Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[CH:12]/[C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=3)/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:22][Si:23]([CH3:30])([CH3:29])[CH2:24][CH2:25][O:26][CH2:27]Cl>CN(C)C=O.O1CCCC1>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[CH:12]/[C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=3)/[C:7](=[O:11])[N:8]2[CH2:27][O:26][CH2:25][CH2:24][Si:23]([CH3:30])([CH3:29])[CH3:22])=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: O=C1Nc2cc(Cl)ccc2/C1=C/c1cccc(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCN1C(=O)/C(=C\c2cccc(Cl)c2)c2ccc(Cl)cc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 90.3 %

Procedure:
To a solution of E/Z-6-chloro-3-(3-chloro-benzylidene)-1,3-dihydro-indol-2-one prepared in example 4a (2.3 g, 7.9 mmol) in N,N-dimethyl-formamide (20 mL) at 0° C. was added NaH (60% in mineral oil) (0.32 g, 7.9 mmol) (Aldrich), followed by the dropwise addition of 2-(trimethylsilyl)ethoxymethyl chloride (1.32 g, 7.9 mmol) in tetrahydrofuran (20 mL). The reaction mixture was stirred at 0° C. for 0.5 h, then poured into ice-water. The crude was extracted with ethyl acetate twice. The combined organic layer was dried over Na2SO4. The solvent was removed and the residue was purified by chromatography (EtOAc:hexanes=1:5) to give E/Z-6-chloro-3-(3-chloro-benzylidene)-1-(2-trimethylsilanyl-ethoxymethyl)-1,3-dihydro-indole-2-one as yellow oil (Yield 3.0 g, 90%).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]3[CH2:23][CH2:22][CH2:21][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[C-:25]#N.[K+]>C(O)C=C>[Cl:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]3[CH2:23][CH2:22][CH2:21][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:18][CH2:19][CH:20]=[CH2:25])=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: [C-]#N
Reactant: CCOC(=O)c1ncn2c1[C@@H]1CCCN1C(=O)c1c(Cl)cccc1-2
Agent: [K+]
Solvent: C=CCO
Product: C=CCOC(=O)c1ncn2c1[C@@H]1CCCN1C(=O)c1c(Cl)cccc1-2

Procedure:
A mixture of 6.9 g (0.02 mmol) of ethyl (S)-8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate, 100 ml of allyl alcohol and 0.5 g of potassium cyanide is heated to boiling ii under reflux for 4 hours, then concentrated to half of the volume, 50 ml of allyl alcohol are added and the resulting mixture is heated to boiling under reflux for a further 10 hours. The mixture is evaporated, the residue is dissolved in chloroform, the chloroform solution is washed with water, the chloroform phase is dried over magnesium sulphate and evaporated. The residue is chromatographed on silica gel while eluting with ethyl acetate and then crystallized from ethyl acetate/hexane. There is obtained allyl (S)-8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate of melting point 122-123°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.[S:23]1[CH:27]=[CH:26][CH:25]=[C:24]1[C:28](O)=[O:29].Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[CH:18][C:19]([NH:22][C:28]([C:24]2[S:23][CH:27]=[CH:26][CH:25]=2)=[O:29])=[CH:20][CH:21]=1
Reactant: O=C(O)c1cccs1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: COc1cc2nccc(Oc3ccc(NC(=O)c4cccs4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 62 h
Yield: 53.9 %

Procedure:
6,7-Dimethoxy-4-(4-aminophenoxy)quinoline (50 mg) and commercially available 2-thiophenecarboxylic acid (46 mg) were dissolved in N,N-dimethylformamide (2 ml), 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide hydrochloride (99 mg) was added, and the admixture was stirred at room temperature for 62 hours. The reaction mixture was then purified in the same manner as described in Example 51 to obtain 37 mg of the title compound (yield: 54%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:17][CH:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:35][C:36]1[S:40][C:39]2[CH:41]=[CH:42][C:43]([C:45]#[N:46])=[CH:44][C:38]=2[CH:37]=1>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])([CH2:35][C:36]2[S:40][C:39]3[CH:41]=[CH:42][C:43]([C:45]#[N:46])=[CH:44][C:38]=3[CH:37]=2)[C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:19][CH:20]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C(C(=O)OCC)c1ccc(OC[C@H]2CCCN2C(=O)OC(C)(C)C)cc1
Reactant: N#Cc1ccc2sc(CBr)cc2c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(Cc1cc2cc(C#N)ccc2s1)(C(=O)OCC)c1ccc(OC[C@H]2CCCN2C(=O)OC(C)(C)C)cc1
Reaction time: 0.5 h
Yield: 85.9 %

