Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][CH:13]2[C:15](=O)[CH:10]([CH2:11][CH2:12]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17][NH:18][CH3:19]>C(Cl)Cl>[CH2:1]([N:8]1[CH2:14][CH:13]2[CH:15]([N:18]([CH3:19])[CH3:17])[CH:10]([CH2:11][CH2:12]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CNC
Reactant: O=C1C2CCC1CN(Cc1ccccc1)C2
Solvent: ClCCl
Product: CN(C)C1C2CCC1CN(Cc1ccccc1)C2
Temperature: 25 °C
Yield: 67 %

Procedure:
To a solution of 3-benzyl-3-azabicyclo[3.2.1]octan-8-one (107 mg, 0.50 mmol) in DCM (2 ml) was added dimethylamine (2 ml, 1M in THF) and the resulting reaction mixture was stirred at room temperature for 1H. Na(AcO)3BH (316 mg, 1.49 mmol) was added and the reaction mixture was stirred at room temperature overnight. When TLC shows completion reaction mixture was diluted with DCM and washed with water and brine. Combined aqueous layers were backextracted with DCM. Combined organic layers were dried over Na2SO4, filtered, concentrated and purified by column chromatography which gave 3-benzyl-N,N-dimethyl-3-azabicyclo[3.2.1]octan-8-amine (80 mg) in 67% yield. 1H NMR (400 MHz, MeOD) δ ppm 7.47-7.23 (m, 5H) 3.86 (s, 2H) 2.88 (d, J=11.62 Hz, 2H) 2.72 (dd, J=12.38, 3.28 Hz, 2H) 2.52 (s, 7H) 2.35 (br. s., 2H) 1.90-1.73 (m, 4H)
Reaction SMILES: O[CH:2]([C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[NH:25][C:24](=[O:29])[CH2:23][CH2:22]2)[CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[CH2:8][CH2:7]1.Cl.[OH-].[Na+].CCOCC>C(O)(=O)C>[Cl:18][C:14]1[CH:13]=[C:12]([N:9]2[CH2:8][CH2:7][N:6]([CH2:5][CH2:4][CH:3]=[CH:2][C:19]3[CH:20]=[C:21]4[C:26](=[CH:27][CH:28]=3)[NH:25][C:24](=[O:29])[CH2:23][CH2:22]4)[CH2:11][CH2:10]2)[CH:17]=[CH:16][CH:15]=1
Reactant: O=C1CCc2cc(C(O)CCCN3CCN(c4cccc(Cl)c4)CC3)ccc2N1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CC(=O)O
Product: O=C1CCc2cc(C=CCCN3CCN(c4cccc(Cl)c4)CC3)ccc2N1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
1.9 Grams of 6-{1-hydroxy-4-[4-(3-chlorophenyl)-1-piperazinyl]butyl}-3,4-dihydrocarbostyril was dissolved in 50 ml of acetic acid and further 2 ml of concentrated hydrochloric acid was added to this solution. The solution was stirred at 80° C. for 30 minutes and the reaction mixture was concentrated under a reduced pressure to dryness to obtain a residue. To the residue were added 10N-NaOH and ether and stirred at a room temperature for 30 minutes. The crystals thus precipitated were collected by filtration and separated by a silica-gel chromatography. Recrystallized from ethanol-chloroform to obtain 6-{4-[4-(3-chlorophenyl)-1-piperazinyl]-1-butenyl}-3,4-dihydrocarbostyril in colorless prism-like crystals. Yield: 1.6 g. Melting point: 175°-176° C.
Reaction SMILES: C[O:2][C:3](=[O:25])[CH2:4][C@H:5]([O:7][Si:8]([C:21]([CH3:24])([CH3:23])[CH3:22])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:6].[OH-].[Na+]>O1CCCC1CO>[C:21]([Si:8]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[O:7][C@H:5]([CH3:6])[CH2:4][C:3]([OH:25])=[O:2])([CH3:22])([CH3:23])[CH3:24]
Reactant: COC(=O)C[C@@H](C)O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: OCC1CCCO1
Product: C[C@H](CC(=O)O)O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C

