Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: BrCC[C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.Cl.CC1C=C(C=CC=1C)C(C1CCNCC1)=O.C(N(CC)CC)C>CN(C)C=O>[NH:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:4]=[CH:5]1
Reactant: BrCCc1c[nH]c2ccccc12
Agent: Cc1ccc(C(=O)C2CCNCC2)cc1C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: c1ccc2[nH]ccc2c1

Procedure:
A solution of 9.6 g of 3-(2-bromoethyl)indole. 11.5 g of 4-(3,4-dimethylbenzoyl)piperidine hydrochloride and 10.1 g of triethylamine in 300 ml of dimethylformamide is treated according to the manipulative procedure described in Example 3(b) to give an indole, which is purified on a silica gel column, eluted with a 5% methanol-benzene mixture and recrystallized from an ethanol-water mixture to give the solid, mp 172°-173° C., 3-{2-[4-(3,4-dimethylbenzoyl)piperidyl]ethyl}indole.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[C:3]=1[C:4]([OH:6])=O.Cl.[CH3:15][O:16][C:17](=[O:27])[CH:18]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[NH2:19].C(N(C(C)C)C(C)C)C.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.F[B-](F)(F)F>O1CCCC1>[NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[C:3]=1[C:4]([NH:19][CH:18]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:17]([O:16][CH3:15])=[O:27])=[O:6]
Reactant: COC(=O)C(N)Cc1ccccc1
Reactant: Nc1cccc([N+](=O)[O-])c1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C(Cc1ccccc1)NC(=O)c1c(N)cccc1[N+](=O)[O-]

Procedure:
1.18 g (6.5 mmol) 2-amino-6-nitrobenzoic acid, 1.0 g (4.6 mmol) D,L-phenylalanine-methylester hydrochloride, 4.05 ml (23.2 mmol) N-ethyldiisopropylamine are combined with 2.5 ml of tetrahydrofuran. 1.71 g (5.1 mmol) O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium-tetrafluoroborate are added to this reaction mixture and it is heated for 12 h to 50° C. Then the solvent is eliminated in vacuo and the crude product is purified by chromatography. The carrier used is silica gel and the eluant used is a mixture of cyclohexane:ethyl acetate (50:50).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[CH2:7](Br)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[OH:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24]([OH:26])=[O:25])=[CH:19][CH:18]=1>CN(C)C=O.C(OCC)C>[OH:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24]([O:26][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:25])=[CH:19][CH:18]=1
Reactant: BrCc1ccccc1
Reactant: O=C(O)Cc1ccc(CO)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: O=C(Cc1ccc(CO)cc1)OCc1ccccc1
Reaction time: 3.5 h
Yield: 82.5 %

Procedure:
2.52 g (23.8 mmol) of sodium carbonate and 8.13 g (47.6 mmol) of benzyl bromide were added to a solution of 3.95 g (23.8 mmol) of 4-Hydroxymethylphenylacetic acid [prepared as described in step (i) above] in 40 ml of N,N-dimethylformamide, and the resulting mixture was stirred for 3.5 hours. At the end of this time, the reaction mixture was diluted with diethyl ether, and the diluted mixture was washed with water and then with a saturated aqueous solution of sodium chloride. The organic phase was dried over anhydrous sodium sulfate, and the solvent was distilled off. The resulting residue was purified by column chromatography through 200 g of silica gel, using a gradient elution method, with mixtures of methylene chloride and ethyl acetate in ratios ranging from 100:5 to 100:10 by volume as the eluent, to give 5.03 g (yield 82%) of the title compound as an oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[OH-].[K+].[F:14][C:15]([F:22])([F:21])[C:16]([F:20])=[C:17]([F:19])[F:18]>CC(C)=O>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([O:10][C:17]([F:19])([F:18])[CH:16]([F:20])[C:15]([F:22])([F:21])[F:14])=[CH:6][CH:5]=1
Reactant: FC(F)=C(F)C(F)(F)F
Reactant: COC(=O)c1ccc(O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Product: COC(=O)c1ccc(OC(F)(F)C(F)C(F)(F)F)cc1

