Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]1[C@@H:7]([NH:8][C:9]([C:11]2[NH:12][C:13]([CH2:17][CH3:18])=[C:14]([Cl:16])[N:15]=2)=[O:10])[CH2:6][CH2:5][N:4]([C:19]2[S:20][C:21]3[C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:26][CH:25]=[CH:24][C:22]=3[N:23]=2)[CH2:3]1.[CH:33](=O)[CH2:34][CH2:35][CH2:36][CH3:37].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[Cl:16][C:14]1[N:15]=[C:11]([C:9]([NH:8][C@H:7]2[CH2:6][CH2:5][N:4]([C:19]3[S:20][C:21]4[C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:26][CH:25]=[CH:24][C:22]=4[N:23]=3)[CH2:3][C@H:2]2[NH:1][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[O:10])[NH:12][C:13]=1[CH2:17][CH3:18]
Reactant: CCCCC=O
Reactant: CCOC(=O)c1cccc2nc(N3CC[C@H](NC(=O)c4nc(Cl)c(CC)[nH]4)[C@H](N)C3)sc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CCCCCN[C@@H]1CN(c2nc3cccc(C(=O)OCC)c3s2)CC[C@@H]1NC(=O)c1nc(Cl)c(CC)[nH]1

Procedure:
The same operation as in Example (77d) was performed using ethyl cis(±)-2-(3-amino-4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}piperidin-1-yl)-1,3-benzothiazole-7-carboxylate obtained by the method described in Example (81e) (30 mg, 0.063 mmol), 1-pentanal (14 μL, 0.13 mmol) and sodium (triacetoxy)borohydride (120 mg, 0.57 mmol), to obtain 30.8 mg of the title compound as a colorless oily substance (90%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[N:7][CH:6]=[CH:5][N:4]=1)#[N:2].[NH2:9][C:10]1[S:11][C:12]([CH2:20][CH3:21])=[CH:13][C:14]=1[C:15](OCC)=O.O=P(Cl)(Cl)[Cl:24]>>[Cl:24][C:15]1[C:14]2[CH:13]=[C:12]([CH2:20][CH3:21])[S:11][C:10]=2[N:9]=[C:1]([C:3]2[CH:8]=[N:7][CH:6]=[CH:5][N:4]=2)[N:2]=1
Reactant: N#Cc1cnccn1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1cc(CC)sc1N
Product: CCc1cc2c(Cl)nc(-c3cnccn3)nc2s1

Procedure:
With the procedure of Example 477, the reaction of 2-cyanopyrazine and 2-amino-5-ethyl-3-ethoxycarbonyl-thiophene, and the subsequent reaction with POCl3 yields 4-chloro-2-(pyrazin-2-yl)-6-ethyl-thieno-[2,3-d]-pyrimidine
Reaction SMILES: [Mg].[Cl:2][CH2:3][C:4]1[CH:5]=[C:6]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:8][CH:9]=1.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]([N:29]([CH3:31])[CH3:30])[CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][C:23]2=[O:28])=[CH:17][CH:16]=1.[Cl-].[NH4+]>CCOCC>[ClH:2].[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([CH:21]([N:29]([CH3:31])[CH3:30])[CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][C:23]2([CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[CH:5]=2)[OH:28])=[CH:19][CH:20]=1
Reactant: CN(C)C(c1ccc(Cl)cc1)C1CCCCC1=O
Reactant: FC(F)(F)c1cccc(CCl)c1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Product: CN(C)C(c1ccc(Cl)cc1)C1CCCCC1(O)Cc1cccc(C(F)(F)F)c1
Product: Cl
Temperature: 25 °C
Yield: 3.5 %