Procedure:
The protected ester (0.84 g, 2.36 mmol) was dissolved in 3:1 tetrahydrofuran-methanol and treated with aqueous sodium hydroxide (1.0 N, 3.0 mL, 3.00 mmol) at ˜42° C. overnight. The reaction was concentrated. The residue was partitioned between ethyl acetate and water and acidified with 1 N aqueous hydrochloric acid. The organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. Purification by flash chromatography (Biotage 40M, 20:80 ethyl acetate-hexanes) gave (R)-3-(tert-butyl-diphenyl-silanyloxy)-butyric acid. (Yield 0.63 g, 69.9%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][CH3:10])[NH2:5].[N:11]([O-])=O.[Na+].O.O.[Sn](Cl)Cl>O.Cl>[F:1][C:2]1[CH:3]=[C:4]([NH:5][NH2:11])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: O=N[O-]
Reactant: COc1ccc(N)cc1F
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: COc1ccc(NN)cc1F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
3-Fluoro-4-methoxyaniline (1, R=H, R2=CH3, R3=F) (95 g, 0.67 mol) was added to concentrated hydrochloric acid (250 mL), the suspension was stirred at ambient temperature for 18 hours, then it was cooled to 0° C. and a solution of sodium nitrite (53.7 g, 0.78 mol) in water (200 mL) was added dropwise at 0-5° C. When the addition was complete, the resulting solution was stirred at 0° C. for 1 hour then it was added dropwise at 0-5° C. to a stirred solution of tin (11) chloride dihydrate (638.9 g, 2.83 mol) in concentrated hydrochloric acid (500 mL). The mixture was allowed to warm to ambient temperature then it was stored at 4° C. for 18 hours. The resulting precipitate was collected by filtration, washed with water (400 ml), and ether (1000 mL) and dried in vacuo. The solid hydrochloride salt was basified by addition to 10% aqueous sodium hydroxide solution (800 mL), the free base was extracted into ether (2×400 mL), and the combined extracts were dried (MgSO4) and the solvent removed in vacuo to give (3-fluoro-4methoxyphenyl)hydrazine (2, R1=H, R3=CH2, R3=F) (51.9 g, 50%) as a yellow solid, mp 46-50° C.; 1HNMR (CDCl3/250 MHz): 1.5 (s, 1H, NH—NH2), 3.85 (s, 3H, OCH3), 5.0 (s, 2H, NH—NH2), 6.44 (m, 1H, phenyl 6-H), 6.60 (dd, 1H, phenyl 5-H), 6.79 (t, 1H, phenyl 2-H).
Reaction SMILES: [CH:1]1[N:5]([C@@H:6]2[O:9][C@H:8]([CH2:10][OH:11])[C@H:7]2[CH2:12][OH:13])[C:4]2[N:14]=[C:15]([NH2:19])[N:16]=[C:17](N)[C:3]=2[N:2]=1.[C@@H]1(N2C3N=CN=C(N)C=3N=C2)O[C@H](COP(O)(O)=O)[C@@H](O)[C@H]1[OH:22]>P([O-])([O-])([O-])=O>[CH:1]1[N:5]([C@@H:6]2[O:9][C@H:8]([CH2:10][OH:11])[C@H:7]2[CH2:12][OH:13])[C:4]2[NH:14][C:15]([NH2:19])=[N:16][C:17](=[O:22])[C:3]=2[N:2]=1
Reactant: Nc1nc(N)c2ncn([C@@H]3O[C@H](CO)[C@H]3CO)c2n1
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@H](COP(=O)(O)O)[C@@H](O)[C@H]1O
Agent: O=P([O-])([O-])[O-]
Product: Nc1nc(=O)c2ncn([C@@H]3O[C@H](CO)[C@H]3CO)c2[nH]1
Temperature: 37 °C
Reaction time: 70 h

Procedure:
After 2.0 g of 2-amino-OXT-A was dissolved in 300 ml of 1/10M phosphate buffer (pH 6.5), 8.0 g of 5'-adenylic acid deaminase (manufactured by Amano Pharmaceutical Co., Ltd., DEAMIZYME®) was added to the solution followed by stirring at 37° C. for 70 hours. After insoluble matters of the reaction solution were removed by filtration, the filtrate was passed through a column packed with 50 ml of activated charcoal powders (manufactured by Wako Pure Chemical Industry K.K., for chromatography). After washing with water, elution was performed with 50% aqueous methanol. By concentrating the desired fraction to dryness, crude OXT-G was obtained. The crude powders were dissolved in 50 ml of water and the OXT-G in the solution was adsorbed onto MCI® GEL CHP 20 (300 ml) followed by elution with water. The desired fraction was concentrated and evaporated to dryness under reduced pressure to give 1.5 g of OXT-G as colorless crystals (yield, 75%).
Reaction SMILES: [S:1]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][S:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH2:17][OH:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(OCC)(=O)C.[O-2].[O-2].[Mn+4]>[S:1]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][S:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH:17]=[O:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCc1ccccc1SCCCCCCSc1ccccc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: CCOC(C)=O
Product: O=Cc1ccccc1SCCCCCCSc1ccccc1

