Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:40])[N:7]([C@H:9]([C:11](=[O:39])[NH:12][C@@H:13]1[C:19](=[O:20])[N:18]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][C:28]([Br:32])=[CH:29][CH:30]=3)[CH:25]=[CH:24][C:23]=2[O:33][CH3:34])[C:17]2[CH:35]=[CH:36][CH:37]=[CH:38][C:16]=2[NH:15][CH2:14]1)[CH3:10])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[N:41]1[CH:46]=[C:45]([C:47]([OH:49])=O)[N:44]=[CH:43][C:42]=1[C:50]([OH:52])=O.O=P(Cl)(Cl)Cl>N1C=CC=CC=1>[Br:32][C:28]1[CH:27]=[C:26]2[C:31](=[CH:30][CH:29]=1)[C:22]([CH2:21][N:18]1[C:17]3[CH:35]=[CH:36][CH:37]=[CH:38][C:16]=3[N:15]([C:47]([C:45]3[CH:46]=[N:41][C:42]([C:50]([N:15]4[C:16]5[CH:38]=[CH:37][CH:36]=[CH:35][C:17]=5[N:18]([CH2:21][C:22]5[C:31]6[C:26](=[CH:27][C:28]([Br:32])=[CH:29][CH:30]=6)[CH:25]=[CH:24][C:23]=5[O:33][CH3:34])[C:19](=[O:20])[C@@H:13]([NH:12][C:11](=[O:39])[C@@H:9]([N:7]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:40])[CH3:8])[CH3:10])[CH2:14]4)=[O:52])=[CH:43][N:44]=3)=[O:49])[CH2:14][C@H:13]([NH:12][C:11](=[O:39])[C@@H:9]([N:7]([CH3:8])[C:6](=[O:40])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH3:10])[C:19]1=[O:20])=[C:23]([O:33][CH3:34])[CH:24]=[CH:25]2
Reactant: COc1ccc2cc(Br)ccc2c1CN1C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)CNc2ccccc21
Reactant: O=C(O)c1cnc(C(=O)O)cn1
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc2cc(Br)ccc2c1CN1C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)CN(C(=O)c2cnc(C(=O)N3C[C@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(=O)N(Cc4c(OC)ccc5cc(Br)ccc45)c4ccccc43)cn2)c2ccccc21
Reaction time: 5 h
Yield: 16 %

Procedure:
To a solution of {(S)-1-[(S)-1-(6-bromo-2-methoxy-naphthalen-1-ylmethyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylcarbamoyl]-ethyl}-methyl-carbamic acid tert-butyl ester (Intermediate 11) (300 mg, 0.49 mmol) and pyrazine-2,5-dicarboxylic acid (41.2 mg, 0.24 mmol) in pyridine (5 mL) at 0° C. was added POCl3 (46 μL, 0.49 mmol) and the cooling bath removed. After 5 h, the mixture was diluted with dichloromethane, washed with water, dried (Na2SO4) and concentrated. The residue was purified by preparative reverse phase HPLC to afford tert-butyl N-[(1S)-2-[[(3S)-5-[(6-bromo-2-methoxy-1-naphthyl)methyl]-1-[5-[(3S)-5-[(6-bromo-2-methoxy-1-naphthyl)methyl]-3-[[(2S)-2-[tert-butoxycarbonyl(methyl)amino]propanoyl]amino]-4-oxo-2,3-dihydro-1,5-benzodiazepine-1-carbonyl]pyrazine-2-carbonyl]-4-oxo-2,3-dihydro-1,5-benzodiazepin-3-yl]amino]-1-methyl-2-oxo-ethyl]-N-methyl-carbamate (52 mg, 7.82%) as an off white solid. LC-MS: 1355.0 (M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[CH:10][C:5]=1[O:6][CH2:7][CH2:8]Cl)([O-:3])=[O:2].[NH2:14][CH2:15][CH2:16][C:17]([N:19]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[S:23][CH2:22][CH:21]=[CH:20]1)=[O:18].[C:30](=[O:33])([O-:32])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[CH:10][C:5]=1[O:6][CH2:7][CH2:8][NH:14][CH2:15][CH2:16][C:17]([N:19]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[S:23][CH2:22][CH2:21][CH2:20]1)=[O:18])([O-:3])=[O:2].[C:5]([O-:18])(=[O:6])/[CH:10]=[CH:11]/[C:30]([O-:32])=[O:33]
Reactant: O=[N+]([O-])c1ccccc1OCCCl
Reactant: NCCC(=O)N1C=CCSc2ccccc21
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: O=C(CCNCCOc1ccccc1[N+](=O)[O-])N1CCCSc2ccccc21
Product: O=C([O-])/C=C/C(=O)[O-]
Yield: 55.4 %