Procedure:
4.1 g of ethyl 2-[4-[((2R)-1-tert-butoxycarbonyl-2-pyrrolidinyl)methoxy]phenyl]-2-ethoxycarbonylacetate was dissolved in 100 ml of tetrahydrofuran. At room temperature, the thus prepared solution was mixed with 0.38 g of 60% sodium hydride and stirred for 30 minutes. With stirring at room temperature, to the resulting reaction solution was added dropwise 10 ml of a tetrahydrofuran solution containing 2.1 g of 2-bromomethylbenzo[b]-thiophene-5-carbonitrile. After concentrating the reaction solution to dryness, the resulting residue was purified by subjecting it to silica gel column chromatography using a toluene/chloroform mixture as an elution solvent, thereby obtaining 4.34 g of the title compound in an oily form.
Reaction SMILES: [NH2:1][C:2]1[N:3]([C:8]2[C:13]([Cl:14])=[CH:12][C:11]([Cl:15])=[CH:10][C:9]=2[Cl:16])[N:4]=[C:5]([CH3:7])[CH:6]=1.[C:17]([CH:20]1[CH2:25][CH2:24][O:23][C:21]1=[O:22])(=O)[CH3:18]>C(O)C>[CH3:7][C:5]1[CH:6]=[C:2]([NH:1]/[C:17](=[C:20]2/[C:21](=[O:22])[O:23][CH2:24][CH2:25]/2)/[CH3:18])[N:3]([C:8]2[C:13]([Cl:14])=[CH:12][C:11]([Cl:15])=[CH:10][C:9]=2[Cl:16])[N:4]=1
Reactant: Cc1cc(N)n(-c2c(Cl)cc(Cl)cc2Cl)n1
Reactant: CC(=O)C1CCOC1=O
Solvent: CCO
Product: C/C(Nc1cc(C)nn1-c1c(Cl)cc(Cl)cc1Cl)=C1/CCOC1=O
Yield: 49.7 %

Procedure:
3-Amino-2-(2,4,6-trichlorophenyl)-5-methylpyrazole (1 g, 3.62 mmol) was dissolved in ethanol (10 mL). α-Acetyl-γ-butyrolactone (0.409 mL, 3.80 mmol) was added, followed by heating under reflux for two days. After ethanol was evaporated, the residue was purified by silica gel column chromatography (10% ethyl acetate/hexane), to give the title compound (700 mg, 1.80 mmol) as a pale yellow oil.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[F:9][C:10]1[C:18]2[O:17][CH2:16][CH2:15][C:14]=2[C:13]([CH2:19][CH2:20][CH2:21][NH:22][C:23](=[O:25])[CH3:24])=[CH:12][CH:11]=1>C(O)(=O)C>[Cl:1][C:12]1[CH:11]=[C:10]([F:9])[C:18]2[O:17][CH2:16][CH2:15][C:14]=2[C:13]=1[CH2:19][CH2:20][CH2:21][NH:22][C:23](=[O:25])[CH3:24]
Reactant: CC(=O)NCCCc1ccc(F)c2c1CCO2
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC(=O)O
Product: CC(=O)NCCCc1c(Cl)cc(F)c2c1CCO2
Reaction time: 72 h