Procedure:
0.22 g (9.0 mmole) of magnesium turnings was stirred in 5 ml of ether of analysis purity. 1.76 g (9.0 mmole) of 3-chloromethylbenzotrifluoride dissolved in 5 ml of ether were added dropwise so that the reaction mixture boiled gently. After completion of the addition the reaction mixture was stirred for a further hour at RT. 2.00 g (7.5 mmole) of the 2-[(4-chlorophenyl)dimethylaminomethyl]cyclohexanone prepared according to Example 58 were dissolved in 10 ml of ether, added dropwise to the Grignard reagent while cooling in an ice bath, and stirred for 15 hours at RT. The reaction mixture was worked up by adding 10 ml of saturated ammonium chloride solution while cooling in an ice bath, and was extracted three times at RT with 15 ml of ether each time. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator (500 to 10 mbar). 1.46 g of crude base (45.6% of theory) were obtained, from which a hydrochloride was precipitated according to Example 1 (3rd stage) with chlorotrimethylsilane/water in 2-butanone. The base was freed from the hydrochloride with 15 ml of water and 5 ml of ammonia solution (25 vol. %), extracted three times with 15 ml of ether each time, and the combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator (500 to 10 mbar). 0.33 g of crude base (10.3% of theory) was obtained, from which 0.12 g of 2-[(4-chlorophenyl)dimethylaminomethyl]-1-(3-trifluoromethylbenzyl)cyclohexanol, hydrochloride (3.6% of theory) was obtained according to the procedure described in Example 1 (3rd Stage) with chlorotrimethylsilane/water in 2-butanone. The hydrochloride decomposes on heating above 115° C.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:5][C:3]=1[NH2:4].Cl[C:25](Cl)([O:27][C:28](=[O:34])OC(Cl)(Cl)Cl)Cl.[CH:36]1(O)[CH2:40]C[CH2:38][CH2:37]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:5][C:3]=1[NH:4][C:28](=[O:34])[O:27][CH:25]1[CH2:38][CH2:37][CH2:36][CH2:40]1
Reactant: OC1CCCC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2ncnc(Oc3ccc(N)c(Cl)c3)c2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COc1cc2ncnc(Oc3ccc(NC(=O)OC4CCCC4)c(Cl)c3)c2cc1OC
Yield: 92.7 %

Procedure:
2-Chloro-4-[(6,7-dimethoxy-4-quinazolinyl)oxy]-aniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (68 mg) in methylene chloride was then dded thereto, and the mixture was heated under reflux for 10 min. Next, 1-cyclopentanol (20 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (62 mg, yield 80%).
Reaction SMILES: O.[NH2:2][NH2:3].[F:4][C:5]([F:12])([F:11])[C:6]([O:8]CC)=O.[OH-].[Na+].[Cl:15][CH2:16][C:17](Cl)=[O:18]>C(#N)C>[Cl:15][CH2:16][C:17]([NH:2][NH:3][C:6](=[O:8])[C:5]([F:4])([F:11])[F:12])=[O:18]
Reactant: CCOC(=O)C(F)(F)F
Reactant: O=C(Cl)CCl
Reactant: NN
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: O=C(CCl)NNC(=O)C(F)(F)F
Temperature: 10 °C
Reaction time: 1 h
Yield: 98.3 %

Procedure:
Hydrazine hydrate (15 g, 35 wt %) is mixed acetonitrile (22.5 mL) and cooled to about 10° C. Ethyl trifluoroacetate (23.3 g) is added over 1 hour. The resulting solution is warmed to 20° C. and stirred for about 1 hour. The solution is cooled to 0-2° C. 50 wt % aqueous NaOH (7.88 g) and chloroacetyl chloride (22.2 g) are added to the reaction solution simultaneously over 2 hours. The reaction mixture is warmed to 15-18° C. and stirred for about 5 hours. Solvent is distilled off under vacuum at about 30° C. Water (50 mL) and ethyl acetate (100 mL) are added to the obtained crude. The organic and aqueous layers are separated and aqueous layer is washed with ethyl acetate (2×50 mL). The organic layers are combined and washed with water (2×50 mL) followed by washing with 15% sodium chloride solution (2×50 mL). The combined organic layer is dried over sodium sulfate. The solvent is completely distilled off under vacuum to afford the title compound. (Yield: 98.3%)
Reaction SMILES: C[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3[C:13](C(C)C)=[C:14]([OH:17])[CH:15]=[CH:16][C:11]=3[C:10]([N+:21]([O-:23])=[O:22])=[C:9]2/[CH:24]=C/N(C)C)=[CH:4][CH:3]=1.S(C1C=CC=CC=1[C:35](OC(=O)C1C=CC=CC=1S(O)(=O)=O)=[O:36])(O)(=O)=O.N1C=CC=CC=1>C1(C)C=CC=CC=1.[OH-].[Na+].CO>[CH3:24][C:9]1[N:8]([C:5]2[CH:6]=[CH:7][C:2]([O:36][CH3:35])=[CH:3][CH:4]=2)[C:12]2[CH:13]=[C:14]([OH:17])[CH:15]=[CH:16][C:11]=2[C:10]=1[N+:21]([O-:23])=[O:22]
Reactant: Cc1ccc(-n2c(/C=C/N(C)C)c([N+](=O)[O-])c3ccc(O)c(C(C)C)c32)cc1
Reactant: O=C(OC(=O)c1ccccc1S(=O)(=O)O)c1ccccc1S(=O)(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Solvent: CO
Product: COc1ccc(-n2c(C)c([N+](=O)[O-])c3ccc(O)cc32)cc1
Yield: 54 %