Procedure:
A mixture of 2-Nitrophenoxyethylchloride (0.26 g), 5-(3-Amino-propionyl)-1,5-benzothiazepine (0.355 g) and potassium carbonate (0.210 g) in toluene (15 ml) was refluxed for 16 hours. After cooling, objective compound (0.184 g) was obtained according to the method of experimental 1. m.p. 178°-180° C.
Reaction SMILES: Cl[CH2:2][CH2:3][CH:4]1[O:8][C:7](=[O:9])[N:6]([CH3:10])[CH2:5]1.[N:11]1([C:17]2[CH:25]=[CH:24][C:20]([C:21]([NH2:23])=[O:22])=[CH:19][CH:18]=2)[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1>>[CH3:10][N:6]1[CH2:5][CH:4]([CH2:3][CH2:2][N:14]2[CH2:13][CH2:12][N:11]([C:17]3[CH:18]=[CH:19][C:20]([C:21]([NH2:23])=[O:22])=[CH:24][CH:25]=3)[CH2:16][CH2:15]2)[O:8][C:7]1=[O:9]
Reactant: CN1CC(CCCl)OC1=O
Reactant: NC(=O)c1ccc(N2CCNCC2)cc1
Product: CN1CC(CCN2CCN(c3ccc(C(N)=O)cc3)CC2)OC1=O

Procedure:
Following the procedure of Example 2, the title compound is prepared from 5-(2-chloroethyl)-3-methyl-2-oxazolidinone and 4-(1-piperazinyl)benzamide.
Reaction SMILES: [C@@H:1]1([N:7]2[C:15](=[O:16])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]2=[O:17])[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1.C[N+]1([O-])CC[O:22]CC1.CC(C)=O.[OH2:30]>[Os](=O)(=O)(=O)=O>[OH:30][C@@H:2]1[C@H:3]([OH:22])[CH2:4][CH2:5][CH2:6][C@H:1]1[N:7]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]1=[O:17]
Reactant: C[N+]1([O-])CCOCC1
Reactant: O
Reactant: O=C1c2ccccc2C(=O)N1[C@H]1C=CCCC1
Agent: O=[Os](=O)(=O)=O
Solvent: CC(C)=O
Product: O=C1c2ccccc2C(=O)N1[C@@H]1CCC[C@@H](O)[C@H]1O
Reaction time: 4 h
Yield: 95 %

Procedure:
To a suspension of 2-[(1R)-cyclohex-2-en-1-yl]-1H-isoindole-1,3(2H)-dione (18) (19.9 mmol, 4.53 g) and 4-methylmorpholine-N-oxide (60 mmol, 7.01 g) in acetone/water (4:1, 62.5 mL), osmium tetroxide (0.2 mmol, 50 mg) was added. The reaction was stirred for 4 h. The mixture was concentrated and saturated sodium sulfite (40 mL) was added. It was then promptly extracted with EtOAc three times. The combined organic layers were washed with water and brine, dried over MgSO4 and concentrated to give the crude product as a white solid (4.94 g, 95% yield). Chiral HPLC [8.53 min]. Analytical data matched published data (Donohoe, J. T.; et al., J. Org. Chem., 2002, 67, 7946-7956)
Reaction SMILES: C([O:3][C:4]([C:6]1[S:7][C:8]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)=[C:9]([CH3:25])[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([S:17](=[O:24])(=[O:23])[N:18]=CN(C)C)=[CH:13][CH:12]=1)=[O:5])C.[OH-].[Na+].O.Cl>C(O)C.C(OC(=O)C)C>[CH3:25][C:9]1[C:10]([C:11]2[CH:12]=[CH:13][C:14]([S:17](=[O:24])(=[O:23])[NH2:18])=[CH:15][CH:16]=2)=[C:6]([C:4]([OH:5])=[O:3])[S:7][C:8]=1[N:26]1[CH2:27][CH2:28][O:29][CH2:30][CH2:31]1
Reactant: CCOC(=O)c1sc(N2CCOCC2)c(C)c1-c1ccc(S(=O)(=O)N=CN(C)C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1c(N2CCOCC2)sc(C(=O)O)c1-c1ccc(S(N)(=O)=O)cc1
Temperature: 97.5 °C
Reaction time: 1 h
Yield: 66.6 %