Procedure:
To a suspension of manganese dioxide (11.78 g, 0.135 mole) in ethyl acetate (30 ml) is added a solution of 2-(6-thiophenoxyhexylthio)benzyl alcohol (1.23 g; 0.0037 mole) in ethyl acetate (20 ml). The reaction is conducted as in Example 1c).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[C:13](=[O:17])[NH:14][CH2:15][CH2:16][C:11]=3[NH:10][C:9]=2[CH:18]=O)=[CH:4][CH:3]=1.[CH3:20][O:21][CH2:22][C:23]([NH:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[NH:31][C:30](=[O:35])[CH2:29]2)=[O:24]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]3[C:13](=[O:17])[NH:14][CH2:15][CH2:16][C:11]=3[NH:10][C:9]=2[CH:18]=[C:29]2[C:28]3[C:32](=[CH:33][CH:34]=[C:26]([NH:25][C:23](=[O:24])[CH2:22][O:21][CH3:20])[CH:27]=3)[NH:31][C:30]2=[O:35])=[CH:6][CH:7]=1
Reactant: COCC(=O)Nc1ccc2c(c1)CC(=O)N2
Reactant: O=Cc1[nH]c2c(c1-c1ccc(F)cc1)C(=O)NCC2
Product: COCC(=O)Nc1ccc2c(c1)C(=Cc1[nH]c3c(c1-c1ccc(F)cc1)C(=O)NCC3)C(=O)N2
Yield: 68.7 %

Procedure:
The title compound was prepared under the same conditions as described in Example 46 with 3-(4-fluoro-phenyl)-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and 2-methoxy-N-(2-oxo-2,3-dihydro-1H-indol-5-yl)-acetamide as starting materials to give N-{3-[3-(4-fluoro-phenyl)-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-ylmethylene]-2-oxo-2,3-dihydro-1H-indol-5-yl}-2-methoxy-acetamide (46 mg, 68.7%) as a red solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH:5]=[C:4]([Cl:19])[N:3]=1>C(O)C.[Ni]>[NH2:8][C:7]1[C:2]([Cl:1])=[N:3][C:4]([Cl:19])=[CH:5][C:6]=1[NH:11][C:12](=[O:18])[O:13][C:14]([CH3:15])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)nc(Cl)c1[N+](=O)[O-]
Agent: [Ni]
Solvent: CCO
Product: CC(C)(C)OC(=O)Nc1cc(Cl)nc(Cl)c1N
Temperature: 50 °C
Reaction time: 3 h

Procedure:
tert-Butyl (2,6-dichloro-3-nitropyridin-4-yl)carbamate (65 g, 0.212 mol) was added to a mixture of Raney-Ni (12.5 g) in ethanol (1.5 L) under H2. The mixture was stirred at 50° C. for 3 h. TLC (petroleum/ethyl acetate=5:1) showed that most of the tert-butyl (2,6-dichloro-3-nitropyridin-4-yl)carbamate was consumed. The mixture was filtered, and the filtrate was concentrated to give crude tert-butyl (3-amino-2,6-dichloropyridin-4-yl)carbamate, which was used for the next step without further purification. 1H NMR (400 MHz, CDCl3) δ: 7.84 (s, 1H), 6.85 (s, 1H), 1.54 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]([OH:16])=O)[CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[NH2:17][C:18]([CH2:23][CH3:24])([CH2:21][CH3:22])[CH2:19][OH:20]>>[CH2:21]([C:18]([NH:17][C:14]([C:12]1[CH:11]=[CH:10][CH:9]=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[N:13]=1)=[O:16])([CH2:19][OH:20])[CH2:23][CH3:24])[CH3:22]
Reactant: O=C(O)c1cccc(-c2cccc(Cl)c2)n1
Reactant: CCC(N)(CC)CO
Product: CCC(CC)(CO)NC(=O)c1cccc(-c2cccc(Cl)c2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-(3-chlorophenyl)-2-pyridinecarboxylic acid (CAN 863704-38-5) and 2-amino-2-ethyl-1-butanol (CAN 19792-52-0) as starting materials, MS (LC/MS): 333.1 (M+H).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([N:5]2[C:9]3=[N:10][CH:11]=[N:12][C:13]([NH2:14])=[C:8]3[C:7]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:17][CH:16]=3)=[N:6]2)[CH2:2]1.[NH:28]1[CH:32]=[C:31]([CH2:33][CH2:34][C:35](O)=[O:36])[N:30]=[CH:29]1.Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C.ON1C2N=CC=CC=2N=N1>CN(C)C=O>[NH2:14][C:13]1[N:12]=[CH:11][N:10]=[C:9]2[N:5]([CH:3]3[CH2:2][N:1]([C:35](=[O:36])[CH2:34][CH2:33][C:31]4[N:30]=[CH:29][NH:28][CH:32]=4)[CH2:4]3)[N:6]=[C:7]([C:15]3[CH:16]=[CH:17][C:18]([O:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:19][CH:20]=3)[C:8]=12
Reactant: O=C(O)CCc1c[nH]cn1
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2C1CNC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2C1CN(C(=O)CCc2c[nH]cn2)C1
Temperature: 25 °C
Yield: 28.6 %