Procedure:
23.6 g of ID-1 were refluxed together with 20.2 g of sulphobenzoic anhydride and 9 ml of pyridine in 200 ml of toluene. The oil formed was taken up in 300 ml of NaOH 1N and again heated to reflux with 200 ml of toluene. After elimination of the solvents by evaporation the precipitate formed was taken up in 500 ml of methanol. The precipitate, a lightly yellow powder, dissolved but recrystallized immediately. The yield was 54%.
Reaction SMILES: [Cr:1].O.[C:3]([OH:6])(=[O:5])[CH3:4]>>[CH3:4][C:3]([O-:6])=[O:5].[CH3:4][C:3]([O-:6])=[O:5].[CH3:4][C:3]([O-:6])=[O:5].[Cr+3:1]
Reactant: CC(=O)O
Reactant: [Cr]
Solvent: O
Product: CC(=O)[O-]
Product: [Cr+3]

Procedure:
Chromium Micelle: Weighed 10 grams of chromic oxide (Cr2O3) and added to a 4 liter beaker. The contents of the beaker were slurried with 200 ml of distilled water. 12.5 ml of glacial acetic acid were added to produce a chromic (III) acetate in solution. 100 grams of chrysotile asbestos (Union Carbide, high purity, grade 7) were added. The contents of the beaker were diluted to 3.5 liters with distilled water, followed by heating to 100° C., and stirring to provide adequate mixing with the chromic acetate. 200 ml of 1 N sodium hydroxide were added to the suspension to precipitate a chromium (III) oxide micelle onto the asbestos surface. The product was removed from the heat source and allowed to cool. The product was collected by vacuum filtration using a Whatman #1 filter. The resulting dark green product was allowed to air dry for 16 hours. The filter cake was dried at 330° F. for 90 minutes. The dry cake was fiberized by use of a blender at high speed for 1 minute. A sample of the product was completely dissolved by treatment with 20% by weight sodium peroxide at 850° C. Elemental analysis is shown in Table I. HF insoluble matter was increased to 53% compared to 8.6% for an untreated chrysotile as shown in Table II.
Reaction SMILES: [OH:1][C:2]1[C:7](O)=[CH:6][C:5]([CH2:9][C:10]#[N:11])=[CH:4][CH:3]=1.[C:12](=[O:15])([O-])[O-].[K+].[K+].[CH2:18](Cl)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl>CN(C)C=O.O>[CH2:18]([O:1][C:2]1[C:7]([O:15][CH2:12][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:6][C:5]([CH2:9][C:10]#[N:11])=[CH:4][CH:3]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: N#CCc1ccc(O)c(O)c1
Reactant: O=C([O-])[O-]
Reactant: ClCc1ccccc1
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CCc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1