Procedure:
Ethyl-3-(4-(N-((dimethylamino)methylene) sulfamoyl)phenyl)-4-methyl-5-morpholinothiophene-2-carboxylate (compound 24d, 0.36 g, 0.77 mmol) was suspended in ethanol (20 ml) and combined with 2N solution of NaOH (1.55 ml) at 25° C. The reaction mixture was heated at 95-100° C. under stirring for 1 hr. The progress of the reaction was monitored by TLC. The resulting reaction mixture was concentrated at a reduced pressure. The residue obtained was diluted with mixture of ethylacetate:water (30:15 ml). To this was added aqueous 10% HCl to bring the pH to between 5 and 6. The aqueous layer was extracted with ethyl acetate (2×20 ml). The combined organic layer was dried over anhydrous Na2SO4. The solvent was evaporated under reduced pressure from the dried organic layer to obtain the title compound (0.196 g, 66%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].CO[CH2:11][CH2:12][C:13](OC)(OC)[CH3:14]>[Cl-].[Zn+2].[Cl-].C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:6]([C:13]([CH3:14])=[CH:12][CH:11]=[N:5]2)=[CH:7][CH:8]=1
Reactant: COCCC(C)(OC)OC
Reactant: Nc1cccc(Cl)c1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCO
Product: Cc1ccnc2cc(Cl)ccc12
Reaction time: 8 h

