Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13][CH2:14][CH3:15])[CH2:8][CH2:7]2)([O-])=O.O.NN>[Ni].C(O)C>[CH2:13]([N:9]1[C:10]2[C:6](=[CH:5][C:4]([NH2:1])=[CH:12][CH:11]=2)[CH2:7][CH2:8]1)[CH2:14][CH3:15]
Reactant: CCCN1CCc2cc([N+](=O)[O-])ccc21
Agent: [Ni]
Agent: NN
Solvent: CCO
Solvent: O
Product: CCCN1CCc2cc(N)ccc21

Procedure:
Approximately 400 mg of Raney nickel is added to a mixture of 3.28 g (15.9 mmol) of 5-nitro-1-propylindoline and 4 ml (80 mmol) of hydrazine hydrate in 60 ml of absolute ethanol. The reaction mixture is heated under reflux for 5 hours. After returning to 23° C., a little silica is added to the flask and the solvent is evaporated off under vacuum. The evaporation residue is placed directly at the top of a chromatography column. The expected product is eluted using a Heptane/AcOEt mixture (1/9). A black oil is obtained which is used directly in the following stage.
Reaction SMILES: Br[C:2]1[C:3]([S:8][CH3:9])=[N:4][CH:5]=[N:6][CH:7]=1.C([Li])CCC.[F:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH:18]=[O:19].Cl>O1CCCC1.CCCCCC>[F:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH:18]([C:2]1[C:3]([S:8][CH3:9])=[N:4][CH:5]=[N:6][CH:7]=1)[OH:19]
Reactant: O=Cc1ccccc1F
Reactant: CSc1ncncc1Br
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CSc1ncncc1C(O)c1ccccc1F
Temperature: -25 °C
Yield: 39.7 %

Procedure:
To a slurry of 20 g (98 mmol) of 5-bromo-4-methylthiopyrimidine in 200 mL of anhydrous tetrahydrofuran at -90° C. was slowly added with stirring and cooling 40 mL (100 mmol) of 2.5M n-butyl lithium in hexane. After a 20-min reaction period, 13.3 g of 2-fluorobenzaldehyde was added with stirring. The solution was allowed to gradually warm to -25° C. It was then poured into dilute aqueous hydrochloric acid with stirring. The resulting mixture was extracted with ether and the ethereal extract was dried over magnesium sulfate, filtered, and partially concentrated by evaporation under reduced pressure. The remaining mixture was diluted with hexane and the solids that formed were collected by filtration to obtain 9.75 g of the title compound as colorless solid melting at 176°-177° C.
Reaction SMILES: [CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)=[C:7]([NH:23][C:24]([NH:26][C:27]2[C:32]([CH:33]([CH3:35])[CH3:34])=[CH:31][C:30]([CH2:36][N:37]3C(=O)C4=CC=CC=C4C3=O)=[CH:29][C:28]=2[CH:48]([CH3:50])[CH3:49])=[O:25])[C:6]1=[O:51])[CH2:2][CH2:3][CH3:4].C(O)C.C(Cl)(Cl)Cl.O.NN>O>[CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)=[C:7]([NH:23][C:24]([NH:26][C:27]2[C:28]([CH:48]([CH3:49])[CH3:50])=[CH:29][C:30]([CH2:36][NH2:37])=[CH:31][C:32]=2[CH:33]([CH3:35])[CH3:34])=[O:25])[C:6]1=[O:51])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1c(=O)c(NC(=O)Nc2c(C(C)C)cc(CN3C(=O)c4ccccc4C3=O)cc2C(C)C)c(-c2cccc(OC)c2)c2cccnc21
Agent: NN
Solvent: CCO
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCCCn1c(=O)c(NC(=O)Nc2c(C(C)C)cc(CN)cc2C(C)C)c(-c2cccc(OC)c2)c2cccnc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.7 %