Procedure:
N-Chlorosuccinimide (47.7 mg) was added to a solution of N-[3-(7-fluoro-2,3-dihydro-benzofuran-4-yl)-propyl]-acetamide (77 mg) in glacial acetic acid (5 ml) at room temperature under nitrogen and the mixture stirred for 72 h. The solution was evaporated and the residue partitioned between sodium carbonate (2N; 10 ml) and ethyl acetate (10 ml). The combined organic extracts were washed with brine (10 ml) and dried (MgSO4). The solvent was evaporated and the residue purified by column chromatography. Eluting with dichloromethane/methanol 50:1 gave the title compound as a colourless gum which crystallised on standing (67 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][N:13]=[C:14]([C:17]([OH:19])=[O:18])[CH2:15][OH:16])[CH2:9][N:8]=[C:7]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:6]=2[CH:26]=1.[N+](=[CH2:29])=[N-]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][N:13]=[C:14]([C:17]([O:19][CH3:29])=[O:18])[CH2:15][OH:16])[CH2:9][N:8]=[C:7]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:6]=2[CH:26]=1
Reactant: O=C(O)C(CO)=NNC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1
Reactant: C=[N+]=[N-]
Product: COC(=O)C(CO)=NNC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1

Procedure:
In the manner given in Example 10, a solution of 7-chloro-2-[(1-carboxy-2-hydroxyethylidene)hydrazino]-5-phenyl-3H-1,4-benzodiazepine can be treated with ethereal diazomethane to give 7-chloro-2-[[1-(methoxycarbonyl)-2-hydroxyethylidene]hydrazino]-5-phenyl-3H-1,4-benzodiazepine.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:11][C:10]3[CH:22]=[CH:23][CH:24]=[N:25][C:9]2=3)[CH:5]=[CH:6][CH:7]=1.[C:26]1([N:36]=[C:37]=[O:38])[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28][CH:27]=1>O1CCOCC1>[C:26]1([NH:36][C:37](=[O:38])[NH:1][C:2]2[CH:3]=[C:4]([N:8]3[C:13](=[O:14])[C:12]([CH2:15][C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)=[N:11][C:10]4[CH:22]=[CH:23][CH:24]=[N:25][C:9]3=4)[CH:5]=[CH:6][CH:7]=2)[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28][CH:27]=1
Reactant: Nc1cccc(-n2c(=O)c(Cc3ccccc3)nc3cccnc32)c1
Reactant: O=C=Nc1cccc2ccccc12
Solvent: C1COCCO1
Product: O=C(Nc1cccc(-n2c(=O)c(Cc3ccccc3)nc3cccnc32)c1)Nc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 4-(3-aminophenyl)-2-benzyl-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (150 mg) and 1-naphthyl isocyanate (94 mg) in dry dioxane (3 ml) was stirred at room temperature for 3 hours. The precipitates were collected and washed with isopropyl ether to give 4-[3-[3-(1-naphthyl)ureido]phenyl]-2-benzyl-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine.
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].[CH2:10]=[C:11]([CH2:14][CH2:15][C:16]#[N:17])[C:12]#[N:13]>>[C:1]1([S:7][CH2:10][CH:11]([CH2:14][CH2:15][C:16]#[N:17])[C:12]#[N:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Sc1ccccc1
Reactant: C=C(C#N)CCC#N
Agent: [Na+]
Agent: [OH-]
Product: N#CCCC(C#N)CSc1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of thiophenol (3.63 g.), 2N aqueous sodium hydroxide (25 ml.) and 2-methyleneglutaronitrile (3.2 g.) was stirred at room temperature for 18 hours. The mixture was extracted with diethyl ether, and the ether extract washed with water and then dried and evaporated to dryness to give 2-(phenylthiomethyl)glutaronitrile which was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[CH:3]=1.C(O)(=O)C.[N:20](OC(C)(C)C)=O>C1COCC1>[CH3:1][C:2]1[N:7]=[CH:6][C:5]2[N:8]=[N:20][N:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=3)[C:4]=2[CH:3]=1
Reactant: CC(C)(C)ON=O
Reactant: Cc1cc(Nc2ccccn2)c(N)cn1
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: Cc1cc2c(cn1)nnn2-c1ccccn1
Reaction time: 8 h
Yield: 71.5 %