Procedure:
A mixture consisting of one mole (149 g) of 4,5-dihydroxyphenylacetonitrile prepared in stage 1, two moles of potassium carbonate (276 g) and 2.2 moles (278.5 g) of benzyl chloride in 745 ml of dimethylformamide is heated to 105°-110° C. for approximately 30 minutes. At the end of the reaction, the reaction mixture is diluted with 2.5 kg of a mixture of ice and water, and is neutralized with hydrochloric acid while being briskly stirred. The expected product, which has precipitated, is filtered off, washed with water, and is again mixed into a paste with ethanol and then with isopropyl:ether.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]([N+:27]([O-:29])=[O:28])=[CH:9][C:10]2[O:14][C:13]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)=[C:12]([C:22](=[O:25])[NH:23][CH3:24])[C:11]=2[CH:26]=1)(=O)=O.[C:32]([NH:36][C:37]([C:39]1[CH:40]=[C:41](B(O)O)[CH:42]=[C:43]([N+:45]([O-:47])=[O:46])[CH:44]=1)=[O:38])([CH3:35])([CH3:34])[CH3:33].C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O.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>[C:32]([NH:36][C:37]([C:39]1[CH:40]=[C:41]([C:7]2[C:8]([N+:27]([O-:29])=[O:28])=[CH:9][C:10]3[O:14][C:13]([C:15]4[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=4)=[C:12]([C:22]([NH:23][CH3:24])=[O:25])[C:11]=3[CH:26]=2)[CH:42]=[C:43]([N+:45]([O-:47])=[O:46])[CH:44]=1)=[O:38])([CH3:35])([CH3:33])[CH3:34]
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc([N+](=O)[O-])c(OS(=O)(=O)C(F)(F)F)cc12
Reactant: CC(C)(C)NC(=O)c1cc(B(O)O)cc([N+](=O)[O-])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: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc([N+](=O)[O-])c(-c3cc(C(=O)NC(C)(C)C)cc([N+](=O)[O-])c3)cc12
Temperature: 99 °C
Yield: 75.7 %

Procedure:
To a mixture of 2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-nitrobenzofuran-5-yl trifluoromethanesulfonate (400 mg), (3-(tert-butylcarbamoyl)-5-nitrophenyl)boronic acid (345 mg) and Cs2CO3 (846 mg) in dioxane (8 mL) and water (1.5 mL) was added tetrakis(triphenylphosphine)palladium(0) (150 mg). The mixture was flushed with nitrogen and then heated at 99° C. for 16 hours. The mixture was diluted with water and extracted with EtOAc (2×100 mL). The organic layers were combined, washed with brine, dried over MgSO4 and concentrated. The residue was purified by silica gel column (hexanes/EtOAc=3:1) to give 5-(3-(tert-butylcarbamoyl)-5-nitrophenyl)-2-(4-fluorophenyl)-N-methyl-6-nitrobenzofuran-3-carboxamide 2 (350 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](C(=O)C)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].ClC1C=CC=C(C(OO)=[O:21])C=1.O[Li].O.O>C(Cl)Cl.CO>[F:1][C:2]1[CH:3]=[C:4]([OH:21])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(C(C)=O)cc1F
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Li]O
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: COc1ccc(O)cc1F
Yield: 72.7 %

