Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:3][C@@H:2]1[CH2:4][O:5][C:6]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[CH:8]=[CH:9][CH:10]=[N:11]2.[Cl:16][C:17]1[CH:25]=[C:24]2[C:20]([CH:21]=[C:22](C3CCNCC=3)[NH:23]2)=[CH:19][CH:18]=1.[CH2:32](O)[CH3:33]>CS(C)=O>[Cl:16][C:17]1[CH:25]=[C:24]2[C:20]([C:21]([C:8]3[CH2:9][CH2:10][N:11]([CH2:3][C@@H:2]([OH:1])[CH2:4][O:5][C:6]4[CH:15]=[CH:14][CH:13]=[C:12]5[C:7]=4[CH:8]=[CH:9][CH:10]=[N:11]5)[CH2:32][CH:33]=3)=[CH:22][NH:23]2)=[CH:19][CH:18]=1
Reactant: Clc1ccc2cc(C3=CCNCC3)[nH]c2c1
Reactant: c1cc(OC[C@H]2CO2)c2cccnc2c1
Reactant: CCO
Solvent: CS(C)=O
Product: O[C@@H](COc1cccc2ncccc12)CN1CC=C(c2c[nH]c3cc(Cl)ccc23)CC1

Procedure:
The title compound was prepared in a fashion similar to that described in Example 1 using (R)-5-(oxiranylmethoxy)quinoline (0.495 g, 2.46 mmol) and 6-chloro-2-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (0.519 g, 2.33 mmol) using ethanol as reaction solvent. Yield 0.840 g (87%) of a tan powder. FDMS m/e=433 (M+ of free base). mp 221°-223° C. α[D]589 =-9.9 (c=1.00, dimethylsulfoxide).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=[CH:15][CH:14]=1.C(=O)(O)[O-].[Na+].[N+]([O-])(O)=O.CC1C=C(C)[N:35]([C:39](N)=[NH:40])N=1>C(O)C>[NH:1]([C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=[CH:15][CH:14]=1)[C:39]([NH2:40])=[NH:35]
Reactant: Nc1ccc2c(c1)C(=Cc1ccnc3ccccc13)C(=O)N2
Reactant: Cc1cc(C)n(C(=N)N)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O=[N+]([O-])O
Product: N=C(N)Nc1ccc2c(c1)C(=Cc1ccnc3ccccc13)C(=O)N2
Yield: 50 %

Procedure:
A mixture of 5-amino-3-(quinol-4-ylmethylene)-2-oxindole (2.873 g, 10 mmol) and sodium bicarbonate (0.168 g, 2 mmol) in refluxing ethanol (100 ml) was treated with 3,5-dimethylpyrazole-1-carboxamidine nitrate (3.018 g, 15 mmol) for 20 h. The solvent was removed from the cooled solution, and the residue was chromatographed on silica gel with gradient elution (1 to 5% EtOH in CHCl3) to afford pure title compound in about 50% yield.
Reaction SMILES: [OH-].[Li+].CC1(C)[O:9][C:8](=[O:10])[C:7]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=2)([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)[C:6](=[O:31])[O:5]1.O1CCCC1.O.Cl>O>[N+:18]([C:15]1[CH:14]=[CH:13][C:12]([CH2:11][C:7]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=2)([C:6]([OH:31])=[O:5])[C:8]([OH:10])=[O:9])=[CH:17][CH:16]=1)([O-:20])=[O:19]
Reactant: CC1(C)OC(=O)C(Cc2ccc([N+](=O)[O-])cc2)(Cc2ccc([N+](=O)[O-])cc2)C(=O)O1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C(Cc1ccc([N+](=O)[O-])cc1)(Cc1ccc([N+](=O)[O-])cc1)C(=O)O