Procedure:
456 g (3 moles) of 4-hydroxybenzoic acid methyl ester, 30 g of 85% potassium hydroxide, and 1 l of acetone were placed in an autoclave. An amount of 562.5 g (3.75 moles) of hexafluoropropylene was introduced under pressure.
Reaction SMILES: [NH2:1][C:2](=[N:8][O:9][C:10](=O)[C:11]([N:21]1[C:29]2[C:24](=[C:25]([NH:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH:26]=[CH:27][CH:28]=2)[CH:23]=[N:22]1)([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[CH2:12][CH3:13])[C:3]([O:5][CH2:6][CH3:7])=[O:4].P(Cl)(Cl)(Cl)=O>N1C=CC=CC=1>[C:34]([O:33][C:31]([NH:30][C:25]1[CH:26]=[CH:27][CH:28]=[C:29]2[C:24]=1[CH:23]=[N:22][N:21]2[C:11]([C:10]1[O:9][N:8]=[C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[N:1]=1)([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[CH2:12][CH3:13])=[O:32])([CH3:37])([CH3:36])[CH3:35]
Reactant: CCOC(=O)C(N)=NOC(=O)C(CC)(c1ccc(Cl)cc1)n1ncc2c(NC(=O)OC(C)(C)C)cccc21
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: CCOC(=O)c1noc(C(CC)(c2ccc(Cl)cc2)n2ncc3c(NC(=O)OC(C)(C)C)cccc32)n1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
To a solution of the product from Step B above (0.18 g, 0.33 mmol) in pyridine (9.0 mL) was added phosphorus oxychloride (0.25 g, 1.65 mmol). The mixture was heated at 70° C. for 7 hours, and stirred at 35° C. overnight, then concentrated to dryness under reduced pressure. The residue was dissolved in EtOAc and washed with saturated NaHCO3, water and brine. The organic layer was separated and dried over Na2SO4. The crude product was purified on a silica gel column using a gradient of 0-50% ethyl acetate in hexanes to give the title compound as light brown solid. LC/MS m/z=526.1[M+H]+.
Reaction SMILES: [N:1]1[CH:6]=[C:5](B(O)O)[CH:4]=[N:3][CH:2]=1.I[C:11]1[C:19]2[C:14](=[N:15][CH:16]=[N:17][C:18]=2[NH2:20])[N:13]([CH:21]([CH3:23])[CH3:22])[N:12]=1.C([O-])([O-])=O.[Na+].[Na+]>CCO.COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:21]([N:13]1[C:14]2=[N:15][CH:16]=[N:17][C:18]([NH2:20])=[C:19]2[C:11]([C:5]2[CH:6]=[N:1][CH:2]=[N:3][CH:4]=2)=[N:12]1)([CH3:23])[CH3:22]
Reactant: CC(C)n1nc(I)c2c(N)ncnc21
Reactant: OB(O)c1cncnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCO
Product: CC(C)n1nc(-c2cncnc2)c2c(N)ncnc21
Temperature: 80 °C

Procedure:
A solution of 5-Pyrimidinylboronic acid (15 mg, 0.14 mmol) in EtOH (3.3 mL) was added to a solution of 3-iodo-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (40 mg, 0.13 mmol) in DME (12 mL). Pd(PPh3)4 (15 mg, 0.015 mmol) and saturated Na2CO3 (1.9 mL) were added and the reaction was heated to 80° C. under an argon atmosphere overnight. After cooling, the reaction was extracted with saturated NaCl and CH2Cl2. Organic phases were combined, concentrated in vacuo and purified by RP-HPLC (MeCN:H2O) to yield BA53. ESI-MS (M+H)+ m/z calcd 256.1, found 256.1.
Reaction SMILES: Br[C:2]1[CH:12]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].C([O-])([O-])=O.[K+].[K+].C1(C)C=CC=CC=1.[CH2:31]([O:37][C:38]1[CH:43]=[CH:42][C:41](B(O)O)=[CH:40][CH:39]=1)[CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH2:31]([O:37][C:38]1[CH:39]=[CH:40][C:41]([C:2]2[CH:12]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:10]=[CH:9][C:3]=2[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:42][CH:43]=1)[CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]
Reactant: CCCCCCOc1ccc(B(O)O)cc1
Reactant: CCOC(=O)c1ccc(C(=O)OCC)c(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCCOc1ccc(-c2cc(C(=O)OCC)ccc2C(=O)OCC)cc1
Temperature: 85 °C
Reaction time: 7 h