Procedure:
A solution of 3′-fluoro-4′-methoxyacetophenone (10 g; 59 mmol) and m-chloroperbenzoic acid (50% purity; 30 g; 89 mmol) in CH2Cl2 (300 mL) was stirred at RT overnight. The solution was washed with saturated aqueous Na2CO3, then filtered through a pad of SiO2 (CH2Cl2 as eluent) and finally chromatographed (SiO2; hex:EtOAc 4:1) to give the crude product (3′-fluoro-4′-methoxy phenyl acetate; 63 g). A solution of this crude material and LiOH.H2O (5 g; 120 mmol) in MeOH:H2O (100 mL of a 9:1 mixture) was stirred at RT overnight. Volatiles were removed in vacuo, and the residue was partitioned between excess aqueous 1 M HCl and EtOAc (aqueous layer pH˜3). The aqueous phase was extracted with EtOAc (2×). The combined organic extracts were dried (Na2SO4) and concentrated in vacuo to give 3-fluoro-4-methoxy phenol (6.1 g; 72%) as an oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C@H:8]([C:13](=[O:24])[NH:14][C@H:15]1[CH2:21][CH2:20][C@@H:19]([CH3:22])[NH:18][CH2:17][CH:16]1[OH:23])[CH2:9][CH:10]([CH3:12])[CH3:11])([CH3:4])([CH3:3])[CH3:2].[CH3:26][O:27][C:28](=[O:37])[C@@H:29]([N:34]=[C:35]=[O:36])[CH2:30][CH:31]([CH3:33])[CH3:32]>>[CH3:26][O:27][C:28](=[O:37])[C@@H:29]([NH:34][C:35]([N:18]1[CH2:17][CH:16]([OH:23])[C@@H:15]([NH:14][C:13](=[O:24])[C@@H:8]([NH:7][C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:25])[CH2:9][CH:10]([CH3:12])[CH3:11])[CH2:21][CH2:20][C@H:19]1[CH3:22])=[O:36])[CH2:30][CH:31]([CH3:33])[CH3:32]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H]1CC[C@@H](C)NCC1O
Reactant: COC(=O)[C@H](CC(C)C)N=C=O
Product: COC(=O)[C@H](CC(C)C)NC(=O)N1CC(O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C)CC[C@H]1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.2 %

Procedure:
[(S)-3-Methyl-1-((4S,7R)-7-methyl-3-hydroxy-azepan-4-ylcarbamoyl)-butyl]-carbamic acid tert-butyl ester (Example 12a–i, 500 mg, 1.4 mmol) was dissolved in TEF (7 ml), then (S)-(−)-2-isocyanato-4-methylvaleric acid methyl ester (180 mg, 1.05 mmol) was added and the reaction mixture was stirred at RT for 2 h. The reaction mixture was concentrated in vacuo by rotary evaporation, and chromatographed (silica gel, 1% to 2% MeOH/CH2Cl2) to yield the title compound as a white solid (91%, 506 mg): LC/Electrospray mass spec: M+H+=529.4.
Reaction SMILES: CO[CH:3]1[CH2:7][CH2:6][CH:5](OC)O1.C(O)(=O)C.C([CH:16]1[C:21](=[O:22])[NH:20][C:18](=[O:19])[C@@:17]1([NH2:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24])C>C(OCC)(=O)C>[CH:7]([NH:28][CH:17]([CH3:18])[CH3:16])([CH3:3])[CH3:6].[CH2:26]([O:25][C:23]([C@@:17]1([N:28]2[CH:3]=[CH:7][CH:6]=[CH:5]2)[CH2:16][C:21](=[O:22])[NH:20][C:18]1=[O:19])=[O:24])[CH3:27]
Reactant: CCOC(=O)[C@]1(N)C(=O)NC(=O)C1CC
Reactant: COC1CCC(OC)O1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(C)NC(C)C
Product: CCOC(=O)[C@@]1(n2cccc2)CC(=O)NC1=O
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 88 %

