Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]([C:14]3[CH:19]=[CH:18][N:17]=[C:16]([Cl:20])[CH:15]=3)=[CH:12][C:11]([C:21](O)=[O:22])=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].ClC1C=C(C2N(C3C=NC=CC=3)N=C(C([N:45]3[CH2:50][CH2:49][NH:48][C:47](=[O:51])[CH2:46]3)=O)C=2)C=C(F)C=1.O=C1CNCCN1>>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]([C:14]3[CH:19]=[CH:18][N:17]=[C:16]([Cl:20])[CH:15]=3)=[CH:12][C:11]([C:21]([N:45]3[CH2:50][CH2:49][NH:48][C:47](=[O:51])[CH2:46]3)=[O:22])=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C1CN(C(=O)c2cc(-c3cc(F)cc(Cl)c3)n(-c3cccnc3)n2)CCN1
Reactant: O=C(O)c1cc(-c2ccnc(Cl)c2)n(-c2ccc(F)c(Cl)c2)n1
Agent: O=C1CNCCN1
Product: O=C1CN(C(=O)c2cc(-c3ccnc(Cl)c3)n(-c3ccc(F)c(Cl)c3)n2)CCN1

Procedure:
100 mg (0.28 mmol) of the compound of Example 68A is reacted analogously to the synthesis of the compound of Example 4 with 30 mg (0.30 mmol) of 2-oxopiperazine. 111 mg (90% of theory) of the title compound is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][NH:10][CH2:11][CH2:12][OH:13])[CH:6]=[CH:7][CH:8]=1.[C:14](Cl)(=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16].N1C=CC=CC=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][NH:10][CH2:11][CH2:12][O:13][C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16])[CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: COc1cccc(CNCCO)c1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: COc1cccc(CNCCOC(=O)C(C)(C)C)c1
Temperature: 85 °C
Reaction time: 2 h

Procedure:
Next, in toluene (100 ml) were added 2-[(3-methoxyphenyl)methylamino]ethanol (8.1 g), pivaloyl chloride (10.8 g, 89.4 mmol), and pyridine (8.5 g, 107 mmol). The mixture was stirred at room temperature for 1 hour and further at 85° C. for 2 hours. After pyridine hydrochloride was removed by filtration, the filtrate was concentrated. The product was purified by silica gel chromatography to give 2,2-dimethylpropionic acid 2-[(3-methoxyphenyl)methylamino]ethyl ester as a colorless oily matter (yield: 10.4 g (78.4%)).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C@@:15]3([CH2:20][CH2:19][O:18][C:17]([NH2:21])=[N:16]3)[C:14]3[CH:13]=[C:12]([Cl:22])[N:11]=[C:10]([F:23])[C:9]=3[O:8][C:5]2=[CH:6][CH:7]=1.[N-:24]=[N+:25]=[N-:26].[Na+].CCO>[Cu]I.O>[N:24]([C:2]1[CH:3]=[C:4]2[C@@:15]3([CH2:20][CH2:19][O:18][C:17]([NH2:21])=[N:16]3)[C:14]3[CH:13]=[C:12]([Cl:22])[N:11]=[C:10]([F:23])[C:9]=3[O:8][C:5]2=[CH:6][CH:7]=1)=[N+:25]=[N-:26]
Reactant: NC1=N[C@@]2(CCO1)c1cc(Br)ccc1Oc1c2cc(Cl)nc1F
Reactant: [N-]=[N+]=[N-]
Agent: [Cu]I
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: [N-]=[N+]=Nc1ccc2c(c1)[C@@]1(CCOC(N)=N1)c1cc(Cl)nc(F)c1O2
Temperature: 85 °C
Yield: 45.7 %