Procedure:
To a solution of N-[1-butyl-4-(3-methoxyphenyl)-1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl]-N′-(2,6-diisopropyl-4-phthalimidomethylphenyl)-urea (393 mg, 0.57 mmol) in a mixed solvent of ethanol/chloroform (10 ml) is added hydrazine monohydrate (0.033 ml, 0.68 mmol) at room temperature, and the mixture is stirred at room temperature for 2 hours. To the mixture is further added hydrazine monohydrate (0.14 ml, 3.4 mmol), and the mixture is stirred at room temperature for 4 days. To the mixture is added water, and the mixture is extracted with ethyl acetate. The organic layer is washed twice with an aqueous sodium hydrogen carbonate solution, and dried over anhydrous magnesium sulfate. The solvent is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography to give the title compound (256 mg, 0.46 mmol).
Reaction SMILES: FC(F)(F)C([O-])=O.[NH2:8][C@H:9]([C:20]([NH:22][C@H:23]([C:28]([NH2:30])=[O:29])[CH2:24][CH:25]([CH3:27])[CH3:26])=[O:21])[CH2:10][CH2:11][CH2:12][NH:13][C:14](=[NH:19])[NH:15][N+:16]([O-:18])=[O:17].[NH:31](C(OC(C)(C)C)=O)[C@H:32]([C:34](O)=[O:35])[CH3:33].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[NH2:31][C@H:32]([C:34]([NH:8][C@H:9]([C:20]([NH:22][C@H:23]([C:28]([NH2:30])=[O:29])[CH2:24][CH:25]([CH3:26])[CH3:27])=[O:21])[CH2:10][CH2:11][CH2:12][NH:13][C:14](=[NH:19])[NH:15][N+:16]([O-:18])=[O:17])=[O:35])[CH3:33]
Reactant: CC(C)C[C@H](NC(=O)[C@@H](N)CCCNC(=N)N[N+](=O)[O-])C(N)=O
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])C(F)(F)F
Solvent: CN(C)C=O
Product: CC(C)C[C@H](NC(=O)[C@H](CCCNC(=N)N[N+](=O)[O-])NC(=O)[C@H](C)N)C(N)=O

Procedure:
443 g of trifluoroacetate of H-Arg(NO2)Leu-NH2 are dissolved in 2 l of DMF. 200 g of Boc-Ala-OH, then 500 g of BOP are added. The pH is adjusted to 7 with pH paper (on small samples of the reaction medium) with the aid of NEM. The medium is stirred and the development of the reaction is followed by TLC. The reaction is terminated after 4 hrs. The medium is evaporated to dryness in vacuo at 25°. The residue is taken up in 2 l of water and 2 l of ethyl acetate. The organic phase is washed with a 5% aqueous solution of NaHCO3, with water, dried and evaporated. The tripeptide is recrystallized in ethyl-acetate/ether, and finally dried in vacuo. It is monitored by TLC and NMR.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[CH:6]2.ClC1C=C(C=CC=1)C(OO)=[O:18]>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:18])[CH:7]=[CH:6]2
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccc2ncccc2c1
Solvent: ClC(Cl)Cl
Product: COc1ccc2[nH]c(=O)ccc2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 6-methoxyquinoline (2.08 g) in CHCl3 (45 mL) at r.t. was added m-chloroperoxybenzoic acid (3.38 g) portionwise over 10 min. After 30 min., CHCl3 (50 mL) was added and the solution washed with saturated aq. NaHCO3 (3×), dried (MgSO4) and concentrated. A portion of this material (500 mg) in DMF (10 mL) was treated with trifluoroacetic anhydride (TFAA) and stirred at r.t. for 17 hr. The TFAA was removed under vacuum and to the resulting solution was added water (60 mL). The mixture was extracted with EtOAc (6×) and the combined organics were dried (MgSO4) and concentrated. Trituration of the resulting material with acetone provided the title compound as a pale yellow solid.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][NH:9][C:10]2[C:18]3[O:17][CH:16]=[CH:15][C:14]=3[CH:13]=[C:12]([N+:19]([O-])=O)[CH:11]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(O)C.O.NN>C1COCC1.[Ni]>[N:1]1([CH2:7][CH2:8][NH:9][C:10]2[C:18]3[O:17][CH:16]=[CH:15][C:14]=3[CH:13]=[C:12]([NH2:19])[CH:11]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1cc(NCCN2CCOCC2)c2occc2c1
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: Nc1cc(NCCN2CCOCC2)c2occc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(2-Morpholin-4-ylethyl)(5-nitro-1-benzofuran-7-yl)amine (450 mg, 1.545 mmol; Intermediate 27) was dissolved in THF (5 mL). After addition of ethanol (100 mL), Raney-nickel (cat.) and hydrazine hydrate (2 mL), the mixture was left stirring at room temperature for 2 h. The product was used directly in the subsequent reaction after filtration through Celite and evaporation of solvent.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1CCOCC1.ClC(OCC(C)C)=O.[F:31][C:32]([F:51])([F:50])[CH2:33][N:34]=[C:35]([NH2:49])[NH:36][C:37]1[CH:42]=[CH:41][N:40]=[C:39]([CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][NH2:48])[N:38]=1>C1COCC1>[F:51][C:32]([F:31])([F:50])[CH2:33][N:34]=[C:35]([NH2:49])[NH:36][C:37]1[CH:42]=[CH:41][N:40]=[C:39]([CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][NH:48][C:13](=[O:15])[CH2:12][NH:11][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[N:38]=1
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Reactant: NCCCCCc1nccc(NC(N)=NCC(F)(F)F)n1
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: NC(=NCC(F)(F)F)Nc1ccnc(CCCCCNC(=O)CNC(=O)OCc2ccccc2)n1
Yield: 34.2 %