Procedure:
Diethyl bromoterephthalate (30.1 g, 100 mmol), K2CO3 (27.6 g, 200 mmol), 140 ml of toluene and 140 ml of H2O were placed in the reaction vessel and flushed with argon for 30 minutes. 4-Hexyloxyphenylboronic acid (26.7 g,120 mmol) (cf. B1) and Pd(PPh3)4 (1.16 g, 1 mmol) were subsequently added under protective gas. The yellowish green, turbid mixture was stirred vigorously under a blanket of protective gas at an internal temperature of 85° C. After 7 hours, the reaction was complete. After phase separation, the organic phase was shaken with dilute HCl/H2O (until neutral). The aqueous phase was shaken with toluene and the organic phases were combined. After filtration from any palladium residues, the solution was evaporated.
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([N:16]2[CH2:20][CH2:19][CH2:18][C:17]2=[O:21])=[N:13][C:12]=1[CH3:22])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH:32]([F:34])[F:33])=[CH:27][CH:26]=1>>[CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([N:16]2[CH2:20][CH2:19][CH:18]([CH2:24][C:25]3[CH:26]=[CH:27][C:28]([O:31][CH:32]([F:33])[F:34])=[CH:29][CH:30]=3)[C:17]2=[O:21])=[N:13][C:12]=1[CH3:22])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1nc(N2CCCC2=O)sc1C(=O)NCc1ccccc1
Reactant: FC(F)Oc1ccc(CBr)cc1
Product: Cc1nc(N2CCC(Cc3ccc(OC(F)F)cc3)C2=O)sc1C(=O)NCc1ccccc1
Yield: 27 %

Procedure:
Following the procedure as described in Example 2, making variation as required to use N-benzyl-4-methyl-2-(2-oxopyrrolidin-1-yl)thiazole-5-carboxamide in place of N-(4-fluorobenzyl)-4-methyl-2-(2-oxopyrrolidin-1-yl)thiazole-5-carboxamide to react with 1-(bromomethyl)-4-(difluoromethoxy)benzene in place of 1-(bromomethyl)-4-(trifluoromethyl)benzene, the title compound was obtained as a white solid in 27% yield: mp 132-133° C. (hexanes/ethyl acetate); 1H NMR (300 MHz, CDCl3) δ 7.41-7.24 (m, 5H), 7.18 (d, J=8.2 Hz, 2H), 7.03 (d, J=8.2 Hz, 2H), 6.46 (dt, J=73.9, 1.0 Hz, 1H), 5.94 (t, J=5.5 Hz, 1H), 4.57 (d, J=5.5 Hz, 2H), 4.11-3.98 (m, 1H), 3.93-3.81 (m, 1H), 3.28-3.16 (m, 1H), 3.08-2.93 (m, 1H), 2.80 (dd, J=13.7, 8.8 Hz, 1H), 2.62 (s, 3H), 2.33-2.19 (m, 1H), 1.99-1.84 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 174.6, 162.3, 155.3, 152.7, 137.8, 135.4, 130.3, 128.8, 127.9, 127.7, 119.9, 119.5, 118.7, 115.9, 45.9, 44.4, 44.1, 35.6, 24.2, 17.3; MS (ES+) m/z 472.3 (M+1).
Reaction SMILES: [CH3:1][C:2]1[C:8](=[O:9])[C:7]2[N:10]3[C@@:14]([O:21][CH3:22])([C@H:15]([CH2:16][O:17][C:18]([NH2:20])=[O:19])[C:6]=2[C:4](=[O:5])[C:3]=1OC)[C@H:13]1[N:23]([CH3:24])[C@H:12]1[CH2:11]3.[CH2:27]([NH2:30])[CH:28]=[CH2:29]>CO>[C:18](=[O:17])([OH:19])[NH2:20].[OH:17][CH2:16][CH:15]1[C:6]2[C:4](=[O:5])[C:3]([NH:30][CH2:27][CH:28]=[CH2:29])=[C:2]([CH3:1])[C:8](=[O:9])[C:7]=2[N:10]2[CH2:11][CH:12]3[N:23]([CH3:24])[CH:13]3[C:14]12[O:21][CH3:22]
Reactant: C=CCN
Reactant: COC1=C(C)C(=O)C2=C(C1=O)[C@@H](COC(N)=O)[C@@]1(OC)[C@@H]3[C@H](CN21)N3C
Solvent: CO
Product: C=CCNC1=C(C)C(=O)C2=C(C1=O)C(CO)C1(OC)C3C(CN21)N3C
Product: NC(=O)O
Yield: 68.9 %