Procedure:
A microwave vial was charged with (S)-7-bromo-3-chloro-1-fluoro-5′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,4′-[1,3]oxazin]-2′-amine (2.08 g, 5.22 mmol), (+)-sodium 1-ascorbate (0.103 g, 0.522 mmol), sodium azide (0.550 ml, 15.65 mmol) and copper(i) iodide (0.035 ml, 1.044 mmol). The vial was sealed, purged with N2 and followed by the addition of trans-n,n′-dimethyl-1,2-cyclohexanediamine (0.247 ml, 1.565 mmol), EtOH (12 mL) and water (4.6 mL). The resulting mixture was heated at 85° C. for 1.5 h. The mixture was poured into water and extracted with EtOAc. The combined organics were washed with brine, dried over Na2SO4, filtered, concentrated and chromatographed on silica gel using 0-50% MeOH/DCM to afford a light yellow solid as (S)-7-azido-3-chloro-1-fluoro-5′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,4′-[1,3]oxazin]-2′-amine (0.86 g, 45.7% yield).
Reaction SMILES: Br.[C:2]1(P(C2C=CC=CC=2)C2C=CC=CC=2)[CH:7]=CC=C[CH:3]=1.C(O)C=C.[C:25]([O:29][CH3:30])(=[O:28])[CH:26]=[CH2:27]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:25]([O:29][CH3:30])(=[O:28])/[CH:26]=[CH:27]/[CH:3]=[CH:2]/[CH3:7]
Reactant: C=CC(=O)OC
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: [Pd+2]
Agent: Br
Agent: CC(=O)[O-]
Solvent: C=CCO
Product: C/C=C/C=C/C(=O)OC
Temperature: 120 °C

Procedure:
A quantity of 1.1 grams palladium acetate, 0.61 cc-47° by weight hydrogen bromide, 5.25 grams triphenyl phosphine, 45 cc allyl alcohol, and 60 cc methyl acrylate is introduced into a reaction chamber and heated to 120°C for a period of 15 hours. Methyl sorbate is produced to the extent of 15% by weight of the final reaction solution.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:17]1[N:18]=[C:19]([CH3:49])[N:20]([C:39]2[CH:48]=[CH:47][C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[CH:40]=2)[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[C:31]([C:36]#[N:37])=[CH:32][CH:33]=[CH:34][CH:35]=2)=[CH:26][CH:25]=1)[CH2:14][CH2:15][CH3:16]>O.C(OCC)(=O)C>[CH2:13]([C:17]1[N:18]=[C:19]([CH3:49])[N:20]([C:39]2[CH:48]=[CH:47][C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[CH:40]=2)[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]2[NH:3][C:4](=[O:7])[O:5][N:37]=2)=[CH:28][CH:29]=1)[CH2:14][CH2:15][CH3:16]
Reactant: CCCCc1nc(C)n(-c2ccc3ccccc3c2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: [NH3+]O
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: O
Product: CCCCc1nc(C)n(-c2ccc3ccccc3c2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 70.2 %

Procedure:
A mixture of hydroxylammonium chloride (1.30 g), sodium hydrogen carbonate (1.97 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 4′-{[4-butyl-2-methyl-1-(2-naphthyl)-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (1.13 g) was added, and the mixture was stirred at 90° C. for 18 hr. The reaction mixture was allowed to cool to room temperature, ethyl acetate and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was dissolved in tetrahydrofuran (10 mL), N,N′-carbonyldiimidazole (0.46 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.42 mL) were added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.89 g, 70%).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([NH:8][N+:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:7])=[CH:4][CH:3]=1>ClC1C=CC(C(Cl)=O)=CC=1>[Cl-:1].[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([N:8]([C:6](=[O:7])[C:5]2[CH:15]=[CH:16][C:2]([Cl:1])=[CH:3][CH:4]=2)[N+:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(N[n+]1ccccc1)c1ccc(Cl)cc1
Agent: O=C(Cl)c1ccc(Cl)cc1
Product: O=C(c1ccc(Cl)cc1)N(C(=O)c1ccc(Cl)cc1)[n+]1ccccc1
Product: [Cl-]
Reaction time: 2 h

