Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:18])([C:9]([F:17])([F:16])[C:10]([F:15])([F:14])[CH:11]([F:13])[F:12])[CH2:3][O:4][CH2:5][CH:6]1[O:8][CH2:7]1.[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>>[O:22]1[CH2:23][CH2:24][N:19]([CH2:7][CH:6]([OH:8])[CH2:5][O:4][CH2:3][C:2]([F:18])([F:1])[C:9]([F:17])([F:16])[C:10]([F:15])([F:14])[CH:11]([F:13])[F:12])[CH2:20][CH2:21]1
Reactant: FC(F)C(F)(F)C(F)(F)C(F)(F)COCC1CO1
Reactant: C1COCCN1
Product: OC(COCC(F)(F)C(F)(F)C(F)(F)C(F)F)CN1CCOCC1
Temperature: 80 °C
Reaction time: 10 h
Yield: 89.1 %

Procedure:
28.8 g of glycidyl 2,2,3,3,4,4,5,5-octafluoropentyl ether was added dropwise to 8.7 g of morpholine. The mixture was then stirred at 80° C. for 10 hours. The reaction mixture was directly purified by silica gel column chromatography. There was obtained 33.4 g of 1-morpholino-3-(2,2,3,3,4,4,5,5-octafluoropentyloxy)-2-propanol (yield 89%).
Reaction SMILES: [CH3:1][NH:2][CH3:3].[CH3:4][O:5][CH2:6][C:7]1[N:12]=[C:11](Cl)[CH:10]=[CH:9][N:8]=1.O>C(O)C>[CH3:4][O:5][CH2:6][C:7]1[N:12]=[C:11]([N:2]([CH3:3])[CH3:1])[CH:10]=[CH:9][N:8]=1
Reactant: CNC
Reactant: COCc1nccc(Cl)n1
Solvent: CCO
Solvent: O
Product: COCc1nccc(N(C)C)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A 33% w/w solution of dimethylamine in ethanol (45 ml) was added dropwise to a stirred solution of 2-methoxymethyl-4-chloropyrimidine (7.54 g) in ethanol (100 ml), cooled over an ice bath. The mixture was allowed to warm to room temperature, and left to stand for 16 hours. After stripping, the residue was treated with water (100 ml), and extracted with chloroform. The extracts were dried (K2CO3) and stripped to give 2-methoxymethyl-4-dimethylaminopyrimidine (7.41 g) as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[OH:12].CI.[C:15](=O)([O-])[O-].[K+].[K+]>CC(C)=O.C(Cl)Cl>[Br:1][C:2]1[C:3]([O:12][CH3:15])=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([F:8])[CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: O=[N+]([O-])c1cc(O)c(Br)cc1F
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Solvent: ClCCl
Product: COc1cc([N+](=O)[O-])c(F)cc1Br
Yield: 94.5 %

Procedure:
A stirred solution of 30.0 g (0.127 mole) of 2-bromo-4-fluoro-5-nitrophenol, 26.9 g (0.19 mole) of methyl iodide, and 26.3 g (0.19 mole) of potassium carbonate in 200 mL of acetone was heated at reflux for five hours. The reaction mixture was filtered, and the filtrate concentrated under reduced pressure to give a residue. The residue was dissolved in methylene chloride and passed through a column of silica gel. The elute was concentrated under reduced pressure to give 30 g of 4-bromo-2-fluoro-5-methoxynitrobenzene; m.p. 74°-76° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:14]C2N=NC=CC=2C=1O)=[O:5])[CH3:2].C(O[C:19](=[O:28])[C:20]1[C:25]([CH3:26])=[CH:24][CH:23]=[N:22][C:21]=1Cl)C>>[CH2:1]([O:3][C:4]([C:6]1[O:14][C:21]2=[N:22][CH:23]=[CH:24][C:25]([CH3:26])=[C:20]2[C:19]=1[OH:28])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1oc2nnccc2c1O
Reactant: CCOC(=O)c1c(C)ccnc1Cl
Product: CCOC(=O)c1oc2nccc(C)c2c1O