Procedure:
To a solution of N-benzyloxycarbonylglycine (0.21 g.) in freshly distilled THF (5 ml.) was added N-methylmorpholine (0.1 g.). The resulting solution was stirred with cooling in an ice-salt bath, and a solution of i-butyl chloroformate (0.136 g.) in a small volume of THF was added in one portion. A precipitate formed immediately, and the mixture was stirred with cooling for 5 minutes. A solution of 4-[2-(2,2,2-trifluoroethyl)guanidino]-2-(5-aminopentyl)pyrimidine (0.35 g.) in THF (10 ml.) was gradually added. The mixture was stirred at room temperature for 2 hours, then evaporated in vacuo. Sodium bicarbonate solution was added to the residue and the mixture extracted with EtOAc. The extract was dried (MgSO4) and evaporated to give a pale yellow oil which was purified by medium pressure chromatography, eluting with 5% v/v MeOH in methylene chloride to give 4-[2-(2,2,2-trifluoroethyl)guanidino]-2-[5-(2-benzyloxycarbonylaminoacetylamino)pentyl]pyrimidine (0.17 g.) which was used without further purification.
Reaction SMILES: Cl[C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:20]#[N:21])=[CH:10][CH:9]=2)[C:5]2[C:22]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:23][CH:24]=[CH:25][C:4]=2[N:3]=1.[CH3:31][CH2:32][O-:33].[Na+]>C(O)C>[C:20]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:11]1[CH:12]=[CH:13][C:8]([CH2:7][N:6]2[C:5]3[C:22]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:23][CH:24]=[CH:25][C:4]=3[N:3]=[C:2]2[O:33][CH2:32][CH3:31])=[CH:9][CH:10]=1)#[N:21]
Reactant: CC[O-]
Reactant: CCOC(=O)c1cccc2nc(Cl)n(Cc3ccc(-c4ccccc4C#N)cc3)c12
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cccc2nc(OCC)n(Cc3ccc(-c4ccccc4C#N)cc3)c12
Yield: 36.2 %