Procedure:
A mixture of 1-(3-azetanyl)-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.10 g, 0.00028 mol), 3-(1H-4-imidazolyl)propanoic acid (0.050 g, 0.00035 mol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.0068 g, 0.00035 mol), N,N-diisopropylethylamine (0.068 g, 0.00053 mol) and 1-hydroxy-7-azabenzotriazole (0.038 g, 0.00028 mol) in anhydrous N,N-dimethylformamide (13 mL) was stirred for eighteen hours at room temperature. The solvent was removed under reduced pressure. The residue was dissolved in dichloromethane (5 mL) and washed with water (2 mL). The solvent was removed under reduced pressure. The residue was purified by RP-HPLC (Hypersilprep HS C18, 8 μm, 250×21.1 mm; 5%-100% over 35 min with 0.1 M ammonium acetate, 21 mL/min) to yield 1-{3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-azetanyl}-3-(1H-4-imidazolyl)-1-propanone (0.040 g, 0.00008 mol).
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][S:18]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([Cl:28])[CH:22]=3)(=[O:20])=[O:19])=[CH:14][CH:15]=2)[C:10]([CH3:29])=[N:9]1)=O)(C)(C)C.I[Si](C)(C)C>C(Cl)(Cl)Cl>[Cl:28][C:23]1[CH:22]=[C:21]([S:18]([NH:17][C:13]2[CH:12]=[C:11]3[C:16](=[CH:15][CH:14]=2)[NH:8][N:9]=[C:10]3[CH3:29])(=[O:19])=[O:20])[CH:26]=[CH:25][C:24]=1[Cl:27]
Reactant: Cc1nn(C(=O)OC(C)(C)C)c2ccc(NS(=O)(=O)c3ccc(Cl)c(Cl)c3)cc12
Agent: C[Si](C)(C)I
Solvent: ClC(Cl)Cl
Product: Cc1n[nH]c2ccc(NS(=O)(=O)c3ccc(Cl)c(Cl)c3)cc12
Yield: 80.1 %

Procedure:
3,4-Dichloro-N-(3-methyl-1H-indazol-5-yl)benzenesulfonamide can be obtained as described in Example 6 from 0.8 g of N-(N-tert-butoxycarbonyl-3-methyl-1H-indazol-5-yl)-3,4-dichlorobenzenesulfonamide, 7.1 ml of chloroform and 0.25 ml of iodotrimethylsilane. 0.5 g of 3,4-dichloro-N-(3-methyl-1H-indazol-5-yl)benzenesulfonamide is thus obtained in the form of a white solid melting at 184° C. (analysis: C14H11Cl2N3O2S.0.04CH2Cl2 % calculated, C, 47.21; H, 3.11; Cl, 19.90; N, 11.80; O, 8.98; S, 9.00. % found C, 47.65; H, 2.56; Cl, 19.97; N, 11.89; S, 8.92).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[NH:11][S:12]([CH3:15])(=[O:14])=[O:13].[Br:16]Br>O1CCOCC1>[Br:16][CH2:9][C:8]([C:5]1[CH:6]=[CH:7][C:2]([OH:1])=[C:3]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:4]=1)=[O:10]
Reactant: BrBr
Reactant: CC(=O)c1ccc(O)c(NS(C)(=O)=O)c1
Solvent: C1COCCO1
Product: CS(=O)(=O)Nc1cc(C(=O)CBr)ccc1O
Reaction time: 1 h
Yield: 90.6 %