Procedure:
2.185 g (52.07 mmol) of lithium hydroxide were added to a suspension of 10.79 g (26.04 mmol) of 2,2-dimethyl-5,5-bis(4-nitrobenzyl)-1,3-dioxane-4,6-dione and 110 ml mixture of tetrahydrofuran:water 9:1. The mixture was subsequently allowed to react for 21.5 hours at 25° C., added to 500 ml water and acidified to pH=1 with 20 ml hydrochloric acid 3N. The mixture was partitioned between water and ethyl acetate; the organic phase was washed repeatedly with water, dried over sodium sulfate, filtered and concentrated by rotary evaporation. The residue 9.54 g (98%) of 2,2-bis(4-nitrobenzyl)malonic acid as white powder was used without further purification.
Reaction SMILES: [CH:1]([NH:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:6][C:5]=1[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([CH3:23])([CH3:22])[CH3:21])[CH:15]=1)=O.C([O:28]OC(C)(C)C)(C)(C)C>ClC1C=CC=CC=1>[C:10]([CH:7]1[CH:8]=[CH:9][C:4]2[C:5](=[C:14]3[C:19](=[CH:1][N:3]=2)[CH:18]=[CH:17][C:16]([C:20]([CH3:21])([CH3:22])[CH3:23])=[CH:15]3)[C:6]1=[O:28])([CH3:12])([CH3:11])[CH3:13]
Reactant: CC(C)(C)c1cccc(-c2cc(C(C)(C)C)ccc2NC=O)c1
Reactant: CC(C)(C)OOC(C)(C)C
Solvent: Clc1ccccc1
Product: CC(C)(C)c1ccc2cnc3c(c2c1)C(=O)C(C(C)(C)C)C=C3
Temperature: 110 °C

Procedure:
The above compound, N-formyl-2-amino-3′,5-di-t-butyl biphenyl (6.5 g, 21 mmol) was dissolved into 50 mL of chlorobenzene to which 5 equivalents of di-t-butyl peroxide was added. The reaction mixture was heated to 110° C. for 72 hours. The reaction mixture was concentrated in half and cooled to 0° C. The precipitate that formed was collected by vacuum filtration. The off-white solid was washed with hexanes to give 2,9-di-tert-butylphenanthridinone as determined by GCMS and not purified any further.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[NH:15][C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1)=[CH:12][C:11]([F:22])=[CH:10][CH:9]=2)=[O:5])[CH3:2].[CH3:23]C(C)([O-])C.[K+].O1CCCC1.[Cl-].[NH4+]>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:23])[C:8]2[C:13]([C:14]=1[NH:15][C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1)=[CH:12][C:11]([F:22])=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1[nH]c2ccc(F)cc2c1Nc1ccncc1
Reactant: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(Nc2ccncc2)c2cc(F)ccc2n1C
Temperature: 0 °C
Reaction time: 1 h
Yield: 30 %

Procedure:
Stir at 0° C., a solution of 5-fluoro-3-(4-pyridinylamino)-1H-indole-2-carboxylic ethyl ester (0.195 mg, 0.65 mmol) in dimethylformamide (3.0 mL) and add a solution of 1M potassium tert-butoxide in tetrahydrofuran (0.8 mL, 0.8 mmol). Stir for 0.5 to 1 h at 0° C. and add lodomethane (0.05 mL, 0.78 mmol). After 1 h, add saturated aqueous ammonium chloride solution (5 mL) and ethyl acetate (10 mL). Separate the layers and reextract with ethyl acetate. Combine the organic layers and wash with water (3×'s), brine and dry with MgSO4. Concentrate the extract to obtain 60 mg (30%) of the title compound as a brown solid: ESI/MS 314 (M+H); HPLC: Rt=1.50 min.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24]([C:26]4[C:27](Cl)=[N:28][CH:29]=[CH:30][CH:31]=4)=[O:25])=[CH:19][CH:18]=3)=[O:16])[CH2:6][C:5]=12.C([O-])([O-])=O.[K+].[K+].[CH3:39][NH2:40].O>CS(C)=O>[CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24]([C:26]4[C:27]([NH:40][CH3:39])=[N:28][CH:29]=[CH:30][CH:31]=4)=[O:25])=[CH:19][CH:18]=3)=[O:16])[CH2:6][C:5]=12
Reactant: O=C(Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1)c1cccnc1Cl
Reactant: CN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CNc1ncccc1C(=O)Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1