Procedure:
This compound was prepared using a method analogous to that of 5-hydroxyfuro[2,3-c]pyridazine-6-carboxylic acid ethyl ester (A.2.3.1), 2-chloro-4-methylnicotinic acid ethyl ester replacing 3-chloropyridazine-4-carboxylic acid ethyl ester;
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:42])[N:5]([CH2:12][C:13]([O:15][C@H:16]([C:27]1[CH:32]=[CH:31][C:30]([O:33][CH:34]([F:36])[F:35])=[C:29]([O:37][CH2:38][CH:39]3[CH2:41][CH2:40]3)[CH:28]=1)[CH2:17][C:18]1[C:23]([Cl:24])=[CH:22][N+:21]([O-:25])=[CH:20][C:19]=1[Cl:26])=[O:14])[C:6]2=[O:11].[CH3:43][O:44][CH2:45][C:46](Cl)=[O:47]>CN(C=O)C.CN(C1C=CN=CC=1)C>[Cl:24][C:23]1[CH:22]=[N+:21]([O-:25])[CH:20]=[C:19]([Cl:26])[C:18]=1[CH2:17][C@@H:16]([C:27]1[CH:32]=[CH:31][C:30]([O:33][CH:34]([F:35])[F:36])=[C:29]([O:37][CH2:38][CH:39]2[CH2:40][CH2:41]2)[CH:28]=1)[O:15][C:13](=[O:14])[CH2:12][N:5]1[C:4](=[O:42])[C:3]2[C:7](=[CH:8][CH:9]=[CH:10][C:2]=2[NH:1][C:46](=[O:47])[CH2:45][O:44][CH3:43])[C:6]1=[O:11]
Reactant: COCC(=O)Cl
Reactant: Nc1cccc2c1C(=O)N(CC(=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC3CC3)c1)C2=O
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: COCC(=O)Nc1cccc2c1C(=O)N(CC(=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC3CC3)c1)C2=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 67.5 %

Procedure:
(S)-4-(2-(2-(4-amino-1,3-dioxoisoindolin-2-yl)acetoxy)-2-(3-(cyclopropylmethoxy)-4 (difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxide (20.0 mg; 0.032 mmol) was dissolved in DMF (2 ml) and cooled down to 0° C. in a ice bath. 2-methoxyacetyl chloride (20.0 mg; 0.184 mmol) and DMAP (0.048 mmol; 5.89 mg) were added to the reaction solution that was stirred a 0° C. for 2 hours. After that time, the reaction was quenched with aqueous HCl (1M) (20 ml) and extracted with EtOAc (20 ml). The organic phase was further washed with HCl (1M) (3×20 ml), dried over Na2SO4 and the solvent removed under reduced pressure to afford the titled compound (15.0 mg; 67% yield). 1H NMR (400 MHz, acetone) δ ppm 10.33-10.47 (m, 1H), 8.80-8.93 (m, 1H), 8.22 (s, 2H), 7.83-7.95 (m, 1H), 7.57-7.67 (m, 1H), 7.16-7.24 (m, 2H), 7.04-7.11 (m, 1H), 6.94 (t, J=75.00 Hz, 1H), 6.13-6.22 (m, 1H), 4.46 (s, 2H), 4.14 (d, J=3.09 Hz, 2H), 3.91-4.06 (m, 2H), 3.65 (s, 3H), 3.49-3.58 (m, 1H), 3.26-3.38 (m, 1H), 1.17-1.39 (m, 1H), 0.54-0.69 (m, 2H), 0.36-0.48 (m, 2H). MS/ESI+ [MH]+=694.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[N:15]=3)[N:12]=[C:11]([C:21](O)=[O:22])[CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.ClC1C=C(C2N(C3C=CC=CN=3)N=C(C([N:45]3[CH2:49][C:48](=[O:50])[NH:47][CH2:46]3)=O)C=2)C=C(F)C=1.Cl.N1C=CNC1=O>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[N:15]=3)[N:12]=[C:11]([C:21]([N:45]3[CH2:49][C:48](=[O:50])[NH:47][CH2:46]3)=[O:22])[CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: O=C(O)c1cc(-c2cc(F)cc(Cl)c2)n(-c2cccc(Cl)n2)n1
Reactant: O=C1CN(C(=O)c2cc(-c3cc(F)cc(Cl)c3)n(-c3ccccn3)n2)CN1
Agent: Cl
Agent: O=c1[nH]cc[nH]1
Product: O=C1CN(C(=O)c2cc(-c3cc(F)cc(Cl)c3)n(-c3cccc(Cl)n3)n2)CN1