Procedure:
To a solution of 6-methyl-N4-(pyridin-2-yl)pyridine-3,4-diamine (550 mg, 2.7 mmol) in THF (30 mL) was added acetic acid (0.17 mL, 6.49 mmol) and tert-butyl nitrite (0.54 mL, 4.12 mmol). The reaction was then heated to reflux and stirred overnight. The reaction was concentrated and the residue was purified by chromatography on silica gel (0-10% [2M NH3 in MeOH]CH2Cl2) to give the desired product as a yellow gum (408 mg, 70%). MS (ESI) mass calcd. C11H9N5, 211.09. m/z found, 212.1 [M+H]+. 1H NMR (500 MHz, CDCl3) δ 9.44 (d, J=0.9, 1H), 8.67-8.62 (m, 1H), 8.37 (s, 1H), 8.31-8.23 m, 1H), 8.01-7.96 (m, 1H), 7.41-7.35 (m, 1H), 2.80 (s, 3H).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])=O.C(=O)([O-])[O-].[K+].[K+].C(OP([CH2:27][C:28]#[N:29])(=O)OCC)C.O>O1CCCC1>[C:28]([CH:27]=[CH:1][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])#[N:29]
Reactant: CCOP(=O)(CC#N)OCC
Reactant: COC(=O)c1cccc(C=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1cccc(C=CC#N)c1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 3-formylbenzoate (2.00 g, 12.2 mmol) in tetrahydrofuran (20 mL) were added potassium carbonate (2.02 g, 14.6 mmol), diethyl(cyanomethyl)phosphonate (2.29 mL, 14.6 mmol) and water (0.4 mL), and the mixture was stirred at 60° C. for 1 hr. To the reaction mixture was added water (50 mL), and the mixture was extracted with ethyl acetate (50 mL, 20 mL). The combined organic layer was washed with saturated brine (10 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give methyl 3-(2-cyanoethenyl)benzoate as a white solid. The obtained compound was used for the next reaction without further purification.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5](B2OC(C)(C)C(C)(C)O2)[CH:4]=[N:3]1.Cl[C:17]1[CH:22]=[C:21]([O:23][C:24]2[C:25]([CH2:33][CH3:34])=[N:26][C:27]([N+:30]([O-:32])=[O:31])=[CH:28][CH:29]=2)[CH:20]=[CH:19][N:18]=1.C([O-])([O-])=O.[K+].[K+]>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>[CH2:33]([C:25]1[C:24]([O:23][C:21]2[CH:22]=[CH:17][N:18]=[C:19]([C:5]3[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=3)[CH:20]=2)=[CH:29][CH:28]=[C:27]([N+:30]([O-:32])=[O:31])[N:26]=1)[CH3:34]
Reactant: CCc1nc([N+](=O)[O-])ccc1Oc1ccnc(Cl)c1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CCc1nc([N+](=O)[O-])ccc1Oc1ccnc(-c2cnn(C)c2)c1
Temperature: 80 °C
Reaction time: 24 h
Yield: 100 %

Procedure:
A mixture of 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (863 mg, 4.15 mmol), 3-((2-chloropyridin-4-yl)oxy)-2-ethyl-6-nitropyridine (892 mg, 3.19 mmol), K2CO3 (1.322 mg, 9.57 mmol) and Pd(PPh3)4 (184 mg, 0.159 mmol) in dioxane (6 mL) and water (1.5 mL) was sparged with Ar, heated at 80° C. for 24 h, then cooled to RT and stirred for 24 h. The mixture was treated with EtOAc, washed with satd. NaHCO3 (1×), then brine (1×), dried over Na2SO4 and concentrated to dryness to afford 2-ethyl-3-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)-6-nitropyridine (100% yield assumed) as a thick oil. Material carried on to the next step without purification. MS (ESI) m/z: 326.1 (M+H+).
Reaction SMILES: [CH3:1][N:2]1[C@@H:12]2[CH2:13][C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[C:16]4[O:21][C@H:6]5[C:7]([CH:9]=[CH:10][C@:11]2([OH:22])[C@:5]5([C:15]=34)[CH2:4][CH2:3]1)=[O:8].[CH:23]1(C=O)[CH2:25][CH2:24]1.C([O-])=O.[NH4+]>C(O)(C)C>[CH2:23]1[CH:25]([CH2:1][N:2]2[C@@H:12]3[CH2:13][C:14]4[CH:19]=[CH:18][C:17]([OH:20])=[C:16]5[O:21][C@H:6]6[C:7]([CH2:9][CH2:10][C@:11]3([OH:22])[C@:5]6([C:15]=45)[CH2:4][CH2:3]2)=[O:8])[CH2:24]1
Reactant: O=CC1CC1
Reactant: CN1CC[C@]23c4c5ccc(O)c4O[C@H]2C(=O)C=C[C@@]3(O)[C@H]1C5
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CC(C)O
Product: O=C1CC[C@@]2(O)[C@H]3Cc4ccc(O)c5c4[C@@]2(CCN3CC2CC2)[C@H]1O5
Temperature: 25 °C
Reaction time: 24 h
Yield: 87.5 %