Procedure:
A mixture of 1 g of N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H) -ylcarbonyl)phenyl]-2-chloropyridine-3-carboxamide, 1 g of K2CO3 and 10 ml of a 40% solution of monomethylamine is heated in 25 ml of dimethylsulfoxide for 8 hours at 100° C. The reaction mixture is poured over water and the pale yellow solid separated. The reaction mixture is filtered and the collected solid washed well with water. After drying the solid is purified by column chromatography on silica gel by elution with 9:1 ethyl acetate:methanol to give 850 mg of the desired product as a pale yellow solid:M+ =437.
Reaction SMILES: [CH3:1][S:2][CH:3]1[NH:6][C:5](=[O:7])[CH2:4]1.[H-].[Na+].Br[CH2:11][C:12]([O:14][CH3:15])=[O:13]>CN(C)C=O.O>[CH3:1][S:2][CH:3]1[N:6]([CH2:11][C:12]([O:14][CH3:15])=[O:13])[C:5](=[O:7])[CH2:4]1
Reactant: CSC1CC(=O)N1
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CN1C(=O)CC1SC
Yield: 63.4 %

Procedure:
4-Methylthioazetidin-2-one (2.34 g, 20 mmole) was dissolved in dry dimethylformamide (40 ml) and treated at 0°-5° C. with sodium hydride (20 mmole). After 3 minutes methyl bromoacetate (3.37 g, 22 mmole) dissolved in dry dimethylformamide (20 ml) was added and the reaction mixture stirred for 3/4 hour at 0°-5° C. After diluting with water (300 ml), the mixture was extracted with ethyl acetate (3×100 ml) and the extracts combined, washed with water, dried (MgSO4) and evaporated. Chromatography of the residue on silica gel eluting with 30% ethyl acetate in petrolether provided methyl (4-methylthio-2-oxoazetidin-1-yl)acetate (2.4 g, 62%) as a mobile liquid. νmax (CHCl3): 1760 (b), 1410, 1240, 1185 cm-1 ; δ(CDCl3): 2.13 (s, 3H, SCH3); 2.95-3.75 (2H, AB of ABX, CH2); 3.88 (s, 3H, OCH3); 3.93 and 4.23 (2H, main peaks of ABq, J=18 Hz, NCH2) and 5.02 (1H, X of ABX, CH).
Reaction SMILES: C(N(C(C)C)CC)(C)C.[CH3:10][C@H:11]1[O:16][C@H:15]([CH3:17])[CH2:14][NH:13][CH2:12]1.[F:18][C:19]1([F:38])[CH2:22][N:21]([C:23]([C:25]2[C:29]3[CH:30]=[C:31]([CH:36]=[O:37])[C:32](F)=[C:33]([F:34])[C:28]=3[O:27][N:26]=2)=[O:24])[CH2:20]1>C(#N)C.O.[Cl-].[Na+].O>[F:38][C:19]1([F:18])[CH2:20][N:21]([C:23]([C:25]2[C:29]3[CH:30]=[C:31]([CH:36]=[O:37])[C:32]([N:13]4[CH2:14][C@@H:15]([CH3:17])[O:16][C@H:11]([CH3:10])[CH2:12]4)=[C:33]([F:34])[C:28]=3[O:27][N:26]=2)=[O:24])[CH2:22]1
Reactant: C[C@@H]1CNC[C@@H](C)O1
Reactant: O=Cc1cc2c(C(=O)N3CC(F)(F)C3)noc2c(F)c1F
Agent: [Cl-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: C[C@@H]1CN(c2c(C=O)cc3c(C(=O)N4CC(F)(F)C4)noc3c2F)C[C@@H](C)O1
Temperature: 25 °C

Procedure:
Diisopropylethylamine (1.432 ml, 8.20 mmol) and (2R,6R)-2,6-dimethylmorpholine (1.027 ml, 8.20 mmol) were added to a solution of 3-(3,3-difluoroazetidine-1-carbonyl)-6,7-difluorobenzo[d]isoxazole-5-carbaldehyde (Intermediate 241, 1.906 g, 6.31 mmol) in acetonitrile (50 ml). The reaction was stirred at reflux for 20 hours. The reaction was cooled to room temp, diluted with water and brine and extracted twice with ethyl acetate. The organic layers were combined, dried over MgSO4 and concentrated. The residue was purified by silica gel column chromatography using a gradient of DCM to ethyl acetate. Fractions were combined and concentrated to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([OH:8])[CH:5]=[C:4]([NH2:9])[N:3]=1.C([O-])(=O)C.[Na+].Br[CH2:16][C:17]([C:19]1[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][CH:20]=1)=O>O.CO>[NH2:1][C:2]1[N:7]=[C:6]([OH:8])[C:5]2[CH:16]=[C:17]([C:19]3[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][CH:20]=3)[NH:9][C:4]=2[N:3]=1
Reactant: Nc1cc(O)nc(N)n1
Reactant: COC(=O)c1ccc(C(=O)CBr)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)c1ccc(-c2cc3c(O)nc(N)nc3[nH]2)cc1
Temperature: 100 °C
Reaction time: 18 h