Procedure:
75 mg (0.21 mmol) of the compound of Example 21A is reacted analogously to the synthesis of the compound of Example 1 with 29 mg (0.23 mmol) of 4-imidazolinone-hydrochloride. 44 mg (49% of theory) of the title compound is obtained.
Reaction SMILES: [CH2:1]([C:3]1[O:4][C:5]2[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[C:6]=2[N:7]=1)[CH3:2].[Br:14]Br>CO>[Br:14][C:11]1[C:5]2[O:4][C:3]([CH2:1][CH3:2])=[N:7][C:6]=2[C:8]([O:12][CH3:13])=[CH:9][CH:10]=1
Reactant: BrBr
Reactant: CCc1nc2c(OC)cccc2o1
Solvent: CO
Product: CCc1nc2c(OC)ccc(Br)c2o1
Temperature: -78 °C
Reaction time: 3.5 h

Procedure:
2-Ethyl-4-methoxybenzoxazole (2.81 g) was dissolved in methanol (80 ml) under nitrogen and the solution cooled to −78° C. Bromine (0.73 ml) was added dropwise. The mixture was allowed to warm gradually to room temperature and stirred for 3.5 h. The methanol was evaporated in vacuo and the residue partitioned between ethyl acetate and aqueous sodium bicarbonate. The combined organic phases were washed with 5% aqueous sodium metabisulphite, evaporated onto silica and purified by flash chromatography eluting with 25%-50% ethyl acetate in hexane to give a mixture of the title compound and 2-ethyl-4-methoxybenzoxazole as a pale yellow liquid (2.28 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([NH:15][C@H:16]1[CH2:20][CH2:19][N:18]([C@@H:21]([CH3:25])[C:22](O)=[O:23])[C:17]1=[O:26])(=[O:14])=[O:13])[CH:6]=[CH:5]2.[NH:27]1[CH2:32][CH2:31][CH2:30][CH:29]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH2:28]1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([NH:15][C@H:16]1[CH2:20][CH2:19][N:18]([C@@H:21]([CH3:25])[C:22]([N:27]3[CH2:32][CH2:31][CH2:30][CH:29]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:38])([CH3:37])[CH3:39])[CH2:28]3)=[O:23])[C:17]1=[O:26])(=[O:14])=[O:13])[CH:6]=[CH:5]2
Reactant: C[C@@H](C(=O)O)N1CC[C@H](NS(=O)(=O)c2ccc3cc(Cl)ccc3c2)C1=O
Reactant: CC(C)(C)OC(=O)NC1CCCNC1
Product: C[C@@H](C(=O)N1CCCC(NC(=O)OC(C)(C)C)C1)N1CC[C@H](NS(=O)(=O)c2ccc3cc(Cl)ccc3c2)C1=O

Procedure:
The title compound was prepared using Intermediate 29 and tert-butyl piperidin-3-ylcarbamate, and the synthetic procedure described for Example 1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](Cl)=[C:8]([C:11]([NH2:13])=[O:12])[CH:7]=[N:6][N:5]2[CH:14]=1.[CH3:15][NH2:16]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9]([NH:16][CH3:15])=[C:8]([C:11]([NH2:13])=[O:12])[CH:7]=[N:6][N:5]2[CH:14]=1
Reactant: NC(=O)c1cnn2cc(Br)cc2c1Cl
Reactant: CN
Product: CNc1c(C(N)=O)cnn2cc(Br)cc12
Yield: 98 %

Procedure:
A solution of 6-bromo-4-chloropyrrolo[1,2-b]pyridazine-3-carboxamide (Preparation 5, 200 mg, 0.733 mmol), and methylamine (0.5 mL, 8M solution in EtOH) was heated to 80° C. for 1 hr in the CEM microwave. The reaction mixture was evaporated in vacuo to give the title compound (192 mg, 98%). HPLC (condition G): retention time=0.77 min. LCMS (condition B): m/z 269.0, 271.0.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10](Br)=[CH:11][CH:12]=2)[C@H:7]([NH:15][C:16](=[O:21])[O:17][CH:18]([CH3:20])[CH3:19])[CH2:6][C@@H:5]1[CH3:22])(=[O:3])[CH3:2].[CH:23]([C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1)=[O:24].C(=O)([O-])[O-].[K+].[K+]>C(O)C.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>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:28]3[CH:29]=[CH:30][C:25]([CH:23]=[O:24])=[CH:26][CH:27]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:15][C:16](=[O:21])[O:17][CH:18]([CH3:20])[CH3:19])[CH2:6][C@@H:5]1[CH3:22])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(Br)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Reactant: O=Cc1ccc(B(O)O)cc1
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: CCO
Product: CC(=O)N1c2ccc(-c3ccc(C=O)cc3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Temperature: 85 °C
Reaction time: 0.5 h