Procedure:
A solution of 1-(p-chlorobenzamido)pyridinium internal salt (20 parts) in p-chlorobenzoyl chloride was allowed to stand for 2 hours at 25° C. The crystalline solid which formed was filtered off, washed and dried to give 1-(bis(p-chlorobenzoyl) amino)pyridinium chloride (20 parts), melting point 195° C.
Reaction SMILES: [CH:1]1([NH:7][C:8]2[N:15]=[CH:14][CH:13]=[CH:12][C:9]=2[C:10]#[N:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([CH:18]([C:22](Cl)=[O:23])[C:19](Cl)=[O:20])C.[CH2:25]([O:27]CC)[CH3:26]>>[CH2:25]([O:27][C:22]([C:18]1[C:19](=[O:20])[N:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[C:8]2[C:9]([C:10]=1[NH2:11])=[CH:12][CH:13]=[CH:14][N:15]=2)=[O:23])[CH3:26]
Reactant: CCC(C(=O)Cl)C(=O)Cl
Reactant: N#Cc1cccnc1NC1CCCCC1
Reactant: CCOCC
Product: CCOC(=O)c1c(N)c2cccnc2n(C2CCCCC2)c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 20.1 g. (0.1 mole) of 2-cyclohexylaminonicotinonitrile in 1000 ml. of anhydrous ethyl ether was added 7.5 g. (0.05 mole) of ethyl malonyl chloride. The mixture was stirred at room temperature for 1 hour. The mixture was filtered and the filtrate was evaporated in a rotary evaporator. The residue was triturated with 30 ml. of ether and was filtered. The filtrate was evaporated and this residue was added to a solution of 2.3 g. (0.1 g. atom) of sodium in 250 ml. of ethanol. The mixture was stirred at room temperature for 5 minutes, diluted with water and was acidified with conc. hydrochloric acid. The solution was cooled in ice and the precipitate which formed was collected, air dried and was recrystallized twice from ethyl acetate to afford 1.0 g. of the title product, m.p. 172°-175° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH2:10][CH3:11].C([Li])CCC.[B:17](OCCCC)([O:23]CCCC)[O:18]CCCC>C1COCC1>[CH2:10]([C:3]1[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=1[B:17]([OH:23])[OH:18])[CH3:11]
Reactant: CCCCOB(OCCCC)OCCCC
Reactant: CCc1cc(OC)ccc1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCc1cc(OC)ccc1B(O)O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 4-bromo-3-ethyl anisole (94 g, 0.437 mol) in THF (900 ml) was cooled to −78° C. n-Butyl lithium (249 ml, 0.55 mol) was added dropwise at the same temperature. Stirring was continued for 1 hr at −78° C. Tri-n-butyl borate (177 ml, 0.655 mol) was added slowly at −78° C. The cooling bath was removed, the reaction mixture was allowed to warm to 0° C. and was quenched with 1.5 N hydrochloric acid at 0° C. The organic layer was separated. The aqueous layer was extracted with ethylacetate and the combined organic layers were washed with brine and concentrated. The residue obtained was stirred in petroleum ether for 30 min. The solid obtained was filtered and dried under vacuum. Yield: 65 g, 82%, as a white solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:12]=[CH:11][C:9]([NH2:10])=[CH:8][C:7]=1[C:13]([F:16])([F:15])[F:14].[C:17](N1C=CN=C1)(N1C=CN=C1)=[O:18].C1COCC1.[NH:34]1[C:38]2=[N:39][CH:40]=[CH:41][C:42]([O:43][C:44]3[CH:50]=[CH:49][C:47]([NH2:48])=[CH:46][CH:45]=3)=[C:37]2[CH:36]=[CH:35]1>ClC(Cl)CCl>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:12]=[CH:11][C:9]([NH:10][C:17]([NH:48][C:47]2[CH:49]=[CH:50][C:44]([O:43][C:42]3[CH:41]=[CH:40][N:39]=[C:38]4[NH:34][CH:35]=[CH:36][C:37]=34)=[CH:45][CH:46]=2)=[O:18])=[CH:8][C:7]=1[C:13]([F:14])([F:15])[F:16]
Reactant: COCCOc1ccc(N)cc1C(F)(F)F
Reactant: Nc1ccc(Oc2ccnc3[nH]ccc23)cc1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: ClCC(Cl)Cl
Product: COCCOc1ccc(NC(=O)Nc2ccc(Oc3ccnc4[nH]ccc34)cc2)cc1C(F)(F)F
Reaction time: 0.5 h
Yield: 79 %