Procedure:
To a solution of ethyl 2-chloro-1-[(2′-cyanobiphenyl-4-yl)-methyl]benzimidazole-7-carboxylate (1.0 g) in ethanol (30 ml) was added NaOEt (0.17 g) and the mixture was heated under reflux for 1 hour. The reaction mixture was concentrated to dryness. The resultant residue was dissolved in ethyl acetate and the solution was washed with water, and then dried. After evaporation of the solvent, the residue was purified by column chromatography on silica gel to give the title compound as colorless crystals(0.37 g, 70%). 1H-NMR and IR spectra indicate that the product according to this working Example is completely identical with that obtained in Working Example 4.
Reaction SMILES: [C:1]1([C:9]([CH:11]([C:13]2[CH:20]=[CH:19][C:16]([O:17][CH3:18])=[CH:15][CH:14]=2)O)=O)[CH:8]=[CH:7][C:4]([O:5][CH3:6])=[CH:3][CH:2]=1.[C]=O.[H][H]>O.O.O.O.C([O-])(=O)C.[Co+2].C([O-])(=O)C.C(O)CCC>[CH3:18][O:17][C:16]1[CH:15]=[CH:14][C:13]([CH2:11][CH2:9][C:1]2[CH:2]=[CH:3][C:4]([O:5][CH3:6])=[CH:7][CH:8]=2)=[CH:20][CH:19]=1
Reactant: COc1ccc(C(=O)C(O)c2ccc(OC)cc2)cc1
Reactant: [H][H]
Agent: [Co+2]
Agent: CC(=O)[O-]
Agent: [C]=O
Solvent: O
Solvent: CCCCO
Product: COc1ccc(CCc2ccc(OC)cc2)cc1
Temperature: 200 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
The autoclave described in EXAMPLE 1 was employed. To this autoclave was charged 11.0 grams (0.040 mole) of anisoin, 2.0 grams (0.0080 mole) of cobalt(II) acetate tetrahydrate, and 70 milliliters of 1-butanol. The autoclave was thereafter charged to 1100 psig with carbon monoxide and heated, with stirring at 800 rpm, to 200° C. Hydrogen was then charged to the autoclave to a total pressure of 3800 psig for a hydrogen to carbon monoxide molar ratio of 2:1. The reaction was allowed to continue for a period of 1 hour, and thereafter cooled to about 70° C. Gas chromatographic analysis of the homogeneous product solution indicated a 90 percent yield of 1,2-bis(4-methoxyphenyl)ethane.
Reaction SMILES: C(OC([NH:8][CH:9]1[CH2:14][CH2:13][CH:12]([CH2:15][C:16]([OH:18])=[O:17])[CH2:11][CH2:10]1)=O)(C)(C)C.C([O-])([O-])=O.[K+].[K+].[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CN(C=O)C.CCOCC>[NH2:8][C@H:9]1[CH2:10][CH2:11][C@H:12]([CH2:15][C:16]([O:18][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:17])[CH2:13][CH2:14]1
Reactant: CC(C)(C)OC(=O)NC1CCC(CC(=O)O)CC1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: N[C@H]1CC[C@H](CC(=O)OCc2ccccc2)CC1
Reaction time: 16.75 h

Procedure:
To a solution of 2-[4-(tert-butoxycarbonylamino)cyclohexyl]acetic acid (1.0 g, 4 mmol) in DMF (10 mL) was added K2CO3 (600 mg, 4 mmol) followed by benzyl bromide (0.5 mL, 4.2 mmol). The resulting mixture was stirred for 16.75 hours, diluted with ether, washed with water (2×) followed by brine, dried over magnesium sulfate and concentrated. The residue was taken up in dichloromethane (12 mL). To this solution was added TFA (3 mL). The resulting solution was stirred for 2.5 hours then concentrated under reduced pressure. The residue was taken up in ethyl acetate, washed with saturated sodium bicarbonate solution followed by brine, dried over magnesium sulfate and concentrated under reduced pressure to give the title compound as a white solid.
Reaction SMILES: FC(F)(F)S([O:6][Si:7]([CH:14]([CH3:16])[CH3:15])([CH:11]([CH3:13])[CH3:12])[CH:8]([CH3:10])[CH3:9])(=O)=O.[F:19][C:20]1[CH:21]=[CH:22][C:23]2[N:24]([C:26]([N:29]3[CH2:33][CH2:32][C@H:31](O)[CH2:30]3)=[N:27][N:28]=2)[CH:25]=1.CCN(CC)CC>CN(C=O)C>[F:19][C:20]1[CH:21]=[CH:22][C:23]2[N:24]([C:26]([N:29]3[CH2:33][CH2:32][C@H:31]([O:6][Si:7]([CH:8]([CH3:9])[CH3:10])([CH:11]([CH3:12])[CH3:13])[CH:14]([CH3:15])[CH3:16])[CH2:30]3)=[N:27][N:28]=2)[CH:25]=1
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Reactant: O[C@H]1CCN(c2nnc3ccc(F)cn23)C1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)[Si](O[C@H]1CCN(c2nnc3ccc(F)cn23)C1)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.7 %