Procedure:
1-methylethyl [(2S,4R)-1-acetyl-6-bromo-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (for a preparation see Intermediate 16) (1 g, 2.71 mmol), (4-formylphenyl)boronic acid (0.487 g, 3.25 mmol, available from Aldrich), Pd(Ph3P)4, (0.156 g, 0.135 mmol) and potassium carbonate (0.487 g, 3.52 mmol) were combined in dry ethanol (7 ml) and dry toluene (7.00 ml) and the reaction mixture was de-gassed for 10 mins. The reaction mixture was heated at 85° C. overnight. The reaction mixture was allowed to cool to r.t. and concentrated. The crude reaction mixture was partitioned between water (15 ml) and ethyl acetate (5 ml) and stirred at r.t. for 30 mins. A light grey solid precipitated out and was filtered off, washed with water (5 ml) and dried in a vacuum oven to give 854 mg of grey solid. LCMS (Method B): Rt=1.00, MH+=395
Reaction SMILES: [F:1][CH:2]([F:35])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]3[CH:14]=[C:15]([OH:18])[CH:16]=[CH:17][C:11]=3[C:10]=2[O:19][C:20]2[CH:25]=[CH:24][C:23](/[CH:26]=[CH:27]/[C:28]([O:30]C(C)(C)C)=[O:29])=[CH:22][CH:21]=2)=[CH:5][CH:4]=1.Cl>C1COCC1>[F:35][CH:2]([F:1])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[S:13][C:12]3[CH:14]=[C:15]([OH:18])[CH:16]=[CH:17][C:11]=3[C:10]=2[O:19][C:20]2[CH:25]=[CH:24][C:23](/[CH:26]=[CH:27]/[C:28]([OH:30])=[O:29])=[CH:22][CH:21]=2)=[CH:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)/C=C/c1ccc(Oc2c(-c3ccc(C(F)F)cc3)sc3cc(O)ccc23)cc1
Agent: Cl
Solvent: C1CCOC1
Product: O=C(O)/C=C/c1ccc(Oc2c(-c3ccc(C(F)F)cc3)sc3cc(O)ccc23)cc1
Temperature: 50 °C
Reaction time: 12 h
Yield: 78.7 %

Procedure:
To a vial containing (E)-tert-butyl 3-(4-((2-(4-(difluoromethyl)phenyl)-6-hydroxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylate (30 mg, 0.061 mmol) in THF (1.0 mL) was added HCl (4.0 N in dioxane, 0.4 mL, 1.600 mmol). The resulting mixture was stirred at 50° C. for 12 h after which time the reaction was concentrated in vacuo and purified by reverse phase HPLC (neutral condition, 3% 1-propanol in 10-100% CH3CN/H2O) to afford (E)-3-(4-((2-(4-(difluoromethyl)phenyl)-6-hydroxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylic acid (21 mg, 0.048 mmol, 79% yield). LC/MS (m/z, M-H): 437.5.
Reaction SMILES: [C:1]([O:6][CH2:7][N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][N:26]([C:29]4[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[C:30]=4[Cl:36])[CH2:25][CH2:24]3)[CH:16]=2)[CH2:11][CH2:10][C:9]1=[O:37])(=[O:5])[CH2:2][CH2:3][CH3:4].C(O)(C(F)(F)F)=O.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>C1COCC1>[C:1]([O:6][CH2:7][N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][N:26]([C:29]4[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[C:30]=4[Cl:36])[CH2:25][CH2:24]3)[CH:16]=2)[CH:11]=[CH:10][C:9]1=[O:37])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)OCN1C(=O)CCc2ccc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)cc21
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: CCCC(=O)OCn1c(=O)ccc2ccc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)cc21
Temperature: 25 °C
Yield: 62.6 %