Procedure:
A solution of 2,6-diamino-4-hydroxypyrimidine (CAS: 56-06-4, 1 g, 7.93 mmol) and sodium acetate (0.85 g, 10.32 mmol) in water (180 mL) was stirred at 100° C. for 30 minutes. Methyl 4-(2-bromoacetyl)benzoate (2.24 g, 8.72 mmol) was suspended in MeOH (25 mL) and was added slowly to the above solution. The reaction mixture was then stirred at 100° C. for 16-20 h and then cooled to room temperature. The residue was filtered and dried. It was then stirred in CH2Cl2 (10 mL) and filtered to provide XI-8-I (1.07 g, 47.5%). LCMS: m/z 285 (M+1)+.
Reaction SMILES: [C:1]12([C:11](Cl)=[O:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[F:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1.C(N(CC)CC)C>C(OCC)C>[F:14][C:15]1[CH:21]=[CH:20][C:18]([NH:19][C:11]([C:1]23[CH2:10][CH:5]4[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]4)[CH2:2]2)[CH2:8]3)=[O:12])=[CH:17][CH:16]=1
Reactant: Nc1ccc(F)cc1
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(F)cc1)C12CC3CC(CC(C3)C1)C2

Procedure:
Subject 2.29 g. of adamantane carboxylic acid chloride (11.5 mmoles) 1.11 g. (10 mmoles) of p-fluoro-aniline and 4.0 ml. of triethylamine to the process of Example 11. Crystallize the residue obtained thereby from ethyl ether to yield the title product, m.p. 170°-171°C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[CH3:11].FC1C=C([N+]([O-])=O)C=CC=1CBr.FC1C=C([N+]([O-])=O)C=CC=1CP(=O)(OCC)OCC.CC1(C)[O:48][CH:47]([CH2:49][O:50][C:51]2[CH:58]=[CH:57][C:54]([CH:55]=O)=[CH:53][CH:52]=2)[CH2:46][O:45]1>>[OH:48][CH:47]([CH2:46][OH:45])[CH2:49][O:50][C:51]1[CH:58]=[CH:57][C:54]([CH:55]=[CH:11][C:3]2[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=2[F:1])=[CH:53][CH:52]=1
Reactant: CC1(C)OCC(COc2ccc(C=O)cc2)O1
Reactant: Cc1ccc([N+](=O)[O-])cc1F
Agent: CCOP(=O)(Cc1ccc([N+](=O)[O-])cc1F)OCC
Agent: O=[N+]([O-])c1ccc(CBr)c(F)c1
Product: O=[N+]([O-])c1ccc(C=Cc2ccc(OCC(O)CO)cc2)c(F)c1