Procedure:
A round bottom flask was charged with noroxymorphone (2.19 g, 0.008 moles), isopropanol (20 mL), and cyclopropanecarboxaldehyde (1.07 g, 0.02 moles, 0.91 mL). Ammonium formate (2.40 g, 0.038 moles) was added. To this solution was added RuCl3 (anhydrous)(10 mg, 0.05 mmole). The reaction mixture was stirred at room temperature for 24 h. HPLC analysis indicated the reaction was complete. To the reaction mixture was added distilled water (1.0 mL) and the mixture was stirred for 16 h at room temperature. Then, the reaction mixture was transferred to a round bottom flask and evaporated under reduced pressure leaving a semi solid. To the semi solid was added distilled water (10 mL). To this solution was added 29% NH3/H2O (˜5 mL) adjusting the pH from 7.0 to 9.4. A white precipitate formed. The precipitate was filtered, washed with distilled water (10 mL), and dried for 16 h at 95° C. yielding (−)-naltrexone (2.35 g, 0.007 moles, 91% yield) as an off white solid.
Reaction SMILES: C1C[C@H](C(O)=O)CC[C@H]1CN.[CH3:12][CH:13]([CH3:33])[C:14]([O:16][C@@H:17]([O:19][C:20]([NH:22][CH2:23][C@H:24]1[CH2:29][CH2:28][C@H:27]([C:30]([OH:32])=[O:31])[CH2:26][CH2:25]1)=[O:21])[CH3:18])=[O:15].C(=O)(O)[O-].[Na+:38].C(#N)C>O>[CH3:12][CH:13]([CH3:33])[C:14]([O:16][C@@H:17]([O:19][C:20]([NH:22][CH2:23][C@H:24]1[CH2:25][CH2:26][C@H:27]([C:30]([O-:32])=[O:31])[CH2:28][CH2:29]1)=[O:21])[CH3:18])=[O:15].[Na+:38]
Reactant: CC(C)C(=O)O[C@H](C)OC(=O)NC[C@H]1CC[C@H](C(=O)O)CC1
Agent: NC[C@H]1CC[C@H](C(=O)O)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CC(C)C(=O)O[C@H](C)OC(=O)NC[C@H]1CC[C@H](C(=O)[O-])CC1