Procedure:
To a stirred solution of Compound 2B (3.26 g, 5.94 mmol) in THF (100 mL) was added TFA (2.74 mL, 35.63 mmol) followed by DDQ (7.01 g, 30.88 mmol) in THF (40 mL). The reaction was stirred at room temperature over the weekend. The reaction was quenched with water (100 mL) and then poured into water (600 mL) and dichloromethane (100 mL). Solid NaHCO3 (100 g) was added and the mixture stirred for approximately 30 minutes. Dichloromethane (200 mL) was added and the mixture filtered. The collected filtrate was transferred to a separating funnel and the layers separated. The aqueous layer was extracted with dichloromethane (2×100 mL) and the combined organics washed with water (3×100 mL, brine (100 mL) and dried over MgSO4. After filtration, the volatiles were removed. The crude material was purified by silica chromatography eluting 0-4% Methanol/(1:1 ethyl acetate/dichloromethane). The oil was recrystallized from methanol to give Compound 2, (2.03 g, 3.72 mmol, 63% yield). 1H-NMR (300 MHz, CDCl3) δ 7.63 (1H, d), 7.45 (1H, d), 7.19-7.06 (2H, m), 6.99-6.90 (1H, m), 6.88-6.78 (2H, m), 6.52 (1H, d), 6.33 (2H, s), 4.06 (2H, t), 3.17-2.99 (4H, bs), 2.74-2.43 (6H, m), 2.35 (2H, t), 1.94-1.54 (6H, m), 0.93 (3H, t).
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=2)=[O:11])=[CH:6][C:5]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:4][N:3]=1.[H-].C([Al+]CC(C)C)C(C)C.C1(C)C=CC=CC=1>C(Cl)Cl>[Cl:19][C:14]1[CH:13]=[C:12]([CH:10]2[O:11][C:2]3=[N:3][CH:4]=[C:5]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:6]=[C:7]3[CH2:8][CH2:9]2)[CH:17]=[CH:16][C:15]=1[Cl:18]
Reactant: CS(=O)(=O)c1cnc(Cl)c(CCC(=O)c2ccc(Cl)c(Cl)c2)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CS(=O)(=O)c1cnc2c(c1)CCC(c1ccc(Cl)c(Cl)c1)O2
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
A solution of 0.39 g of 3-[2-chloro-5-(methylsulfonyl)-3-pyridinyl]-1-(3,4-dichlorophenyl)propan-1-one in 15 ml of methylene chloride was cooled to -70° C. under nitrogen and then a solution of 1.0 ml of 1.5M diisobutylaluminum hydride/toluene was added dropwise over 3 minutes while keeping the temperature below -65° C. After an additional 5 minutes, the mixture was quenched by careful addition of 1.5 ml of a mixture consisting of 10% water, 40% acetic acid and 50% ether. The reaction mixture was then allowed to warm to 0° C. and was partitioned between water and methylene chloride. The methylene chloride layer was washed with aqueous saturated sodium bicarbonate solution, dried over magnesium sulfate and filtered, and the filtrate was concentrated to a colorless solid, 3-[2-chloro-5-(methylsulfonyl)-3-pyridinyl]-1-(3,4-dichlorophenyl)propan-1-ol. This solid was dissolved in 2 ml of anhydrous dimethyl sulfoxide and added to a stirred suspension of 0.07 g of 50% sodium hydride (previously freed of oil by washing with hexane) in 10 ml of dimethyl sulfoxide under nitrogen. Gas evolution took place and the mixture first became lavender and then cherry red. After 15 minutes, it was partitioned between ethyl acetate and 1N hydrochloric acid. The yellow ethyl acetate layer was washed with water and then twice with aqueous saturated sodium chloride solution, dried over magnesium sulfate and filtered and the filtrate was concentrated to leave a pale yellow solid. This solid was recrystallized from a mixture of 2-propanol and ethyl acetate to give 2-(3,4-dichlorophenyl)-3,4-dihydro-6-(methylsulfonyl)-2H-pyrano[2,3-b]pyridine melting at about 171.5°-172.5° C. This material exhibited the same spectral characteristics as the material prepared by the procedure described in Example 17. This compound has the following structural formula: ##STR7##
Reaction SMILES: Cl[CH:2]([C:6](=O)[CH3:7])[CH2:3][C:4]#[N:5].[NH2:9][C:10]1[C:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:14][CH:13]=[CH:12][N:11]=1.C(N(CC)CC)C>C(O)C>[CH2:17]([O:16][C:15]1[C:10]2[N:11]([C:2]([CH2:3][C:4]#[N:5])=[C:6]([CH3:7])[N:9]=2)[CH:12]=[CH:13][CH:14]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC(=O)C(Cl)CC#N
Reactant: Nc1ncccc1OCc1ccccc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1nc2c(OCc3ccccc3)cccn2c1CC#N