Procedure:
2-Fluoro-4-nitrotoluene (commercially available) was converted with the use of N-bromosuccimimide into the intermediate 2-fluoro-4-nitrobenzyl bromide, and subsequently into diethyl 2-fluoro-4-nitrobenzylphosphonate, in accordance with the specification of D. H. Wadsworth et al. in the Journal of Organic Chemistry, Vol. 30 (1965) p. 680-685. The title compound was prepared by the same procedure as described in Example 2. Making use of 23.6 g of 4-((2,2-dimethyl-1,3-dioxa-4-cyclopentyl)methyloxy)benzaldehyde and 29.1 g of diethyl 2-fluoro-4-nitrobenzyl phosphonate there were obtained in all 21 g of 4-(2,3-dihydroxypropyloxy)-2'-fluoro-4'nitrostilbene with a melting point of 110° C. and a clearing temperature of 129° C.
Reaction SMILES: [F:1][C:2]1([F:25])[CH2:6][CH2:5][C@@H:4]([C@@:7]([OH:24])([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[C:8]([O:10][CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[O:9])[CH2:3]1.[CH:26](=O)[CH3:27].C([BH3-])#N.[Na+]>CO.C(Cl)(Cl)Cl>[F:25][C:2]1([F:1])[CH2:6][CH2:5][C@@H:4]([C@@:7]([OH:24])([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[C:8]([O:10][CH:11]2[CH2:12][CH2:13][N:14]([CH2:26][CH3:27])[CH2:15][CH2:16]2)=[O:9])[CH2:3]1
Reactant: O=C(OC1CCNCC1)[C@](O)(c1ccc(Cl)cc1)[C@@H]1CCC(F)(F)C1
Reactant: CC=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCN1CCC(OC(=O)[C@](O)(c2ccc(Cl)cc2)[C@@H]2CCC(F)(F)C2)CC1
Reaction time: 2 h

Procedure:
To a solution of 25 mg of piperidin-4-yl (2R)-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(4-chlorophenyl)ethanoate in 1 ml of methanol, 50 mg of acetaldehyde and 10 mg of sodium cyanoborohydride were added at room temperature, followed by two hours' stirring at the same temperature. The reaction liquid was diluted with chloroform, washed successively with saturated sodium hydrogencarbonate solution and with saturated brine, and dried over anhydrous sodium sulfate. Distilling the solvent off under reduced pressure, the residue was purified on preparative thin layer chromatography (Kieselgel™60F254, Art5744 (Merck), chloroform/methanol=10/1) to provide the title compound.
Reaction SMILES: [CH3:1][N:2]1[C@@H:19]2[CH2:20][C:7]3[CH:8]=[CH:9][C:10]([O:21][CH3:22])=[C:11]4[O:12][C@H:13]5[C:14]([CH:16]=[CH:17][C@@H:18]2[C@:5]5([C:6]=34)[CH2:4][CH2:3]1)=[O:15].[C:23]1(C)C=CC(S(O)(=O)=O)=CC=1.CO.C1C=CC=CC=1>O>[CH3:1][N:2]1[C@@H:19]2[CH2:20][C:7]3[CH:8]=[CH:9][C:10]([O:21][CH3:22])=[C:11]4[O:12][C@H:13]5[C:14]([O:15][CH3:23])=[CH:16][CH:17]=[C:18]2[C@:5]5([C:6]=34)[CH2:4][CH2:3]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: COc1ccc2c3c1O[C@H]1C(=O)C=C[C@H]4[C@@H](C2)N(C)CC[C@]314
Solvent: O
Solvent: c1ccccc1
Solvent: CO
Product: COC1=CC=C2[C@H]3Cc4ccc(OC)c5c4[C@@]2(CCN3C)[C@H]1O5
Yield: 26.8 %

Procedure:
Seki (18 Chem. Pharm. Bull. 671-676, 1970) discloses a method for preparing Δ6,8-diene compounds, such as thebaine, from α,β-unsaturated ketones such as codeinone, which may be obtained from the natural alkaloid codeine. Codeinone was added to a mixture of p-toluenesulfonic acid (dehydrated prior to reaction), absolute methanol and dried benzene, the solution refluxed for 3 hours under azeotropic removal of water, and the reaction mixture purified by washing with diluted sodium hydroxide, to obtain thebaine. A reported maximum yield of 26.8% was reported when using 1.1-0.15 molar equivalents of p-toluenesulfonic acid to codeinone. Eppenberger et al. (51 Helv. Chim. Acta 381, 1968) report a four step method for converting dihydrocodeinone to thebaine which results in a similar yield of 27%. Schwartz et al. (97 J. Am. Chem. Soc. 1239, 1975) demonstrate the total synthesis of thebaine in which the key step is the oxidative coupling of a reticuline derivative to a salutaridine derivative. The overall yield of dl-thebaine, however, was only in the 1-2% range based on isovanillin. Reaction of salutaridinol with an organic or inorganic acid halide or acid anhydride, followed by treatment with a strong base, is taught as a method of thebaine production in U.S. Pat. No. 3,894,026 to Sohar et al. A yield as high as 50.3% was reported (See, Col. 4, Line 29). Barber et al. (18 J. Med. Chem. 1074-1077, 1975) report synthesizing thebaine (as well as oripavine) from codeine and morphine. Barber et al. teach methylation of the potassium salt of codeine to give codeine methyl ether followed by oxidation with γ-MnO2 (See also, U.S. Pat. No. 4,045,440 to Rapoport et al., 1977). These authors claim a 67% yield of oxycodone from codeine. European Patent Application No. EP 0 889 045 A1 likewise teaches a process for the production of thebaine from the more readily available morphinans codeine and morphine. Such method provides for converting the starting material to an alkali metal or quaternary ammonium cation and reacting the same with a compound of the formula RX wherein R is an alkyl or acyl group and X is a leaving group.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5]([NH2:9])=[CH:6][C:7]=1[F:8].C(N(CC)CC)C.O=[S:19](Cl)Cl>ClCCl>[F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]2[C:4]([CH:3]=1)=[N:10][S:19][N:9]=2
Reactant: Nc1cc(F)c(F)cc1N
Reactant: O=S(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Fc1cc2nsnc2cc1F
Temperature: 25 °C
Yield: 58.1 %