Procedure:
4-(2-Methoxyethoxy)-3-(trifluoromethyl)aniline (540 mg, 2.29 mmol) was dissolved in 1,1,2-trichloroethane (5 mL), and carbonyldiimidazole (409 mg) was added thereto under ice-cooling, followed by stirring for 30 minutes. Then, THF (10 mL) and 4-(1H-pyrrolo[2,3-b]pyridin-4-yloxy)aniline (517 mg, 2.29 mmol) were added thereto, followed by stirring at room temperature for 20 hours. The reaction solution was partitioned between ethyl acetate (10 mL) and water (20 mL). The organic layer was washed with saturated brine and concentrated under reduced pressure. The residue was purified by silica-gel column chromatography (ethyl acetate) to give 1-[4-(2-methoxyethoxy)-3-(trifluoromethyl)phenyl]-3-[4-(1H-pyrrolo[2,3-b]pyridin-4-yloxy)phenyl]urea (880 mg, 79%) as colorless crystals.
Reaction SMILES: C([NH:8][CH2:9][CH:10]([CH2:12][S:13]([CH:16]([CH3:18])[CH3:17])(=[O:15])=[O:14])[OH:11])(OC(C)(C)C)=O.C(Cl)[Cl:20]>>[NH2:8][CH2:9][CH:10]([CH2:12][S:13]([CH:16]([CH3:18])[CH3:17])(=[O:15])=[O:14])[OH:11].[ClH:20]
Reactant: CC(C)S(=O)(=O)CC(O)CNC(=O)OC(C)(C)C
Reactant: ClCCl
Product: CC(C)S(=O)(=O)CC(O)CN
Product: Cl

Procedure:
BOC-NHCH2CH(OH)CH2SO2CH(CH3)2 (3.19 g, 11.35 mmole) was dissolved in 75 ml CH2Cl2 and purged with HCl gas over two hours. The mixture was stripped, triturated with ethyl ether, and filtered. The solid was washed with ethyl ether and dried giving 2.21 g of product.
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[C:6]([N+:9]([O-:11])=[O:10])[CH:5]=[C:4]([Cl:12])[CH:3]=1.[C:13](OCC)(=[O:15])C>>[Cl:12][C:4]1[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[C:7]2[O:8][C:13](=[O:15])[NH:1][C:2]=2[CH:3]=1
Reactant: CCOC(C)=O
Reactant: Nc1cc(Cl)cc([N+](=O)[O-])c1O
Product: O=c1[nH]c2cc(Cl)cc([N+](=O)[O-])c2o1
Temperature: 22.5 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
188.6 g (1 mole) of 6-amino-4-chloro-2-nitrophenol prepared according to Example 1c was suspended in 1000 ml of ethyl acetate under mild nitrogen purge and the optional present water was removed by azeotropic distillation of 250 ml of the solvent. The mixture was cooled to 20-25° C. and 224 g of carbonyldiimidazole was added as a slurry in 650 ml of ethyl acetate. An additional 100 ml of ethyl acetate was added and the mixture was vigorously stirred during two hours, without the application of cooling. 1000 ml of water was added and the mixture was stirred for 15 minutes. 1450-1500 ml of ethyl acetate was distilled off at about 200 mBar and about 50° C. The mixture was cooled to 0-5° C., 225 ml of 36% HCl was added and the mixture was cooled again to 0-5° C. and stirred at this temperature for 15 minutes. The solid was filtered off, washed with 400 ml of 1N HCl, washed twice with 500 ml of cold water and once with 500 ml of cold water/ethanol (4/1), and dried at 50° C. and 100 mbar under a gentle nitrogen stream till dry. Yield about 99%.
Reaction SMILES: Cl[C:2]1[N:6]=[C:5]([CH:7]2[CH2:12][CH:11]([C:13]3[CH:18]=[CH:17][C:16]([CH2:19][CH3:20])=[CH:15][CH:14]=3)[CH2:10][N:9]([C:21]([N:23]3[CH2:28][CH2:27][CH:26]([OH:29])[CH2:25][CH2:24]3)=[O:22])[CH2:8]2)[O:4][N:3]=1.[CH2:30]([NH:32][CH2:33][CH3:34])[CH3:31]>C(O)C>[CH2:30]([N:32]([CH2:33][CH3:34])[C:2]1[N:6]=[C:5]([CH:7]2[CH2:12][CH:11]([C:13]3[CH:18]=[CH:17][C:16]([CH2:19][CH3:20])=[CH:15][CH:14]=3)[CH2:10][N:9]([C:21]([N:23]3[CH2:28][CH2:27][CH:26]([OH:29])[CH2:25][CH2:24]3)=[O:22])[CH2:8]2)[O:4][N:3]=1)[CH3:31]
Reactant: CCc1ccc(C2CC(c3nc(Cl)no3)CN(C(=O)N3CCC(O)CC3)C2)cc1
Reactant: CCNCC
Solvent: CCO
Product: CCc1ccc(C2CC(c3nc(N(CC)CC)no3)CN(C(=O)N3CCC(O)CC3)C2)cc1
Reaction time: 5 h