Procedure:
To a solution of 100 mg (0.275 mmol) of N-methylmitomycin A in 15 ml of anhydrous methanol, 58 mg (1 mmol) of allylamine was added with stirring. The reaction mixture was stirred overnight, whereupon TLC indicated the absence of starting material. The solvent was then evaporated under reduced pressure and the residue was chromatographed using silica-gel as adsorbent. The fraction obtained by eluting the colum with ethyl acetate was evaporated to dryness. Recrystallization from a mixture of ethyl acetate and hexane gave 38.5 mg (38% yield) of the desired product as purple-colored crystals having a melting point of 70°-71° C. (decomposing) and providing the following analysis:
Reaction SMILES: CC(C)([O-])C.[K+].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=1[CH2:15][CH:16]=O.[Br:18][C:19]1[CH:24]=[C:23]([NH:25]C(=O)OC(C)(C)C)[C:22]([CH:33]=O)=[CH:21][N:20]=1.Cl>O1CCOCC1.O.C(OCC)(=O)C>[Br:18][C:19]1[CH:24]=[C:23]2[C:22]([CH:33]=[C:15]([C:9]3[CH:10]=[C:11]([F:14])[CH:12]=[CH:13][C:8]=3[Cl:7])[CH:16]=[N:25]2)=[CH:21][N:20]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(Br)ncc1C=O
Reactant: O=CCc1cc(F)ccc1Cl
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: Fc1ccc(Cl)c(-c2cnc3cc(Br)ncc3c2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 29.6 %

Procedure:
To a slurry of potassium tert-butoxide (94 mg, 0.8 mmol) in 1,4-dioxane (1 mL) cooled at 0° C. was added 2-(2-chloro-5-fluorophenyl)acetaldehyde (98 mg, 0.4 mmol) as a solution in 1,4-dioxane (0.6 mL). The reaction mixture was stirred for 10 minutes at this temperature, and then tert-butyl 2-bromo-5-formylpyridin-4-ylcarbamate (60 mg, 0.2 mmol) was added as a solution in dioxane (0.6 mL). The reaction mixture was allowed to warm to room temperature, and after 30 minutes a 5.0M solution of hydrogen chloride in water (0.5 mL) was added and the mixture was heated at 100° C. for 1 hour. The cooled reaction mixture was diluted with ethyl acetate (50 mL) and washed with water (50 mL). The organic layer was separated, dried over sodium sulfate, filtered, and evaporated in vacuo to afford a residue that was purified by flash chromatography (silica, 4 g, ISCO, 0-50% ethyl acetate in heptane) to afford the title compound as an off-white solid (20 mg, 30%), which was used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9](=[CH:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=1)[NH:8][CH2:7][CH2:6]2.[CH3:26][O:27][C:28]1[CH:29]=[C:30]([CH:34]=[C:35]([O:39][CH3:40])[C:36]=1[O:37][CH3:38])[C:31](Cl)=[O:32].N1C=CC=CC=1>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])/[C:9](=[CH:15]/[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=1)/[N:8]([C:31](=[O:32])[C:30]1[CH:29]=[C:28]([O:27][CH3:26])[C:36]([O:37][CH3:38])=[C:35]([O:39][CH3:40])[CH:34]=1)[CH2:7][CH2:6]2
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Reactant: COc1ccc(C=C2NCCc3cc(OC)c(OC)cc32)cc1OC
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: COc1ccc(/C=C2/c3cc(OC)c(OC)cc3CCN2C(=O)c2cc(OC)c(OC)c(OC)c2)cc1OC