Procedure:
To a stirred 60° C. dioxane (35 mL) solution of 1-[4-hydroxy-3-[(methylsulfonyl)amino]phenyl]ethanone (2.06 g, 8.7 mmol) was rapidly added Br2 (1.48 g, 9.2 mmol). After one hour, the solution was cooled, concentrated and diluted with H2O. After filtration, the product was washed thoroughly with H2O, then with i-PrOH (9 mL), and air-dried to obtain the title compound (2.43 g, 84%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([OH:12])[CH:11]=1)[N:8]=[C:7]([CH3:13])[CH:6]=[CH:5]2.I[CH:15]([CH3:17])[CH3:16].C([O-])([O-])=O.[K+].[K+].O>CC(C)=O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([O:12][CH:15]([CH3:17])[CH3:16])[CH:11]=1)[N:8]=[C:7]([CH3:13])[CH:6]=[CH:5]2
Reactant: CC(C)I
Reactant: Cc1ccc2cc(F)cc(O)c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: Cc1ccc2cc(F)cc(OC(C)C)c2n1
Temperature: 70 °C
Yield: 89.6 %

Procedure:
To 6-fluoro-2-methylquinolin-8-ol (1.0 g, 5.6 mmol) in acetone (20 mL) were added 2-iodopropane (1.9 g, 11 mmol) and K2CO3 (2.3 g, 17 mmol). The reaction was heated to 70° C. for 20 hours in a sealed tube and then cooled. Water was added and the aqueous phase was extracted with DCM. The combined organic phases were washed with brine, dried with MgSO4, filtered and concentrated under reduced pressure to yield 6-fluoro-8-isopropoxy-2-methylquinoline (1.1 g, 89% yield) as a dark oil.
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].C(=O)(O)[O-].[Na+].[I-].[Na+].[CH:30]1(CBr)[CH2:32][CH2:31]1.Cl>CN(C)C=O.C(O)C>[CH:19]1[C:14]2[CH2:13][C@H:12]3[N:2]([CH2:1][CH:30]4[CH2:32][CH2:31]4)[CH2:3][CH2:4][C@:5]45[C@H:6]([C:7]([CH2:9][CH2:10][C@@:11]34[OH:22])=[O:8])[O:21][C:16]([C:15]=25)=[C:17]([OH:20])[CH:18]=1
Reactant: CN1CC[C@]23c4c5ccc(O)c4O[C@H]2C(=O)C=C[C@@]3(O)[C@H]1C5
Reactant: BrCC1CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [I-]
Solvent: CN(C)C=O
Solvent: CCO
Product: O=C1CC[C@@]2(O)[C@H]3Cc4ccc(O)c5c4[C@@]2(CCN3CC2CC2)[C@H]1O5
Temperature: 70 °C

Procedure:
Steps (S1)-(S3) of Scheme 9 are as described for the corresponding reactions of Scheme 8. In step (S4) of Scheme 9, noroxymorphone prepared as described above is taken up in a solvent, e.g., ethanol or dimethyl formamide, to which sodium bicarbonate, sodium iodide, and ally bromide are added. The mixture is heated to a temperature of about 70° C. and the reaction allowed to proceed until deemed complete. The pH is adjusted with hydrochloric acid and naloxone is isolated as the hydrochloride salt. In a similar manner, in step (S5) of Scheme 9, noroxymorphone prepared as described above is taken up in a solvent, e.g., ethanol or dimethyl formamide, to which sodium bicarbonate, sodium iodide, and cyclopropylmethyl bromide are added. The mixture is heated to a temperature of about 70° C. and the reaction allowed to proceed until deemed complete. The pH is adjusted with hydrochloric acid and naltrexone is isolated as the hydrochloride salt.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH3:9])=[CH:7][N:6]=[C:5]([CH2:10][N:11]2[N:39]=[C:15]3[CH2:16][C:17](=O)[C:18]4[CH2:19][S:20][N:21]=[C:22]([N:23]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:13]([C:14]=43)=[N:12]2)[C:4]=1[CH3:40].C1(P(=[CH:60][C:61]([O:63][CH3:64])=[O:62])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1>C(OCC)(=O)C>[C:34]([O:33][C:31]([N:23]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:22]1[C:13]2[C:14]3[C:15](=[N:39][N:11]([CH2:10][C:5]4[C:4]([CH3:40])=[C:3]([O:2][CH3:1])[C:8]([CH3:9])=[CH:7][N:6]=4)[N:12]=2)[CH:16]=[C:17]([CH2:60][C:61]([O:63][CH3:64])=[O:62])[C:18]=3[CH2:19][S:20][N:21]=1)=[O:32])([CH3:35])([CH3:36])[CH3:37]
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1c(C)cnc(CN2N=C3CC(=O)C4=C3C(=N2)C(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)=NSC4)c1C
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)Cc1cc2nn(Cc3ncc(C)c(OC)c3C)nc3c-2c1CSN=C3N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 60 °C
Reaction time: 10 h
Yield: 33.3 %