Procedure:
To a mixture containing 3-chloroaniline (1.59 g), ferric chloride hexahydrate (5.4 g), zinc chloride (0.2 g), ethanol (20 ml of 95% aqueous solution) preheated to 60° C. was added 1,3,3-trimethoxybutane (1.48 g). The resulting mixture was refluxed for two hours and allowed to stand overnight. The volatile matrials were then removed in vacuo and the residue rendered basic with 10% aqueous sodium hydroxide. The resulting mixture was partitioned between water and diethyl ether (3 times). The combined ether layer was dried over magnesium sulfate. Rotary evaporation of the ether solution gave a dark liquid. The liquid was added to a silica gel column and eluted with hexane/ethyl acetate (3:1) to give the desired product as tan crystals.
Reaction SMILES: [CH2:1]([O:3][N:4]=[C:5]1[CH2:9][NH:8][CH:7]([C:10]([OH:12])=O)[CH2:6]1)[CH3:2].[C:13]1([CH:19]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:20](Cl)=[O:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH2:29]([N:31]([CH2:35][CH3:36])[CH2:32][CH2:33][NH2:34])[CH3:30]>>[CH2:29]([N:31]([CH2:35][CH3:36])[CH2:32][CH2:33][NH:34][C:10]([C@@H:7]1[CH2:6][C:5](=[N:4][O:3][CH2:1][CH3:2])[CH2:9][N:8]1[C:20](=[O:21])[CH:19]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:12])[CH3:30]
Reactant: CCON=C1CNC(C(=O)O)C1
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Reactant: CCN(CC)CCN
Product: CCON=C1C[C@@H](C(=O)NCCN(CC)CC)N(C(=O)C(c2ccccc2)c2ccccc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-tert-butoxycarbonyl)-4-(ethoxyimino)-2-pyrrolidinecarboxylic acid, diphenylacetyl chloride, and N1,N1-diethyl-1,2-ethanediamine the title compound was obtained in 50% purity by LC/MS. MS(ESI+): m/z=465.4.
Reaction SMILES: C(P(=O)(OCC)[O:4][CH2:5]C)#N.[H-].[Na+].[F:13][C:14]1[C:22]([CH:23]=O)=[C:18]2[CH:19]=[CH:20][O:21][C:17]2=[CH:16][CH:15]=1.[C:25](OCC)(=[O:27])C>O1CCCC1.[Cl-].[Na+].O>[CH3:5][O:4][CH:19]([O:27][CH3:25])[CH2:20][O:21][C:17]1[CH:16]=[CH:15][C:14]([F:13])=[C:22]([CH3:23])[CH:18]=1
Reactant: O=Cc1c(F)ccc2occc12
Reactant: CCOP(=O)(C#N)OCC
Reactant: CCOC(C)=O
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(COc1ccc(F)c(C)c1)OC
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of diethyl cyanophosphonate (2.79 g) in dry tetrahydrofuran (10 ml) was added to a suspension of sodium hydride (60% oil dispersion; 0.63 g) in THF (16 ml) over 5 mins with ice cooling. After 15 min, a solution of 5-fluorobenzofuran-4-carbaldehyde (2.15 g) in THF (10 ml) was added and after 5 mins the solution was warmed up and stirred at room temperature for 3 h. Brine (20 ml) and ethyl acetate (20 ml) were added, the phases separated and the aqueous extracted with ethyl acetate (2×25 ml). The extracts were dried and evaporated and the residue purified by chromatography (Biotage Flash 40; 90 g; ethyl acetate:hexane 1:9) to give the title compound as a cream solid (1.97 g)
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[C:24](=[O:27])([O-])[O-].[K+].[K+].O[C:31]1[CH:39]=[CH:38][CH:37]=[C:36]2[C:32]=1[CH:33]=C[NH:35]2>CC(N(C)C)=O>[NH:35]1[C:36]2[C:32](=[CH:31][CH:39]=[CH:38][CH:37]=2)[CH:33]=[C:24]1[O:27][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: O=C([O-])[O-]
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCCCC1
Reactant: Oc1cccc2[nH]ccc12
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COc1cc2c(Oc3cc4ccccc4[nH]3)ncnc2cc1OCCCN1CCCCC1
Temperature: 85 °C
Reaction time: 3 h
Yield: 50.9 %

Procedure:
A mixture of 4-chloro-6-methoxy-7-(3-piperidinopropoxy)quinazoline (200 mg, 0.595 mmol), (prepared as described for the starting material in Example 67), potassium carbonate (411 mg, 2.98 mmol) and 4-hydroxyindole (103 mg, 0.774 mmol) in DMA (2.0 ml) was stirred at 85° C. for 3 hours and allowed to cool to ambient temperature. The reaction mixture was filtered and the filtrate evaporated to give a solid residue. The residue was purified by silica column chromatography, with gradient elution using dichloromethane with 0%, 2%, 4%, 10% methanolic ammonia to give 4-(indolyloxy)-6-methoxy-7-(3-piperidinopropoxy)quinazoline (131 mg, 51%).
Reaction SMILES: [C:1]([NH:9][CH:10]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:11](=[O:33])[CH2:12][NH:13][C@H:14]1[CH2:20][CH2:19][CH2:18][CH2:17][N:16]([CH2:21][C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])[C:15]1=[O:32])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>O1CCCC1.O>[C:1]([NH:9][CH:10]([CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[CH:11]([OH:33])[CH2:12][NH:13][C@H:14]1[CH2:20][CH2:19][CH2:18][CH2:17][N:16]([CH2:21][C:22]([O:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[O:23])[C:15]1=[O:32])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CN1CCCC[C@H](NCC(=O)C(Cc2ccccc2)NC(=O)c2ccccc2)C1=O)OCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(CN1CCCC[C@H](NCC(O)C(Cc2ccccc2)NC(=O)c2ccccc2)C1=O)OCc1ccccc1
Reaction time: 4 h