Procedure:
A suspension of 6 parts of 3,4-dihydro-6,7-dimethoxy-1-[(3,4-dimethoxyphenyl)methylene]isoquinoline and 6 parts of 3,4,5-trimethoxybenzoyl chloride in 50 parts of pyridine is heated at the boiling point under reflux in a nitrogen atmosphere for 45 minutes, whereupon 180 parts of chloroform is introduced. The resultant solution is washed with water, dried over anhydrous sodium sulfate, and stripped of solvent by vacuum distillation. The residue is taken up in benzene; and the benzene solution is chromatographed on silica gel, using benzene and mixtures thereof with increasing amounts of ethyl acetate as developing solvents. From an eluate comprising 30% ethyl acetate in benzene, on evaporation of solvent, (Z)-1,2,3,4-tetrahydro-6,7-dimethoxy-2-(3,4,5-trimethoxybenzoyl)-1-[(3,4-dimethoxyphenyl)methylene]isoquinoline melting at 195°-200° is obtained as the residue.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[O:9][CH2:8][CH2:7][N:6](C(OC(C)(C)C)=O)[CH2:5][CH:4]1[C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=1.[N:25]1([CH2:30][C:31](O)=[O:32])[CH:29]=[N:28][CH:27]=[N:26]1>>[ClH:23].[Cl:24][C:19]1[CH:18]=[C:17]([CH:4]2[CH:3]([CH2:2][NH:1][C:31](=[O:32])[CH2:30][N:25]3[CH:29]=[N:28][CH:27]=[N:26]3)[O:9][CH2:8][CH2:7][NH:6][CH2:5]2)[CH:22]=[CH:21][C:20]=1[Cl:23]
Reactant: O=C(O)Cn1cncn1
Reactant: CC(C)(C)OC(=O)N1CCOC(CN)C(c2ccc(Cl)c(Cl)c2)C1
Product: Cl
Product: O=C(Cn1cncn1)NCC1OCCNCC1c1ccc(Cl)c(Cl)c1

Procedure:
Using tert-butyl (6RS,7SR)-7-(aminomethyl)-6-(3,4-dichlorophenyl)-1,4-oxazepane-4-carboxylate and 2-(1H-1,2,4-triazol-1-yl)acetic acid, and by a method similar to that of Example 39, step A and Example 449, step B, the title compound was obtained.
Reaction SMILES: ClC(Cl)(Cl)[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.ClC1C=C(Cl)C(Cl)=CC=1Cl.[Cl-:22].[Cl-:23].[Cl-:24].[Al+3]>C1(C)C(C)=CC=CC=1>[Cl:22][C:7]1[CH:8]=[CH:9][C:4]([OH:3])=[C:5]([Cl:23])[C:6]=1[Cl:24]
Reactant: [Cl-]
Reactant: ClC(Cl)(Cl)Oc1ccccc1
Agent: Clc1cc(Cl)c(Cl)cc1Cl
Agent: [Al+3]
Solvent: Cc1ccccc1C
Product: Oc1ccc(Cl)c(Cl)c1Cl
Yield: 97 %

Procedure:
A mixture of trichloroanisole (0.1 g mol; 21.15 g) and 1,2,4,5-tetrachlorobenzene (10 g) in xylene (80 ml) was heated at 80° C. with aluminium trichloride (0.05 mole; 6.65 g) for five hours. Trichlorophenol was isolated in 97% yield (based on trichloroanisole) as described in Example I below. Unchanged tetrachlorobenzene, together with xylene self condensation product (total 13.25 g) was isolated from the neutral product fraction after solvent removal.
Reaction SMILES: [Br:1][C:2]1[C:11]([OH:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH2:13][N:14]([CH3:29])[C:15](=[O:28])[C:16]1[CH:21]=[CH:20][C:19]([CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:18][CH:17]=1)=[CH:7]2.[CH3:30][O:31][C:32](=[O:49])[CH:33](OS(C(F)(F)F)(=O)=O)[CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(C)=O>[CH3:30][O:31][C:32](=[O:49])[CH:33]([O:12][C:11]1[CH:10]=[CH:9][C:8]2[C:3](=[CH:4][CH:5]=[C:6]([CH2:13][N:14]([C:15](=[O:28])[C:16]3[CH:17]=[CH:18][C:19]([CH:22]4[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]4)=[CH:20][CH:21]=3)[CH3:29])[CH:7]=2)[C:2]=1[Br:1])[CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: CN(Cc1ccc2c(Br)c(O)ccc2c1)C(=O)c1ccc(C2CCCCC2)cc1
Reactant: COC(=O)C(Cc1ccccc1)OS(=O)(=O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: COC(=O)C(Cc1ccccc1)Oc1ccc2cc(CN(C)C(=O)c3ccc(C4CCCCC4)cc3)ccc2c1Br
Temperature: 25 °C
Reaction time: 3 h
Yield: 48 %