Procedure:
A solution of 0.86 g. of 3-chloro-4-oxopentanonitrile, 0.92 g. of 2-amino-3-phenylmethoxypyridine and 0.5 ml. of triethylamine in 15 ml. of ethanol was stirred for 16 hours, then concentrated to remove the triethylamine and ethanol. The residue was dissolved in methylene chlorideand washed with water. The methylene chloride was concentrated and the residual oil was dissolved in 20 ml. of boiling acetonitrile, filtered, cooled, and treated with hydrogen chloride/methanol with cooling to give 0.22 g. of the desired product (m.p. 163°-166° C.).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5](=[O:11])[CH2:6][C:7]([O:9][CH3:10])=[O:8].C(N(CC)CC)C.C(NC1C=CC(S([N:33]=[N+:34]=[N-])(=O)=O)=CC=1)(=O)C>C(#N)C>[CH3:10][O:9][C:7](=[O:8])[C:6](=[N+:33]=[N-:34])[C:5](=[O:11])[CH2:4][C:3]([O:2][CH3:1])=[O:12]
Reactant: CC(=O)Nc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Reactant: COC(=O)CC(=O)CC(=O)OC
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)CC(=O)C(=[N+]=[N-])C(=O)OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 3-ketoglutaric acid dimethyl ester 15.0 g, triethylamine 9.6 g and acetonitrile 300 ml is portionwise added 4-acetylaminobenzensulfonylazide 20.7 g at 0° C. The mixture is stirred at room temperature for 30 minutes. After removal of the precipitate by filtration the filtrate is concentrated in vacuo. The residue is diluted with a mixture of hexane and diethyl ether (1:1). The insoluble materials are removed by filtration and the filtrate is concentrated in vacuo. The residue is purified with column chromatography (silica gel 225 g, solvent; hexane:ethyl acetate=5:1→3:1) to give 2-diazo-3-ketoglutaric acid dimethyl ester as a pale yellow oil, 16.03 g.
Reaction SMILES: Cl.[O:2]1[C@:14]2([CH3:20])[C@@:15]34[CH2:17][CH2:18][NH:19][C@@H:9]([C@:10]3([O:22][CH3:23])[CH2:11][CH2:12][C:13]2=[O:21])[CH2:8][C:7]2=[C:16]4[C:3]1=[C:4]([O:24][CH3:25])[CH:5]=[CH:6]2.C(=O)([O-])[O-].[K+].[K+].[C:32]1([CH2:38][CH2:39][Br:40])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.CN(C)C=O>O>[BrH:40].[O:2]1[C@:14]2([CH3:20])[C@@:15]34[CH2:17][CH2:18][N:19]([CH2:39][CH2:38][C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=5)[C@@H:9]([C@:10]3([O:22][CH3:23])[CH2:11][CH2:12][C:13]2=[O:21])[CH2:8][C:7]2=[C:16]4[C:3]1=[C:4]([O:24][CH3:25])[CH:5]=[CH:6]2
Reactant: COc1ccc2c3c1O[C@@]1(C)C(=O)CC[C@@]4(OC)[C@@H](C2)NCC[C@]314
Reactant: BrCCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Br
Product: COc1ccc2c3c1O[C@@]1(C)C(=O)CC[C@@]4(OC)[C@@H](C2)N(CCc2ccccc2)CC[C@]314
Temperature: 80 °C
Reaction time: 2 h
Yield: 44.5 %