Procedure:
To a solution of (S)-3-[[3-(benzoylamino)-2-oxo-4-phenylbutyl]amino]-hexahydro-2-oxo-1H-azepine-1-acetic acid, phenylmethyl ester (2.5 mmole) in tetrahydrofuran (25 ml.) and water (2.5 ml.) is added sodium borohydride (10.0 mmole) portionwise over a 10 minute period. After the addition is completed, the reaction mixture is stirred for 4 hours, and slowly quenched with concentrated hydrochloric acid. The mixture is diluted with ethyl acetate (50 ml.), washed with water (2×), saturated sodium bicarbonate (2×), and saturated sodium chloride (2×), dried (Na2SO4), and concentrated under reduced pressure to give (S)-3-[[3-(benzoylamino)-2-hydroxy-4-phenylbutyl]amino]hexahydro-2-oxo-1H-azepine-1-acetic acid, phenylmethyl ester.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.O.[NH2:13][NH2:14].C(O)C>C(O)(=O)C>[NH:13]([C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1)[NH2:14]
Reactant: NN
Reactant: Clc1ccc2ccccc2n1
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: NNc1ccc2ccccc2n1

Procedure:
2-Hydrazinoquinoline (35.70 g; 0.224 mol) obtained in a customary manner (e.g., as disclosed in J. Chem. Soc., 103, 1978) from 2-chloroquinoline and hydrazine hydrate, 56.29 g (0.149 mol, mol ratio 1.5) of di-p-diethylaminostyryl ketone, 450 ml of ethanol and 74.8 ml of acetic acid were refluxed for 3 hours with stirring. The reaction mixture was cooled with water. The crystals that precipitated were separated by filtration, and hot-filtered using 150 cc of ethanol to afford 27.12 g (yield 35%) of yellow crystals having a melting point of 180° to 182° C. Recrystallization from methyl ethyl ketone afforded crystals having a melting point of 182° to 183° C.
Reaction SMILES: [CH3:1][C@@H:2]([C@@H:8]1[C@@:12]2([CH3:28])[C@@H:13]([OH:27])[CH2:14][C@@H:15]3[C@@:20]4([CH3:26])[CH2:21][CH2:22][C@@H:23]([OH:25])[CH2:24][C@H:19]4[CH2:18][CH2:17][C@H:16]3[C@@H:11]2[CH2:10][CH2:9]1)[CH2:3][CH2:4][C:5]([OH:7])=[O:6]>C(Cl)(Cl)Cl.C(O)C>[OH:27][C@@H:13]1[C@@:12]2([CH3:28])[C@@H:11]([CH2:10][CH2:9][C@@H:8]2[C@H:2]([CH3:1])[CH2:3][CH2:4][C:5]([OH:7])=[O:6])[C@H:16]2[C@@H:15]([C@:20]3([CH3:26])[C@H:19]([CH2:18][CH2:17]2)[CH2:24][C:23](=[O:25])[CH2:22][CH2:21]3)[CH2:14]1
Reactant: C[C@H](CCC(=O)O)[C@H]1CC[C@H]2[C@@H]3CC[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: C[C@H](CCC(=O)O)[C@H]1CC[C@H]2[C@@H]3CC[C@@H]4CC(=O)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Yield: 25.9 %

Procedure:
The above mixture of oxidation products of deoxycholic acid (310 mg) resulted from the eluate of chloroform-ethanol (97:3, v/v) was dissolved in a small amount of chloroform-ethanol (99:1, v/v) and the solution was absorbed on silica gel (20 g) column. The column was eluted with chloroform-ethanol (98:2, v/v) and then with chloroform-ethanol (97:3, v/v). Each 10 ml portions of the eluate was collected in a fraction tube. Fractions which showed a corresponding single spot by thin layer chromatography were combined and the solvent was distilled off by a rotary evaporator. As the results, 12α-hydroxy-3-keto-5β-cholanic acid (80 mg) was obtained from the first half of the fractions eluted with chloroform-ethanol (98:2, v/v) and 12α-hydroxy-3-keto-4-cholenic acid (10 mg) was obtained from the latter half thereof. 12α-Hydroxy-3-keto-5β-pregnan-20α-carboxylic acid (5 mg) was obtained from the first half of the fractions eluted with chloroform-ethanol (97:3, v/v) and 12α-hydroxy-3-keto-chola-1,4 -dienic acid (10 mg) was obtained from the latter half thereof.
Reaction SMILES: C[C:2]([C:4]1[CH:9]=[CH:8][C:7]([F:10])=[C:6]([Cl:11])[CH:5]=1)=[O:3].Br[O-].[Na+].S([O-])(O)=[O:16].[Na+].Cl>>[Cl:11][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=1[F:10])[C:2]([OH:3])=[O:16]
Reactant: O=S([O-])O
Reactant: CC(=O)c1ccc(F)c(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [O-]Br
Product: O=C(O)c1ccc(F)c(Cl)c1
Yield: 74 %