Procedure:
Triisopropylsilyl trifluoromethanesulfonate (250 mg, 0.81 mmol) was added to a solution of Intermediate 26a (150 mg, 0.67 mmol) and Et3N (101 mg, 1.00 mmol) in DMF (2 mL) and the mixture stirred at RT for 1 h. The reaction mixture was applied to an SCX-2 cartridge (5 g) and washed with MeOH. The product was eluted with 2M NH3 in MeOH; concentration in vacuo gave the title compound (220 mg, 86%). LCMS (Method 4): Rt 4.15 min, m/z 379 [MH+].
Reaction SMILES: [Cl:1][C:2]1[C:11]2[N:10]([CH3:12])[O:9][C@H:8]3[NH:13][C@H:14]([C:16]([O:18][C@@H:19]4[C@:28]5([OH:29])[C@@H:23]([C@H:24]([CH:31]([CH3:34])[CH2:32][OH:33])[CH2:25][CH2:26][C@H:27]5[CH3:30])[CH:22]=[C:21]([CH3:35])[C@H:20]4[O:36][C:37](=[O:39])[CH3:38])=[O:17])[CH2:15][C@@:7]3([OH:40])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:41](N1C=CN=C1)([N:43]1[CH:47]=[CH:46][N:45]=[CH:44]1)=[O:42]>ClCCl.O>[Cl:1][C:2]1[C:11]2[N:10]([CH3:12])[O:9][C@H:8]3[NH:13][C@H:14]([C:16]([O:18][C@@H:19]4[C@:28]5([OH:29])[C@@H:23]([C@H:24]([CH:31]([CH3:34])[CH2:32][O:33][C:41]([N:43]6[CH:47]=[CH:46][N:45]=[CH:44]6)=[O:42])[CH2:25][CH2:26][C@H:27]5[CH3:30])[CH:22]=[C:21]([CH3:35])[C@H:20]4[O:36][C:37](=[O:39])[CH3:38])=[O:17])[CH2:15][C@@:7]3([OH:40])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(=O)O[C@@H]1C(C)=C[C@@H]2[C@H](C(C)CO)CC[C@@H](C)[C@]2(O)[C@H]1OC(=O)[C@@H]1C[C@@]2(O)c3cccc(Cl)c3N(C)O[C@H]2N1
Solvent: O
Solvent: ClCCl
Product: CC(=O)O[C@@H]1C(C)=C[C@@H]2[C@H](C(C)COC(=O)n3ccnc3)CC[C@@H](C)[C@]2(O)[C@H]1OC(=O)[C@@H]1C[C@@]2(O)c3cccc(Cl)c3N(C)O[C@H]2N1
Reaction time: 18 h
Yield: 45.7 %