Procedure:
2,5-Dimethoxytetrahydrofuran (7.4 g) and 2.5% aqueous acetic acid (50 g) were added to ethyl (2R)-2-amino-2-ethoxycarbonylsuccinimide (10 g) and the mixture was stirred at 70° C. for 1.5 hours. The reaction solution was cooled and insoluble materials were dissolved by addition of ethyl acetate (50 ml) and stirring. The mixture was placed for a while and the organic layer was separated from the aqueous layer, washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo, diisopropylether (37 g) and ethyl acetate (9.2 g) were added to the residue and diisopropylamine (6.2 g) was added and the mixture was stirred at 0-5° C. of inner temperature. The precipitated crystals were filtered, washed with diisopropylether and dried to give (2R)-2-ethoxycarbonyl-2-(pyrrol-1-yl)succinimide diisopropylamine salt (yield 88%).
Reaction SMILES: [NH2:1][C:2]1[CH:13]=[CH:12][C:5]([C:6]([O:8][CH2:9][CH:10]=[CH2:11])=[O:7])=[CH:4][CH:3]=1.[C:14]12([C:24]3[CH:25]=[C:26]([CH:30]=[CH:31][C:32]=3[O:33][CH3:34])[C:27](Cl)=[O:28])[CH2:23][CH:18]3[CH2:19][CH:20]([CH2:22][CH:16]([CH2:17]3)[CH2:15]1)[CH2:21]2>>[C:14]12([C:24]3[CH:25]=[C:26]([CH:30]=[CH:31][C:32]=3[O:33][CH3:34])[C:27]([NH:1][C:2]3[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH:10]=[CH2:11])=[O:7])=[CH:12][CH:13]=3)=[O:28])[CH2:15][CH:16]3[CH2:22][CH:20]([CH2:19][CH:18]([CH2:17]3)[CH2:23]1)[CH2:21]2
Reactant: C=CCOC(=O)c1ccc(N)cc1
Reactant: COc1ccc(C(=O)Cl)cc1C12CC3CC(CC(C3)C1)C2
Product: C=CCOC(=O)c1ccc(NC(=O)c2ccc(OC)c(C34CC5CC(CC(C5)C3)C4)c2)cc1

Procedure:
In a manner analogous to Example 1(a) starting with 12.6 g (71 mmoles) of allyl 4-aminobenzoate and 21.6 g (71 mmoles) of 3-(1-adamantyl)-4-methoxy benzoyl chloride, 32 g of the expected amide whose melting point is 191°-192° C. are isolated.
Reaction SMILES: C[N:2]([C:19]1[CH:20]=[N:21][CH:22]=[CH:23][C:24]=1N1CCCCC1C)[C:3](=O)C1C=C(C(F)(F)F)C=C(C(F)(F)F)C=1.[F:32][C:33]1[C:38]([F:39])=[CH:37][C:36](B(O)O)=[C:35]([O:43][CH3:44])[CH:34]=1>CCCCCCC.CCOC(C)=O>[F:32][C:33]1[C:38]([F:39])=[CH:37][C:36]([C:24]2[CH:23]=[CH:22][N:21]=[CH:20][C:19]=2[NH:2][CH3:3])=[C:35]([O:43][CH3:44])[CH:34]=1
Reactant: COc1cc(F)c(F)cc1B(O)O
Reactant: CC1CCCCN1c1ccncc1N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CNc1cnccc1-c1cc(F)c(F)cc1OC

Procedure:
The title compound was prepared in analogy to example 72, from (4-iodo-pyridin-3-yl)-methyl-amine (example 98, intermediate b) and 4,5-difluoro-2-methoxyphenylboronic acid (CAS RN 870777-32-5) and using a gradient of n-heptane:EtOAc (100:0 to 50:50) for the chromatographic separation. Light brown solid (91%). MS (ESI): m/z=251.099 [M+H]+.
Reaction SMILES: NN.[Si:3]([O:10][CH2:11][C:12]1[CH:13]=[C:14]([CH:27]=[CH:28][CH:29]=1)[CH2:15][N:16]1C(=O)C2C(=CC=CC=2)C1=O)([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4].O.ClCCl>C(O)C>[Si:3]([O:10][CH2:11][C:12]1[CH:13]=[C:14]([CH:27]=[CH:28][CH:29]=1)[CH2:15][NH2:16])([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4]
Reactant: CC(C)(C)[Si](C)(C)OCc1cccc(CN2C(=O)c3ccccc3C2=O)c1
Agent: NN
Solvent: O
Solvent: ClCCl
Solvent: CCO
Product: CC(C)(C)[Si](C)(C)OCc1cccc(CN)c1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
At room temperature, a hydrazine solution (35% strength in water, 0.6 ml, 6.6 mmol) is added to a solution of 2-[3-({[tert-butyl(dimethyl)silyl]oxy}methyl)benzyl]-1H-isoindole-1,3(2H)-dione (1.7 g, 4.4 mmol) in ethanol (44 ml), the mixture is stirred at room temperature for 15 h and water is added. After addition of dichloromethane and phase separation, the aqueous phase is extracted with dichloromethane. The combined organic phases are dried (sodium sulfate), filtered and concentrated under reduced pressure. The desired product is used without further purification for the next reaction.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH2:10]>N1C=CC=CC=1.CCOCC>[C:1]([O-:8])(=[O:10])[CH3:2].[C:1]([O-:8])(=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O
Solvent: CCOCC
Solvent: c1ccncc1
Product: CC(=O)[O-]
Product: O=C([O-])c1ccccc1
Reaction time: 8 h