Procedure:
To a solution of 45.0 mg (0.098 mmol) of the oxadiazole from Example 25A in 0.61 ml of ethanol were added 143 mg (1.96 mmol) of diethylamine, and then the reaction mixture was stirred in the microwave at 80 for 5 h. Another 143 mg (1.96 mmol) of diethylamine were added and the mixture was stirred in the microwave at 80° C. for a further 2 h. The solvent was removed under reduced pressure and the crude product was purified by means of preparative HPLC. Yield: 35.6 mg (80% of theory)
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[C:10]([F:13])([F:12])[F:11].[H-].[Na+].[H][H].Cl[C:19]1[N:23]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:22]=[N:21][N:20]=1>O1CCCC1>[C:24]1([N:23]2[C:19]([NH:1][C:2]3[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=3[C:10]([F:11])([F:12])[F:13])=[N:20][N:21]=[N:22]2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: Clc1nnnn1-c1ccccc1
Reactant: [H][H]
Reactant: N#Cc1ccc(N)c(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#Cc1ccc(Nc2nnnn2-c2ccccc2)c(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 93.9 %

Procedure:
4-Amino-3-trifluoromethyl-benzonitrile (0.9 g) was added to a tetrahydrofuran solution (25 ml) of sodium hydride (0.5 g; 60% in oil) at room temperature. The mixture was stirred at room temperature for about 10 minutes until the generation of hydrogen gas was ceased. Then, 5-chloro-1-phenyltetrazole (0.9 g) was added thereto and the mixture was stirred for 2 hours. The reaction solution was poured into 100 ml of ice water and the organic layer was distilled off under reduced pressure. Activated carbon was added to the aqueous layer and the aqueous layer was filtered. Then, the pH of the filtrate was adjusted to 2-3 with concentrated hydrochloric acid. The precipitated crystals were collated by filtration and washed with water and n-hexane to obtain 1-phenyl-5-(4-cyano-2-trifluoromethylanilino)tetrazole (1.5 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH:15]=[C:14]([CH2:16][CH2:17][CH:18]=O)[O:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[C:20]1([CH:26]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[C:33]1([CH:26]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:27]2[CH2:28][CH2:29][N:30]([CH2:18][CH2:17][CH2:16][C:14]3[O:13][N:12]=[C:11]([C:5]4[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=4)[CH:15]=3)[CH2:31][CH2:32]2)[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: COc1ccc(-c2cc(CCC=O)on2)cc1OC
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(-c2cc(CCCN3CCN(C(c4ccccc4)c4ccccc4)CC3)on2)cc1OC
Yield: 92.4 %

Procedure:
About 2 min after dissolving 3-[3-(3,4-dimethoxyphenyl)isoxazol-5-yl]propanal (10 mg, 0.04 mmol) and 1-(diphenylmethyl)piperazine (10 mg, 0.04 mmol) in 2 mL of dry methylene chloride, were added NaBH(OAc)3 (24 mg, 0.12 mmol) and molecular sieves (5 beads). The reaction mixture was reacted for 18.2 hr and followed the same processes as in Example 1 to obtain 18.4 mg (96.5%) of the target compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.[C:12]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:17]=[CH:16][C:15]([C:18](Cl)=[O:19])=[CH:14][CH:13]=1.C(N(CC)CC)C>C1COCC1>[O:11]=[C:7]1[C:8]2[C:4](=[CH:3][C:2]([NH:1][C:18]([C:15]3[CH:16]=[CH:17][C:12]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)=[CH:13][CH:14]=3)=[O:19])=[CH:10][CH:9]=2)[CH2:5][CH2:6]1
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Reactant: Nc1ccc2c(c1)CCC2=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1ccc2c(c1)CCC2=O)c1ccc(-c2ccccc2)cc1
Yield: 60 %