Procedure:
The 3-chloro-4-fluoroacetophenone is then reacted with an aqueous solution of sodium hypobromite, the aqeuous phase is treated with sodium hydrogensulfite and acidified with hydrochloric acid, and the precipitated product is recrystallized from benzene. 3-Chloro-4-fluorobenzoic acid obtained in a yield of 74%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:18](=[O:21])(=[O:20])[NH2:19])[C:10]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:5]([OH:7])=[O:6].Br[CH2:23][CH2:24][CH:25]=[CH2:26].C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)CC=C>[CH2:26]([NH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:18](=[O:21])(=[O:20])[NH2:19])[C:10]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:5]([OH:7])=[O:6])[CH2:25][CH:24]=[CH2:23]
Reactant: C=CCCBr
Reactant: Nc1cc(C(=O)O)cc(S(N)(=O)=O)c1Oc1ccccc1
Agent: C=CCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: C=CCCNc1cc(C(=O)O)cc(S(N)(=O)=O)c1Oc1ccccc1
Reaction time: 0.5 h
Yield: 35 %

Procedure:
A solution of 3-amino-4-phenoxy-5-sulfamylbenzoic acid (7.5 g), 4-bromo-1-butene (12 ml), and p-toluenesulfonic acid (500 mg) in 3-buten-1-ol (35 ml) was heated under reflux for 6 days. Most of the solvent was recovered by distillation. The concentrated solution was diluted with pet. ether and stirred for 1/2 hour. The ester of the product was collected (3.9 g) and hydrolyzed in 10% by weight methanolic KOH at room temperature. A second crop of 4.0 g was a mixture of the esters of starting material and product. These were not separated. The 3.9 g crop afforded 3.1 g (35%) of 3-(but-3-enylamino)-4-phenoxy-5-sulfamylbenzoic acid which was clean by tlc. Recrystallization from ether/pet. ether gave colorless crystals. The analytical sample was sublimed in vacuum. The product had mp 228°-32° (dec); ir (Nujol) 3350, 3200, 2600 (broad), 1680, 1610, 1585, 1540 and 1515 cm-1 ; nmr (CDCl3 /d6 -DMSO/D2O-washed) 2.17 (q, 2H), 3.13 (t, 2H), 3.13 (t, 2H), 4.6-6.0 (m, 3H, vinyl), 6.8-7.5 (m, C6H5), 7.55 (d, J=2, CH), and 7.95 ppm (d, CH); mass spectrum m/e 321 (100%) and 363 (M+).
Reaction SMILES: S(O)(O)(=O)=O.[CH:6]1[C:22]2[CH2:21][C@H:20]3[N:23]([CH2:25][CH2:26][C@@:12]45[C@H:19]3[CH:18]=[CH:17][C@H:15]([OH:16])[C@@H:13]4[O:14][C:10]([C:11]=25)=[C:8]([OH:9])[CH:7]=1)[CH3:24].[O:27]=[C:28]([O-:39])[C@@H:29]([C@H:31]([C@@H:33]([C@@H:35]([CH2:37][OH:38])[OH:36])[OH:34])[OH:32])[OH:30].[Na+]>>[O:27]=[C:28]([OH:39])[C@@H:29]([C@H:31]([C@@H:33]([C@@H:35]([CH2:37][OH:38])[OH:36])[OH:34])[OH:32])[OH:30].[CH:6]1[C:22]2[CH2:21][C@H:20]3[N:23]([CH2:25][CH2:26][C@@:12]45[C@H:19]3[CH:18]=[CH:17][C@H:15]([OH:16])[C@@H:13]4[O:14][C:10]([C:11]=25)=[C:8]([OH:9])[CH:7]=1)[CH3:24]
Reactant: O=C([O-])[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: CN1CC[C@]23c4c5ccc(O)c4O[C@H]2[C@@H](O)C=C[C@H]3[C@H]1C5
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: O=C(O)[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO

Procedure:
A pharmaceutical composition prepared according to claim 20, wherein morphine sulfate and sodium gluconate are dissolved in a suitable solvent to yield morphine gluconate.
Reaction SMILES: B(O)(O)[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.I[C:14]1[C:22]2[C:17](=[N:18][CH:19]=[N:20][C:21]=2[NH2:23])[N:16]([CH:24]([CH3:26])[CH3:25])[N:15]=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>[NH:6]1[C:7]2[C:3](=[C:2]([C:14]3[C:22]4[C:17](=[N:18][CH:19]=[N:20][C:21]=4[NH2:23])[N:16]([CH:24]([CH3:26])[CH3:25])[N:15]=3)[CH:10]=[CH:9][CH:8]=2)[CH:4]=[CH:5]1
Reactant: CC(C)n1nc(I)c2c(N)ncnc21
Reactant: OB(O)c1cccc2[nH]ccc12
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: CCO
Solvent: COCCOC
Product: CC(C)n1nc(-c2cccc3[nH]ccc23)c2c(N)ncnc21
Temperature: 80 °C
Yield: 50 %

Procedure:
A solution of 1H-indol-4-yl-4-boronic acid (40 mg, 0.25 mmol) in EtOH (1.65 ml) was added to a solution of 3-iodo-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (30 mg, 0.1 mmol) in DME (6 ml). Pd(PPh3)4 (30 mg, 0.03 mmol) and saturated Na2CO3 (0.95 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:0.1% TFA) to yield BA91 (14.6 mg, 50% yield). ESI-MS (M+H)+ m/z calcd 293.1, found 293.1.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16].O.[OH-].[Na+:20].[S:21]([O-:24])([O-:23])=[O:22].[Na+].[Na+]>C(O)CC>[Na+:20].[S:21]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O-:17])=[O:16])([OH:24])(=[O:23])=[O:22]
Reactant: O=C(O)CCCCCCCCCCCCCBr
Reactant: O=S([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCCO
Product: O=C([O-])CCCCCCCCCCCCCS(=O)(=O)O

Procedure:
Above prepared 14-bromo-tetradecanoic acid (8.34 g, 26.0 mmol) was dissolved in n-propanol (10 mL), water (25 mL) and 1M aqueous solution of sodium hydroxide (32 mL) and sodium sulfite (5.00 g, 39.7 mmol) was added. Reaction mixture was heated to reflux for 22 hrs. After cooling down white precipitate was filtered off. Conc. hydrochloric acid was added to give acidic pH and precipitate was centrifuged and decantated two times with water (2×50 ml). After lyophilization 14-sulfo-tetradecanoic acid sodium salt was obtained as a white solid.
Reaction SMILES: Cl.[CH3:2][O:3][NH2:4].[C:5](=[O:8])([O-])[O-].[K+].[K+].Cl.[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1CCl>O>[CH3:2][O:3][N:4]=[C:5]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][N:12]=1)[OH:8]
Reactant: O=C([O-])[O-]
Reactant: CON
Reactant: ClCc1ccccn1
Agent: Cl
Agent: [K+]
Solvent: O
Product: CON=C(O)c1ccccn1
Reaction time: 4 h
Yield: 69 %

Procedure:
6.8 g (0.08 mol) of an O-methylhydroxylamine hydrochloric acid salt was dissolved in 20 ml of water, and 22.4 g (0.16 mole) of potassium carbonate dissolved in 20 ml of water was dropwise added thereto at 0° C. 14.2 g (0.08 mol) of a picolinyl chloride hydrochloric acid salt was further added thereto, and the resulting solution was stirred at 0° to 10° C. for 4 hours. The reaction product thus obtained was extracted with methylene chloride several times. The organic phase was dried over anhydrous sodium sulfate to obtain 8.4 g of N-methoxypyridine-2-carboximidic acid.