Procedure:
The 1α-hydroxy-38-triethylsilyloxy-compound from Example 9(b) (2 g) was treated with benzoyl chloride (2 ml) in pyridine (25 ml). After 30 min water was added and the mixture diluted with ether. After acid work-up, the solvent was removed and the resulting oil stirred overnight in THF:H2O: AcOH; 8:1:3 (36 ml). After dilution with ether and aqueous work-up, the crude benzoate-alcohol was taken up in benzene (40 ml). Triethylamine (7 ml), acetic anhydride (3 ml) and 4-dimethylaminopyridine (15 mg) were added. After 30 min, water was added and the mixture diluted with ether. Acid work-up and chromatography through silica (10 g) gave 1.76 g 83%) of the title acetate-benzoate as an oil. 1Hnmr δ 8.05 (m. W=12 Hz, 2H, aryl), 7.5 (m, W=10 Hz, 3H, aryl), 6.58 (d, J=11 Hz, C-6H), 5.88 (m, W=16 Hz, C-1H, 7H), 5.15 (m, W=10 Hz, C-3H, 19H2, 22H, 23H), 2.05 (s, OAc), 0.57 (s, C-18H3).
Reaction SMILES: [H-].[Na+].[CH2:3]([C:5]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:29]3[N:30]=[N:31][N:32]([C:34]([C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=4)([C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)[C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[N:33]=3)=[CH:19][CH:18]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:53][CH2:54][CH2:55][OH:56])[N:11]=2)[N:6]=1)[CH3:4].[H][H].CI.C1C[O:64][CH2:63][CH2:62]1>O>[CH2:3]([C:5]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:29]3[N:30]=[N:31][N:32]([C:34]([C:47]4[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=4)([C:41]4[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=4)[C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[N:33]=3)=[CH:21][CH:22]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:53][CH2:54][C:55]([O:64][CH2:63][CH3:62])=[O:56])[N:11]=2)[N:6]=1)[CH3:4]
Reactant: [H][H]
Reactant: CCc1cc(OCc2ccc(-c3ccccc3-c3nnn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)cc2)c2nc(OCCO)ccc2n1
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: CCOC(=O)COc1ccc2nc(CC)cc(OCc3ccc(-c4ccccc4-c4nnn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc3)c2n1
Reaction time: 72 h

Procedure:
Sodium hydride (60% dispersion in mineral oil, 62 mg) was added in a solution of 2-ethyl-6-(2-hydroxyethoxy)-4-[(2'-(2-triphenylmethyl-2H-tetrazol-5-yl)biphenyl-4-yl)methoxy]-1,5-naphthyridine (1.0 g) in THF (10 ml). The mixture was stirred until evolution of hydrogen had ceased and then methyl iodide (0.09 ml) was added. The solution was left to stand for 72 hours and then water (30 ml) was added. The mixture was extracted with ether (2×20 ml) and the combined extracts were dried (MgSO4). Volatile material was removed by evaporation and the residue was triturated with hexane to give 2-ethyl-6-(2-methoxyethoxy)-4-[(2'-(2-triphenylmethyl-2H-tetrazol-5-yl)biphenyl-4-yl)methoxy]-1,5-naphthyridine (A) (0.86 g), as a foam; NMR (d6 -DMSO): 1.3(t, 3H), 2.8(q, 2H), 3.25(s, 3H), 3.6-3.7(m, 2H), 4.45-4.55(m, 2H), 5.4(s, 2H), 6.8-6.9(m, 6H), 7.1-7.7(complex m, 18H), 7.8(dd, 1H), 8.15(d, 1H).