Procedure:
A mixture of N-(5-bromo-6-hydroxy-naphthalen-2-ylmethyl)-4-cyclohexyl-N-methyl-benzamide (799 mg, 1.51 mmol), prepared in the previous step, 3-phenyl-2-trifluoromethanesulfonyloxypropionic acid methyl ester (1.66 mmol), prepared in step 2 of Example 7, and cesium carbonate (985 mg, 3.0 mmol) in acetone was stirred at room temperature for 3 h. The reaction was partitioned between water and ethyl acetate. The aqueous layer was separated and extracted three times with ethyl acetate. The combined extracts were dried (Na2SO4) and the solvent removed under reduced pressure. Purification of the residue by column chromatography using 10%-20% ethyl acetate-hexanes as the eluent gave 2-(1-bromo-6-{[(4-cyclohexyl-benzoyl)-methyl-amino]-methyl}-naphthalen-2-yloxy)-3-phenyl-propionic acid methyl ester (445 mg, 48%), LCMS ES+(Calc'd: 613.2; Found: 614.3).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15]([Cl:16])=[CH:14][C:13]2[C:8](=[C:9](OS(C(F)(F)F)(=O)=O)[CH:10]=[CH:11][CH:12]=2)[CH:7]=1)=[O:5])[CH3:2].O.[CH3:26][N:27](C)C=O>[C-]#N.[C-]#N.[Zn+2].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:3][C:4]([C:6]1[C:15]([Cl:16])=[CH:14][C:13]2[C:8](=[C:9]([C:26]#[N:27])[CH:10]=[CH:11][CH:12]=2)[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2c(OS(=O)(=O)C(F)(F)F)cccc2cc1Cl
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Product: CCOC(=O)c1cc2c(C#N)cccc2cc1Cl
Temperature: 125 °C
Reaction time: 0.5 h

Procedure:
Zn(CN)2 (1.50 g, 12.80 mmol, 2.0 equiv) and Pd(PPh3)4 (296 mg, 0.26 mmol, 0.04 equiv) were added at room temperature under an atmosphere of argon to a degassed solution of 3-chloro-8-trifluoromethanesulfonyloxy-naphthalene-2-carboxylic acid ethyl ester (2.45 g, 6.40 mmol) in N,N-dimethylformamide (25 ml). The mixture was heated to 125° C. After 30 minutes, TLC analysis indicated complete conversion. After cooling, water was added, and the mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. Purification via flash chromatography (gradient of hexane/EtOAc 100:0 to 90:10) afforded the title compound (1.43 g, 86%, 1:1.3 mixture of regioisomers A:B) as a white solid. For analytical purposes, the regioisomers could be separated by careful chromatography on silica gel. Regioisomer A: 1H NMR (400 MHz, CDCl3): δ=8.41 (s, 1H), 8.32 (s, 1H), 8.13 (br d, J=8.3 Hz, 1H), 8.01 (dd, J=7.1/1.0 Hz, 1H), 7.60 (dd, J=8.3/7.3 Hz, 1H), 4.47 (q, J=7.1 Hz, 2H), 1.45 (t, J=7.1 Hz, 3H). MS (ES+): 260 (M+H)+. Regioisomer B: 1H NMR (400 MHz, CDCl3): δ=8.65 (s, 1H), 8.02 (d, J=8.3 Hz, 1H), 8.02 (s, 1H), 7.96 (dd, J=7.4/1.3 Hz, 1H), 7.65 (dd, J=8.3/7.4 Hz, 1H), 4.49 (q, J=7.1 Hz, 2H), 1.46 (t, J=7.3 Hz, 3H). MS (ES+): 260 (M+H)+.
Reaction SMILES: [NH2:1][NH2:2].[CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[N:13]=[C:14]=[S:15]>C(OCC)C>[NH2:1][NH:2][C:14]([NH:13][C:4]1[CH:5]=[CH:6][C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:3]=1)=[S:15]
Reactant: S=C=Nc1ccc2ccccc2c1
Reactant: NN
Solvent: CCOCC
Product: NNC(=S)Nc1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Anhydrous hydrazine (1.1 g, 0.035 mole) was dissolved in 150 ml of diethyl ether in a round-bottomed flask. 2-Naphthyl isothiocyanate (4.6 g, 0.25 mole) was added dropwise to the mixture keeping the pot temperature below 30° during the addition. The reaction mixture was stirred overnight at room temperature. The reactants were then cooled and the title product filtered off. The product was air-dried, yield 4.5 g, m.p. 174°-6°.
Reaction SMILES: C(O[C:6]([N:8](C)[CH2:9][C:10]([NH:12][CH2:13][CH2:14][CH2:15][P+:16]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:11])=O)(C)(C)C.[Cl-:36].Cl.C(OCC)C.N>C(Cl)Cl.CO>[CH3:6][NH:8][CH2:9][C:10]([NH:12][CH2:13][CH2:14][CH2:15][P+:16]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:11].[Cl-:36]
Reactant: CN(CC(=O)NCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)OC(C)(C)C
Agent: Cl
Agent: N
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCOCC
Solvent: CO
Product: CNCC(=O)NCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 0.1 %