Procedure:
To (1S,2R,4aS,5S,8R,8aR)-2-(acetyloxy)-8a-hydroxy-5-[2-hydroxy-1-methylethyl]-3,8-dimethyl-1,2,4a,5,6,7,8,8a-octahydronaphthalen-1-yl (2S,3aR,9bR)-6-chloro-9b-hydroxy-5-methyl-1,2,3,3a,5,9b-hexahydropyrrolo[2,3-c][2,1]benzoxazine-2-carboxylate(Preparation 140, 0.30 g, 0.52 mmol) in dichloromethane was added 1,1′-carbonyldiimidazole (0.92 g, 0.57 mmol) and the reaction mixture was stirred for 18 h. The reaction mixture was diluted with water and extracted with dichloromethane. The organic extracts were washed with brine, dried and then concentrated in vacuo. The crude product was purified by flash chromatography eluting with ethyl acetate:hexane (2:1) to give the title compound (0.16 g, 46%).
Reaction SMILES: Cl[CH2:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][CH:5]=1.[F:11][C:12]([F:21])([F:20])[C:13]1[CH:14]=[N:15][C:16](=[O:19])[NH:17][CH:18]=1.C(N(CC)CC)C>ClCCl>[Cl:10][C:7]1[CH:8]=[CH:9][C:4]([O:3][CH2:2][N:17]2[CH:18]=[C:13]([C:12]([F:20])([F:21])[F:11])[CH:14]=[N:15][C:16]2=[O:19])=[CH:5][CH:6]=1
Reactant: O=c1ncc(C(F)(F)F)c[nH]1
Reactant: ClCOc1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=c1ncc(C(F)(F)F)cn1COc1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
A solution of 1-chloromethoxy-4-chloro-benzene [see Preparation 11] (0.35 mmol) in dichloromethane (1 ml) was added with stirring at room temperature to a solution prepared from 5-trifluoromethyl-pyrimidin-2-one (0.33 mmol) and triethylamine (0.33 mmol) in dichloromethane (5 ml). The mixture was stirred at room temperature for 24 h and then it was stirred at 70° C. for 30 min, the solvent was then distilled off, the residue triturated with water, the residual material extracted with chloroform and the dried (MgSO4) chloroform solution evaporated to yield the product, 60 mg (62%), as a mixture of the N- and O-isomers in the ratio 5:1. The isomers were separated by their different solubilities in ether, the O-isomer being the more soluble. The title compound, the N-isomer had m.p. 98° C. (Found C46.78; H2.88. Calc. for C12H8ClF3N2O3 : C47.30; H2.65)1H NMR (CDCl3): δ 5.85 (CH2), 6.8-7.4 (Ph), 8.15 (H-4, J4.6 3 Hz) 8.76 (H-6) MS [70 eV; m/z (% rel. int.)]; 177 (100), 150(10), 75(5), IR (KBr); 1690cm-1 (CO).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12]C)=[CH:4][CH:3]=1.Cl.N1C=CC=CC=1.Cl>>[CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[CH:4][CH:3]=1
Reactant: COc1ccc(C)c2ccccc12
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccc(O)c2ccccc12
Temperature: 200 °C

Procedure:
4-Methyl-1-methoxynaphthalene (4) (145 g) was mixed with pyridine hydrochloride (250 g) and the mixture was heated at 200° C. for 3 hours. The mixture was cooled, treated with dilute hydrochloric acid, and extracted with ether. The ether extract was dried (MgSO4), filtered and the solvent removed, leaving a black oil which was extracted with petroleum b.p. 60°-80° C. (4×100 cm3). 4-Methyl-1-naphthol (5) was obtained as near colourless oily crystals which darken on storage.
Reaction SMILES: C([O:3][C:4]([C:6]1[S:7][CH:8]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[CH2:18][C:19](=[O:33])[NH:20][C:21]4[CH:27]=[C:26]([N:28]5[CH:32]=[CH:31][CH:30]=[CH:29]5)[CH:25]=[CH:24][C:22]=4[N:23]=3)[CH:12]=2)[N:10]=1)=O)C.[NH3:34]>>[O:33]=[C:19]1[CH2:18][C:17]([C:13]2[CH:12]=[C:11]([C:9]3[N:10]=[C:6]([C:4]([NH2:34])=[O:3])[S:7][CH:8]=3)[CH:16]=[CH:15][CH:14]=2)=[N:23][C:22]2[CH:24]=[CH:25][C:26]([N:28]3[CH:32]=[CH:31][CH:30]=[CH:29]3)=[CH:27][C:21]=2[NH:20]1
Reactant: N
Reactant: CCOC(=O)c1nc(-c2cccc(C3=Nc4ccc(-n5cccc5)cc4NC(=O)C3)c2)cs1
Product: NC(=O)c1nc(-c2cccc(C3=Nc4ccc(-n5cccc5)cc4NC(=O)C3)c2)cs1