Procedure:
Following the general procedure for the formation of the corresponding sodium carboxylates of acyloxyalkyl carbamates of tranexamic acid, 90.0 mg (0.2854 mmol) of (+)-trans-4-({[(1S)-1-(2-methylpropanoyloxy)ethoxy]carbonylamino}methyl)-cyclohexanecarboxylic acid 15 was reacted with 24.0 mg (0.2854 mmol) of sodium bicarbonate (NaHCO3) in 4 mL of a mixture of acetonitrile and water (1:1) to yield 96.3 mg (quant.) of the title compound 16 as a colorless powder. The enantiomeric excesses were determined with an analytical Waters 2690/ZQ LC/MS apparatus using a ChiralPak AD-RH column, an isocratic eluent consisting of 30% acetonitrile/70% water/0.05% formic acid, and a flowrate of 60 μL/min (Rf=12.1 min; e.e. =98.5%). 1H NMR (400 MHz, DMSO-d6): δ=0.72-0.84 (br. m, 2H), 1.057 (d, J=6.4 Hz, 3H), 1.059 (d, J=6.8 Hz, 3H), 1.20-1.32 (br. m, 3H), 1.38 (d, J=5.2 Hz, 3H), 1.59-1.73 (br. m, 3H), 1.75-1.83 (m, 2H), 2.43-2.53 (m, 1H), 2.72-2.84 (br. m, 2H), 6.62 (q, J=5.6 Hz, 1H), 7.42 (t, J=5.6 Hz, 1H). MS (ESI) m/z 338.16 (M+Na)+; 314.12 (M−H)−.
Reaction SMILES: [OH-].[NH4+:2].[C:3]([C:10]1[S:14][C:13]([N+:15]([O-:17])=[O:16])=[C:12]([S:18](Cl)(=[O:20])=[O:19])[C:11]=1[CH2:22][NH:23][S:24]([CH3:27])(=[O:26])=[O:25])([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4]>C(#N)C>[C:3]([C:10]1[S:14][C:13]([N+:15]([O-:17])=[O:16])=[C:12]([S:18]([NH2:2])(=[O:20])=[O:19])[C:11]=1[CH2:22][NH:23][S:24]([CH3:27])(=[O:26])=[O:25])([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4]
Reactant: CC(C)(C)OC(=O)c1sc([N+](=O)[O-])c(S(=O)(=O)Cl)c1CNS(C)(=O)=O
Reactant: [NH4+]
Agent: [OH-]
Solvent: CC#N
Product: CC(C)(C)OC(=O)c1sc([N+](=O)[O-])c(S(N)(=O)=O)c1CNS(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 84 %

Procedure:
Concentrated aqueous ammonium hydroxide solution (3 mL) was added to a solution of Boc-4-(methanesulfonylamino-methyl)-2-nitro-thiophene-3-sulfonyl chloride (3.30 g, 7.59 mmol) in acetonitrile (90 mL) at 0° C. The mixture was stirred at 0° C. for 45 min, and then was partitioned between half-saturated aqueous sodium bicarbonate solution (150 mL) and ethyl acetate (2×150 mL). The combined organic layers were dried over sodium sulfate, filtered and were concentrated in vacuo. Purification of the residue by flash column chromatography (Teledyne Isco RediSep column; 20-90% ethyl acetate in hexanes) afforded the desired product, Boc-4-(methanesulfonylamino-methyl)-2-nitro-thiophene-3-sulfonic acid amide (2.64 g, 6.35 mmol, 84%), as a yellow solid. 1H NMR (400 MHz, CDCl3) δ: 1.54 (9H, s), 3.35 (3H, s), 5.12 (2H, s), 5.81 (2H, bs), 7.61 (1H, s).
Reaction SMILES: C[O:2][C:3](=[O:33])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:18](=[S:19])[N:17]([C:20]3[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[C:22]([C:28]([F:31])([F:30])[F:29])[CH:21]=3)[C:16](=[O:32])[C:12]32[CH2:15][CH2:14][CH2:13]3)=[CH:7][CH:6]=1.[OH-].[Na+]>CO>[C:26]([C:23]1[CH:24]=[CH:25][C:20]([N:17]2[C:16](=[O:32])[C:12]3([CH2:13][CH2:14][CH2:15]3)[N:11]([C:8]3[CH:7]=[CH:6][C:5]([CH2:4][C:3]([OH:33])=[O:2])=[CH:10][CH:9]=3)[C:18]2=[S:19])=[CH:21][C:22]=1[C:28]([F:30])([F:31])[F:29])#[N:27]
Reactant: COC(=O)Cc1ccc(N2C(=S)N(c3ccc(C#N)c(C(F)(F)F)c3)C(=O)C23CCC3)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: N#Cc1ccc(N2C(=O)C3(CCC3)N(c3ccc(CC(=O)O)cc3)C2=S)cc1C(F)(F)F
Yield: 95 %