Procedure:
A mixture of 4,5α-epoxy-3,14-dimethoxy-5-methylmorphinan-6-one hydrochloride (H. Schmidhammer et al., Helv. Chim. Acta Vol. 77:1585-1589, 1994) (2.24 g, 6.12 mmol), potassium carbonate (3.0 g, 21.9 mmol), 2-phenylethyl bromide (1.05 ml, 7.74 mmol), and 15 ml of anhydrous N,N-dimethyl formamide was stirred at 80° C. (bath temperature) for 2 h. After cooling and addition of 110 ml of H2O, the mixture was extracted with diethyl ether (3×60 ml). The combined organic layers were washed with H2O(3×70 ml), dried over Na2SO4 and evaporated. The residue (2.9 yellow oil) was converted into the hydrobromide salt in the usual way and crystallized from MeOH to give 1.4 g (63%) of 4,5α-epoxy-3,14-dimethoxy-5-methyl-17-(2-phenyl)ethylmorphinan-6-one hydrobromide (compound 7) as colorless crystals. A small portion of this material was recrystallized from MeOH for analyses. M.p. 94-96° C. IR (KBr): 3400 (+NH), 1720 (CO) cm-1. CI-MS: m/z 434 (M+ +1). 1H-NMR (DMSO-d6) δ 10.15 (s, +NH), 7.30 (m, 5 arom. H), 6.74 (d, J=8.2 Hz, 1 arom. H), 6.68 (d, J=8.2 Hz, 1 arom.), 3.87 (s, OCH3 --C(3)), 3.58 (s, OCH3 --C(14)), 1.60 (s, CH3 --C(5)). Analysis calculated for C27H31NO4. HBr (514.44): C 63.04, H 6.27, N 2.72; found: C 63.18, H 6.60, N 2.39. A solution of the compound 7 (1.4 g, 3.32 mmol) in 5 ml of 48% HBr was refluxed for 30 min and then evaporated. The residue was dissolved in MeOH and again evaporated (this operation was repeated once) to afford a brownish crystalline residue (1.8 g) which was treated with hot MeOH to yield 590 mg (42%) of the compound 8.HBr. A small portion was recrystallized for analyses. M.p.>316° C. IR (KBr):3400 (+NH, OH), 1722 (CO)cm-1. CI-MS: m/z 420 (M+ +1). 1H-NMR (DMSO-d6) δ 8.95 and 8.45 (2s, +NH,OH), 6.90 (m, 5 arom. H), 6.23 (dd, J=8.2, 8.2 Hz, 2 arom. H), 2.97 s, OCH3), 1.08 (s, CH3 --C(5)). Analysis calculated for C26H29NO4. HBr. 0.2 MeoH (506.85): C 62.09, H 6.13, N 2.76, Br 16.77; found: C 61.79, H 6.18, N 2.63, Br 16.12.
Reaction SMILES: [Br:1][C:2]1[CH:13]=[CH:12][C:5]([CH2:6][C@@H:7](C(O)=O)[NH2:8])=[CH:4][CH:3]=1.[CH3:14][C:15]([CH3:17])=O.[CH2:18]([N:25]1[C:29](=[O:30])[CH:28]=[CH:27][C:26]1=[O:31])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1(C)C=CC=CC=1>[CH2:18]([N:25]1[C:29](=[O:30])[CH:28]2[CH:27]([C:15]([CH3:17])([CH3:14])[NH:8][CH:7]2[CH2:6][C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:13][CH:12]=2)[C:26]1=[O:31])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CC(C)=O
Reactant: N[C@@H](Cc1ccc(Br)cc1)C(=O)O
Reactant: O=C1C=CC(=O)N1Cc1ccccc1
Solvent: Cc1ccccc1
Product: CC1(C)NC(Cc2ccc(Br)cc2)C2C(=O)N(Cc3ccccc3)C(=O)C21
Yield: 25.1 %

Procedure:
8.83 g (36.2 mmol) of 4-bromophenylalanine, 4.74 g (81.7 mmol) acetone and 7.00 g (37.43 mmol) of N-benzylmaleimide were heated under reflux for 68 hours. in 140 ml of toluene with the addition of molecular sieve A4. The solvent was removed in a vacuum and the residue was separated chromatographically (hexane/ethyl acetate 1:1+1% triethylamine). As the main product there were obtained 3.88 g of (3aRS,4RS,6aSR)-2-benzyl-4-(4-bromo-benzyl)-6,6-dimethyl-tetrahydro-pyrrolo[3,4-c]pyrrol-1,3-dione as a colourless oil which, after the addition of a small amount of methanol, crystallized overnight to colourless needles. M.p.: 142°-143° C. FAB-MS: 427 ([M+H]+, 58); 257 (66); 240 (8); 200 (6); 91 (58). 2.12 g of (3aRS,4SR,6aSR)-2-benzyl-4-(4-bromobenzyl)-6,6-dimethyl-tetrahydro-pyrrolo[3,4-c]pyrrole-1,3-dione were obtained as a byproduct as a colourless oil. FAB-MS: 427 ([M+H]+, 88); 257 (89); 91 (100).