Procedure:
To a solution of 4,5-difluorobenzene-1,2-diamine (2.0 g, 0.014 mol) and triethylamine (7.8 mL, 0.056 mol) in dichloromethane (80 mL) was added SOCl2 (4.04 mL, 0.055 mol) dropwise at room temperature. The resulting reaction mixture was heated to reflux overnight. The reaction mixture was then allowed to cool to room temperature, and quenched with water carefully. The resulting mixture was extracted with dichloromethane, dried over Na2SO4 and concentrated on a rotary evaporator to give a white solid as the crude compound. The crude product was purified by flash column chromatography (silica gel, hexanes) to afford 5,6-difluorobenzo[1,2,5]thiadiazole as a white crystalline solid (1.4 g, 58% yield). 1H NMR (CDCl3 500 MHz): δ: 7.76 (t, 2H, J=8.5 Hz). 13C NMR (CDCl3, 500 MHz): δ 154.94, 154.78, 152.86, 152.70, 150.89, 150.85, 150.81, 106.26, 106.21, 106.14, 106.09. Anal. calcd. for (C6H2F2N2S): C, 41.86; H, 1.17; N, 16.27. Found: C, 41.41; H, 1.22; H, 15.87. m.p: 64-65° C.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([OH:8])=O.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.CCN(C(C)C)C(C)C.[C:33]([O:37][C:38](=[O:48])[CH2:39][NH:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)([CH3:36])([CH3:35])[CH3:34]>ClCCl.C(OCC)(=O)C>[C:33]([O:37][C:38](=[O:48])[CH2:39][N:40]([C:6]([C:2]1[NH:1][CH:5]=[CH:4][CH:3]=1)=[O:8])[CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)([CH3:36])([CH3:34])[CH3:35]
Reactant: O=C(O)c1ccc[nH]1
Reactant: CC(C)(C)OC(=O)CNCc1ccccc1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CN(Cc1ccccc1)C(=O)c1ccc[nH]1
Reaction time: 0.5 h
Yield: 34.4 %