Procedure:
A sample of 4-[3-(4-oxo-7-pyrrol-1-yl-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl)-phenyl]-thiazole-2-carboxylic acid ethyl ester (Example 28) (0.07 g) was reacted with ammonia in an analogous manner to the procedure described in Example 27 to give the title compound (0.05 g) as a light-yellow solid.
Reaction SMILES: [C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[C:22]([C:25]([OH:27])=[O:26])[CH:23]=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:28][Si](C=[N+]=[N-])(C)C>C1C=CC=CC=1.CO>[C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[C:22]([C:25]([O:27][CH3:28])=[O:26])[CH:23]=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: C[C@H](Nc1nccc(-n2cnc3ccc(C(=O)O)cc32)n1)c1ccccc1
Solvent: CO
Solvent: c1ccccc1
Product: COC(=O)c1ccc2ncn(-c3ccnc(N[C@@H](C)c4ccccc4)n3)c2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-[(S)-1-phenylethylamino]-4-[6-carboxy-benzimidazol-1-yl]pyrimidine in 0.2 mL of benzene and 0.1 mL of methanol was added 0.015 mL of (trimethylsilyl)diazomethane (2 M in hexanes). The solution was stirred for 30 min at room temperature then concentrated. The product was purified by chromatography to afford the title compound. Partial 1H NMR (500 MHz CD3OD): δ 8.9 (s, 1H); 8.63 (br, 1H); 8.42 (d J=5.0 Hz, 1H); 8.09 (d J=11 Hz, 1H); 7.87 (d J=11 Hz, 1H); 6.83 (d J=5.0 Hz, 1H); 5.29 m, 1H); 3.98 (s, 3H); 1.64 (d J=7.0 Hz, 3H).
Reaction SMILES: [P:1](=[O:42])([O:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])([O:34][CH3:35])[O:2][CH:3]([CH2:11][O:12]C(C1C=CC(OC)=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:4][O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]>C(Cl)(Cl)Cl.CO>[P:1](=[O:42])([O:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])([O:34][CH3:35])[O:2][CH:3]([CH2:11][OH:12])[CH2:4][O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCOCC(COC(c1ccccc1)(c1ccccc1)c1ccc(OC)cc1)OP(=O)(OC)OCCCCC
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCCCCOCC(CO)OP(=O)(OC)OCCCCC
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.5 %

Procedure:
To a solution of 13.5 g of phosphoric acid, 1-[[(4-methoxyphenyl)diphenylmethoxy]-methyl]-2-(pentyloxy)ethyl methyl pentyl ester in 68 ml of chloroform and 136 ml of methyl alcohol heated to boiling is slowly added 6.8 g of Amberlyst®-15 resin. The heat is removed and the mixture stirred at ambient temperature for 2 hours. The volatiles are removed and the residue dissolved in chloroform then washed with dilute sodium bicarbonate, dried and evaporated to an oily residue which is purified on silica gel using 1:1 ethyl acetate:hexanes to give 6 g of the desired compound as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[C:13]([N+:15]([O-])=O)[CH:12]=[C:11]([NH:18][C:19](=[O:21])[CH3:20])[CH:10]=1>CO.C(OCC)(=O)C.[Pd]>[NH2:15][C:13]1[CH:12]=[C:11]([NH:18][C:19](=[O:21])[CH3:20])[CH:10]=[C:9]([C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])[CH:14]=1
Reactant: CC(=O)Nc1cc(-c2ccc(F)cc2F)cc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(=O)Nc1cc(N)cc(-c2ccc(F)cc2F)c1
Reaction time: 12 h
Yield: 89 %

Procedure:
To a solution of N-(2′,4′-difluoro-5-nitrobiphenyl-3-yl)acetamide (4 g, 13.7 mmol) in methanol (30 ml) and ethyl acetate (15 ml) was added 10% Pd/C (400 mg, 0.1 eq.) and the reaction vessel was purged with nitrogen gas for 5 min. The mixture was then hydrogenated with H2 balloon for 12 h. The mixture was filtered through a pad of celite and the filtrate was concentrated under reduced pressure to afford the compound in 89% yield (3.2 g). 1H NMR (300 MHz, DMSO-d6): δ 9.77 (br s, 1H), 7.46-7.42 (m, 1H), 7.35-7.28 (m, 1H), 7.2-7.15 (m, 1H), 6.99 (br s, 1H), 8.86 (d, 1H), 6.39 (d, 1H), 5.45 (br s, 2H), 2.02 (s, 3H).