Procedure:
A mixture of {4-[7-(4-cyano-3-trifluoromethylphenyl)-8-oxo-6-thioxo-5,7-diaza-spiro[3.4]oct-5-yl]phenyl}acetic acid methyl ester (46b) (0.095 g, 0.2 mmol) and a solution of sodium hydroxide (1 ml, 2M) in methanol (2 ml) was stirred at room temperature for 2 hours. The methanol was evaporated. The residue was adjusted to pH 5 by aq. 2M HCl and then the mixture was extracted with ethyl acetate (3×10 ml). The organic layer was dried over MgSO4 and concentrated to dryness to obtain {4-[7-(4-cyano-3-trifluoromethylphenyl)-8-oxo-6-thioxo-5,7-diaza-spiro[3.4]oct-5-yl]phenyl}acetic acid (46c) [RD147] (0.087 g, 0.19 mmol, 95%), the structure of which is illustrated in Formula 16.
Reaction SMILES: [CH2:1]([N:4]([CH2:19][CH2:20][CH3:21])[CH2:5][CH2:6][CH2:7][CH2:8][NH:9][CH2:10][C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=1)[CH2:2][CH3:3].C=O.[CH:24](O)=O.[OH-].[Na+]>O.C(O)C>[CH2:19]([N:4]([CH2:1][CH2:2][CH3:3])[CH2:5][CH2:6][CH2:7][CH2:8][N:9]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([C:15]#[N:16])=[CH:17][CH:18]=1)[CH3:24])[CH2:20][CH3:21]
Reactant: O=CO
Reactant: CCCN(CCC)CCCCNCc1ccc(C#N)cc1
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCN(CCC)CCCCN(C)Cc1ccc(C#N)cc1
Yield: 94.8 %

Procedure:
16 g (56 mmol, 1.0 equivalent) of 4-[(4-dipropylaminobutyl)amino]methylbenzonitrile (2a), 50 ml of ethanol, 11.9 g (139 mmol, 2.5 equivalents) of a formaldehyde aqueous solution (35%), and 12.8 g (278 mmol, 5 equivalents) of formic acid were charged in a 300 ml four-necked flask. The mixture was reacted at 80° C. for one hour. The raw material was then disappeared. The reaction solution was slowly added to a solution prepared by dissolving 40 g of sodium hydroxide in 200 ml of distilled water. The reaction solution was extracted with 200 ml of chloroform. This operation was repeated twice. The chloroform layer was then dried over anhydrous sodium sulfate. The solvent was then concentrated, thereby obtaining 16 g of 4-[(4-dipropylaminobutyl)methylamino]methylbenzonitrile (2b) as a slightly yellow oily substance (yield: 95%). [HPLC: 99% (HPLC measurement conditions A)]
Reaction SMILES: [CH2:1]([C:5]1[CH:12]=[CH:11][C:10]([CH:13]([CH3:15])[CH3:14])=[CH:9][C:6]=1[CH2:7][Cl:8])[CH:2]([CH3:4])[CH3:3].[Br:16]Br>[Fe].C(Cl)(Cl)(Cl)Cl>[Br:16][C:11]1[C:10]([CH:13]([CH3:15])[CH3:14])=[CH:9][C:6]([CH2:7][Cl:8])=[C:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[CH:12]=1
Reactant: CC(C)Cc1ccc(C(C)C)cc1CCl
Reactant: BrBr
Agent: [Fe]
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)Cc1cc(Br)c(C(C)C)cc1CCl

Procedure:
In a flask are placed 225 parts of 2-isobutyl-5-isopropylbenzyl chloride, 300 parts of carbon tetrachloride and 2.5 parts of iron powder. Bromine (160 parts) in 100 parts of carbon tetrachloride is added dropwise during 7 hr. The solution is washed twice with hydrochloric acid then with sodium bicarbonate solution, dilute sodium bisulfite solution, and water. The solution is dried, the carbon tetrachloride removed, and the 4-bromo-2-isobutyl-5-isopropylbenzyl chloride distilled under reduced pressure.