Procedure:
To a solution of N2-(tert-butoxycarbonyl)-N2-methyl-N-[3-(triphenylphosphonio)propyl]glycinamide chloride (7.6 g, 14 mol) in methylene chloride (38 mL) and methanol (4.2 mL) was added 2.0 M HCl in diethyl ether (16 mL, 32 mmol), and the mixture was stirred overnight at room temperature. The solution was cooled to 0° C. and treated with 7 M ammonia in methanol (6.0 mL, 42 mmol), giving an immediate white precipitate. After 30 minutes, the slurry was filtered and the flask and filter cake were rinsed with methylene chloride (68 mL). The filtrate was concentrated to give the title compound (6.2 g, 100%) as a crude white solid.
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH:10]=[C:9](OC)[CH:8]=[CH:7][C:5]=2[N:6]=1.CC1(C)C(C)(C)OB([C:21]2[CH:22]=[CH:23][C:24]([N:27]3CCOC[CH2:28]3)=[N:25][CH:26]=2)O1.[CH3:34][O:35]C1C=CC2N=C(C3C=NC(N)=NC=3)SC=2C=1>>[CH3:34][O:35][C:8]1[CH:9]=[CH:10][C:4]2[S:3][C:2]([C:21]3[CH:22]=[CH:23][C:24]([NH:27][CH3:28])=[N:25][CH:26]=3)=[N:6][C:5]=2[CH:7]=1
Reactant: COc1ccc2nc(-c3cnc(N)nc3)sc2c1
Reactant: CC1(C)OB(c2ccc(N3CCOCC3)nc2)OC1(C)C
Reactant: COc1ccc2nc(Br)sc2c1
Product: CNc1ccc(-c2nc3cc(OC)ccc3s2)cn1

Procedure:
2-Bromo-6-methoxy-1,3-benzothiazole (49 mg, 0.20 mmol), 4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]morpholine (70 mg, 0.24 mmol) were reacted according to the procedure used for the preparation of 5-(6-methoxy-1,3-benzothiazol-2-yl)pyrimidin-2-amine, with the following exceptions: The reaction was heated for 4 h before the solvent was evaporated under reduced pressure. The residue was dissolved in MeOH/DCM 1:1 and filtered through silica. The filtrate was concentrated and the crude product was purified by preparative HPLC to give the title compound (0.6 mg). 1H NMR (CHLOROFORM-d) δ 8.79 (d, 1 H) 8.18 (dd, 1 H) 7.90 (d, 1 H) 7.35 (d, 1 H) 7.08 (dd, 1 H) 6.71 (d, 1 H) 3.90 (s, 3 H) 3.87-3.83 (m, 4 H) 3.67-3.63 (m, 4 H); MS m/z (M+H) 328.