Procedure:
5-amino-indan-1-one (73 mg, 0.50 mmol) in THF (6 mL) with 4-biphenylcarbonyl chloride (140 mg, 0.65 mmol) in presence of triethylamine (90 μL, 0.65 mmol) according to method A gave biphenyl-4-carboxylic acid (1-oxo-indan-5-yl)-amide (100 mg, 0.30 mmol, 60% yield) as a brown powder after purification by washing the crude product with ethyl acetate.
Reaction SMILES: [Na].[CH:2]1[C:18]2[CH2:17][C@H:16]3[N:19]([CH2:21][CH2:22][C@@:8]45[C@H:15]3[CH:14]=[CH:13][C@H:11]([OH:12])[C@@H:9]4[O:10][C:6]([C:7]=25)=[C:4]([OH:5])[CH:3]=1)[CH3:20].Br[CH2:24][CH2:25][CH2:26][C:27]#[N:28]>C(O)C>[C:27]([CH2:26][CH2:25][CH2:24][O:5][C:4]1[CH:3]=[CH:2][C:18]2[CH2:17][C@H:16]3[N:19]([CH3:20])[CH2:21][CH2:22][C@:8]45[C:7]=2[C:6]=1[O:10][C@H:9]4[C@@H:11]([OH:12])[CH:13]=[CH:14][C@@H:15]35)#[N:28]
Reactant: N#CCCCBr
Reactant: CN1CC[C@]23c4c5ccc(O)c4O[C@H]2[C@@H](O)C=C[C@H]3[C@H]1C5
Agent: [Na]
Solvent: CCO
Product: CN1CC[C@]23c4c5ccc(OCCCC#N)c4O[C@H]2[C@@H](O)C=C[C@H]3[C@H]1C5
Temperature: 25 °C
Reaction time: 16 h
Yield: 94.6 %

Procedure:
To a solution of 0.973 g of sodium dissolved in 100 ml of abs. ethanol was added 12.1 g (0.042 mol) of morphine. After heating at reflux for 1 hr, the reaction mixture was cooled to room temperature and 6.3 g of 4-bromobutyronitrile was added; then heating under reflux was resumed for 16 hr. After removal of the ethanol, the residue was dissolved in chloroform (150 ml). The chloroform solution was washed with 2 N sodium hydroxide (2 × 50 ml) and with water (50 ml). After drying, the solvent was removed in vacuo to give 14.0 g of crude 3-(3-cyanopropoxy)-7,8-didehydro-4,5 α-epoxy-17-methylmorphinan-6 α-ol. A sample of this compound was distilled, b.p. 260°-265°/0.25 mm; [α]D25 -104.09°(c 1.06, MeOH).
Reaction SMILES: C([O:3][C:4](=[O:22])[CH2:5][O:6][C:7]1[C:19]([Cl:20])=[C:18]([Cl:21])[C:10]2[S:11][C:12]([CH:14]([OH:17])[CH2:15][CH3:16])=[CH:13][C:9]=2[CH:8]=1)C.[OH-].[Na+].Cl>C(O)C.C(OCC)C>[Cl:20][C:19]1[C:7]([O:6][CH2:5][C:4]([OH:22])=[O:3])=[CH:8][C:9]2[CH:13]=[C:12]([CH:14]([OH:17])[CH2:15][CH3:16])[S:11][C:10]=2[C:18]=1[Cl:21]
Reactant: CCOC(=O)COc1cc2cc(C(O)CC)sc2c(Cl)c1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOCC
Product: CCC(O)c1cc2cc(OCC(=O)O)c(Cl)c(Cl)c2s1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 85.6 %

Procedure:
To 9.5 g of ethyl[[6,7-dichloro-2-(1-hydroxypropyl)benzo[b]thien-5-yl]oxy]acetate in 210 ml of ethanol is added 180 ml of 6N sodium hydroxide solution and the mixture is stirred at 100° for 30 mins. The cooled mixture is concentrated in vacuo to give a white slurry which is diluted with 400 ml of ice water and 300 ml of ethyl ether. With stirring and efficient cooling, the mixture is acidified with 6N hydrochloric acid. The acidic mixture is extracted with ethyl ether. The ether extracts are washed, dried over anhydrous magnesium sulfate and evaporated to dryness. Recrystallization of the residue from ethyl ether and hexane gives 7.5 g of [[6,7-dichloro-2-(1-hydroxypropyl)benzo[b]thien-5-yl]oxy]acetic acid, mp 156°-158°.
Reaction SMILES: [CH2:1]([N:10]([C@@H:27]([CH3:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C@@H:11]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C@H:12]([OH:20])[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.IN1C(=[O:41])CCC1=O>>[C:1]([N:10]([C@@H:27]([CH3:34])[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C@@H:11]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C@H:12]([OH:20])[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])(=[O:41])[CH:2]=[CH:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: C[C@@H](c1ccccc1)N(CC=Cc1ccccc1)[C@@H](c1ccccc1)[C@H](O)C(=O)OC(C)(C)C
Reactant: O=C1CCC(=O)N1I
Product: C[C@@H](c1ccccc1)N(C(=O)C=Cc1ccccc1)[C@@H](c1ccccc1)[C@H](O)C(=O)OC(C)(C)C
Yield: 44.8 %