Procedure:
To a suspension containing 3.00 g (27.0 mmol) of pyrrole-2-carboxylic acid in 75 mL of anhydrous dichloromethane under a nitrogen atmosphere at 0° C. was added 6.96 g (27.0 mmol of BOPCl and 14.1 mL (81.0 mmol) of DIEA. After stirring for 30 minutes, 5.97 g (27.0 mmol) of N-(benzyl)glycine-t-butyl ester was added and the reaction allowed to warn to room temperature overnight. The reaction was diluted with ethyl acetate and washed with a 5% potassium hydrogensulfate, saturated sodium bicarbonate solution and brine. The organic phase was dried over magnesium sulfate, filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using a gradient of 100% hexane to (60% hexane/ethyl acetate to afford 2.92 g (34.4%) of the title compound is a white solid. FAB MS [M+H] m/z Calcd: 315, Found: 315.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:10]=[CH:9][C:7](C)([NH2:8])[CH2:6][CH:5]=1.[C:14]([C:18]1[CH:33]=[CH:32][CH:31]=[CH:30][C:19]=1[O:20][C:21]1[C:26]([N:27]=[C:28]=[S:29])=[CH:25][CH:24]=[CH:23][N:22]=1)([CH3:17])([CH3:16])[CH3:15].[CH2:34]1COCC1>>[C:14]([C:18]1[CH:33]=[CH:32][CH:31]=[CH:30][C:19]=1[O:20][C:21]1[C:26]([NH:27][C:28]([NH:8][C:7]2[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:12])[F:13])=[CH:10][C:9]=2[CH3:34])=[S:29])=[CH:25][CH:24]=[CH:23][N:22]=1)([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)c1ccccc1Oc1ncccc1N=C=S
Reactant: CC1(N)C=CC(OC(F)(F)F)=CC1
Reactant: C1CCOC1
Product: Cc1cc(OC(F)(F)F)ccc1NC(=S)Nc1cccnc1Oc1ccccc1C(C)(C)C
Temperature: 60 °C
Reaction time: 18 h
Yield: 45 %

Procedure:
To a solution of 4-trifluoromethoxy-1-methyl-aniline (32 mg, 0.17 mmol) in THF (1 mL) was slowly added 1c (40 mg, 0.14 mmol). The reaction was stirred 18 h at 60° C. and concentrated. The residue was purified by column chromatography on silica gel using a continuous gradient from 0% to 40% ethyl acetate in hexanes as eluent to afford 105a (36 mg, 45%). [M+H]+=476.08.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1.[F:18][C:19]1[CH:20]=[C:21]([CH:25]=[C:26]([F:29])[C:27]=1[F:28])[C:22](Cl)=[O:23]>N1C=CC=CC=1>[F:18][C:19]1[CH:20]=[C:21]([CH:25]=[C:26]([F:29])[C:27]=1[F:28])[C:22]([NH:15][C:14]1[CH:16]=[CH:17][C:11]([C:9]2[N:10]=[C:5]3[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][N:6]3[CH:8]=2)=[CH:12][CH:13]=1)=[O:23]
Reactant: Cc1ccc2nc(-c3ccc(N)cc3)cn2c1
Reactant: O=C(Cl)c1cc(F)c(F)c(F)c1
Solvent: c1ccncc1
Product: Cc1ccc2nc(-c3ccc(NC(=O)c4cc(F)c(F)c(F)c4)cc3)cn2c1
Yield: 72.2 %

Procedure:
Prepared as described in the Amide Coupling section using 4-(6-methylimidazo[1,2-a]pyridin-2-yl)aniline (0.50 g, 2.24 mmol) and 3,4,5-trifluorobenzoyl chloride (0.436 g, 2.24 mmol) in dry pyridine (20 ml) to give the title compound (0.617 g, 72%) as a colourless solid, after work-up and recrystallisation from AcOH.
Reaction SMILES: [CH:1]1[C:6]([NH2:7])=[CH:5][CH:4]=[C:3]([NH2:8])[CH:2]=1.[C:9]([NH:16][CH2:17][C:18]([OH:20])=O)([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].C1([N:27]=C=NC2CCCCC2)CCCCC1>O1CCCC1>[C:12]([O:11][C:9]([NH:16][CH2:17][C:18]([NH:27][NH:7][C:6]1[CH:5]=[CH:4][C:3]([NH2:8])=[CH:2][CH:1]=1)=[O:20])=[O:10])([CH3:15])([CH3:14])[CH3:13]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: Nc1ccc(N)cc1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCC(=O)NNc1ccc(N)cc1
Reaction time: 5 h

Procedure:
8.65 g (0.08 mol) of p-phenylenediamine are dissolved in 300 ml of absolute tetrahydrofuran (THF) together with 15.3 g (0.088 mol) of N-Boc-glycine, and 18.05g (0.088 mol) of dicyclohexylcarbodiimide is added in portions. After 5 h, the deposited precipitate is filtered off with suction, the filtrate is concentrated, and the product is purified by chromatography on silica gel by means of ethyl acetate/methanol/acetic acid and then crystallized from ethyl acetate/petroleum ether. The yield of the process was 13.5 g with a melting point 144° C.