithium aluminum hydride to provide 2,6-dimethylbenzylamine, which is reacted with excess methyl iodide producing 2,6dimethylbenzyltrimethylammonium iodide. The trimethylammonium group is displaced with diethyl-2acetamidomalonate to form the amido diester, which is subsequently acidolysed to form the racemic mixture of 2,6-dimethylphenylalanine.