Procedure:
Compound (28) from Example 13 (0.200 g, 0.44 mmol) was treated with N-iodosuccinimide (0.197 g, 0.88 mmol) using standard iodoetherification conditions. Flash chromatography of the product on silica gel [ethyl acetate/petroleum (1:9)] afforded the title compound (54) (Rf 0.50) as a yellow oil (0.093 g, 45%). δH (200 MHz; CDCl3) 7.72 (1H, d, J=16.0, CH=CHPh), 7.57-7.22 (15H, m, Ph), 6.51 (1H, d, J=16.0, PhCH=CH), 5.45 (1H, d, J=4.9, CHCHOH), 4.25 (1H, d, J=4.9, PhCHCH), 3.81 (1H, d, J=6.5, PhCHCH3), 1.92 (1H, br s, OH), 1.34 (3H, d, J=6.5, PhCHCH3), 1.32 (9H, s, (CH3)3C). The corresponding 3-(α-methylbenzylamino) derivative (Rf 0.25) was also recovered as a colourless oil (0.045 g, 30%. δH (200 MHz; CDCl3) 7.48-7.14 (10H, m, Ph), 4.50 (1H, d, J=3.8, CHCHOH), 4.09 (1H, d, J=3.8, PhCHCH), 3.76 (1H, q, J=6.6, PhCHCH3), 1.38 (3H, d, J=6.6, PhCHCH3), 1.31 (9H, s, (CH3)3C).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][C:16]([NH2:18])=[S:17])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:20]([I:22])[CH3:21]>>[IH:22].[C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][C:16](=[NH:18])[S:17][CH2:20][CH3:21])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCc1cccc(NC(N)=S)c1
Reactant: CCI
Product: CCSC(=N)Nc1cccc(CNC(=O)OC(C)(C)C)c1
Product: I
Yield: 68 %

Procedure:
Using the compound obtained in Example 24 as a starting material and also using ethyl iodide as a reagent, the same procedure of Example 4 gave 178 mg of the titled compound (yield, 68%).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][CH2:5][CH2:6][OH:7].[N+:8]([O-:11])([OH:10])=[O:9].C([O-])(O)=O.[Na+]>CC(O)CC>[N+:8]([O-:11])([O-:10])=[O:9].[CH3:1][NH2+:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][N+:8]([O-:10])=[O:9]
Reactant: O=[N+]([O-])O
Reactant: CNCCCCO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCC(C)O
Product: C[NH2+]CCCCO[N+](=O)[O-]
Product: O=[N+]([O-])[O-]
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 52.2 %

Procedure:
5 g 4-(Methylamino)butan-1-ol (0.049 mol) is slowly added to 15 g HNO3 (100%, 0.24 mol) at −10° C., care being taken that the temperature does not rise above 10° C. The mixture is stirred for 10 min at 0° C., then poured on ice (15 g) and stirred for 2 h at room temperature. 33 g 2-Butanol is added slowly at 0° C., the obtained mixture (pH 0-1) neutralised (to pH 6) with 15.6 g NaHCO3 at 0° C., filtered and the organic phase dried over MgSO4. 1.2 g Norrit 2× is added, the mixture filtered, and the filtrate evaporated to give 5.4 g (52%) N-methyl-N-(4-nitroxybutyl)ammonium nitrate. 1H-NMR (200 MHz, DMSO-d6): 1.56-1.78 (m, 4H); 2.54 (t, J=5.5, 3H); 2.84-2.97 (m, 2H); 4.52 (t, J=5.9, 2H); 8.30 (br. s, 2H).