Procedure:
A mixture composed of di-tert-butyl {2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-8-oxo-2,7,8,9-tetrahydro-6-thia-1,2,3,5-tetraazabenzo[cd]azulen-4-yl}imidodicarbonate of Example 40 (752 mg), methyl triphenylphosphanylideneacetate (617 mg) and toluene (14 ml) was heated with stirring at 60° C. for 10 hours. Ethyl acetate was added to the reaction mixture, followed by washing with water. Then, the organic layer was dried over sodium sulfate and filtered, and then the filtrate was concentrated under reduced pressure. The concentrated residue was purified by silica gel column chromatography (ethyl acetate-chloroform) to obtain the title compound (275 mg, 33%) as an oil.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]([NH:11]C(=O)OCC)=[N:10][C:5]2=[N:4][CH:3]=1.[OH-].[Na+].Cl>>[CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]([NH2:11])=[N:10][C:5]2=[N:4][CH:3]=1
Reactant: CCOC(=O)Nc1nc2ncc(C)nc2s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1cnc2nc(N)sc2n1
Temperature: 100 °C
Yield: 50.6 %

Procedure:
Ethyl 6-methylthiazolo[5,4-b]pyrazin-2-ylcarbamate (660 mg, 2.77 mmol) was suspended in 1N NaOH (15 ml, 15.00 mmol) and heated in a 100° C. oil bath for 4 h and cooled to ambient temperature. The mixture was acidified with 1N HCl and the resulting precipitate was filtered off and washed with ether, affording 6-methylthiazolo[5,4-b]pyrazin-2-amine (233 mg, 1.402 mmol, 50.6% yield) as a yellow powder. 1H NMR (500 MHz, DMSO-d6) δ ppm 8.26 (s, 2H) 8.12 (s, 1H) 2.43 (s, 3H). MS (LC/MS) R.T.=0.66; [M+H]+=167.0.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([F:11])[CH:10]=1)[C:5](O)=[O:6].CN(C=O)C.C(Cl)(=O)C([Cl:20])=O>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([F:11])[CH:10]=1)[C:5]([Cl:20])=[O:6]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cc(F)cc(Br)c1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cc(F)cc(Br)c1
Temperature: 25 °C
Reaction time: 1.67 h

Procedure:
10 g of 3-bromo-5-fluoro-benzoic acid are suspended in 100 ml of DCM, 0.5 ml DMF and 4.5 ml oxalyl chloride (1.15 Eq) are added and the resulting mixture is stirred for 100 minutes at RT. The solvent is removed by vacuo and the benzoic acid chloride is isolated by distillation.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH2:11][CH:12](SC)[C:13](=[O:16])[NH:14][N:15]=2)[CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8].Cl.O>[OH-].[Na+]>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:11]=[CH:12][C:13](=[O:16])[NH:14][N:15]=2)[CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8]
Reactant: CSC1CC(c2cc(Cl)c(C)c(Cl)c2)=NNC1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1c(Cl)cc(-c2ccc(=O)[nH]n2)cc1Cl
Yield: 94.1 %

Procedure:
A suspension of 1.52 g (0.005 mole) of 6-(3,5-dichloro-4-methylphenyl)-4-methylthio-4,5-dihydro-3(2H)-pyridazinone, prepared as described in Example 1(d), in 30 ml of 1N aqueous sodium hydroxide was refluxed for 1 hour. The reaction mixture was allowed to cool and then acidified by adding concentrated hydrochloric acid, whilst water-cooling. The crystals which precipitated were collected by filtration, thoroughly washed with water and then dried to give 1.2 g (yield 94%) of the desired 6-(3,5-dichloro-4-methylphenyl)-3(2H)pyridazinone, melting at 254°-258° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:9][C:10]([C:12]2[C:17]([NH:18][C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)=[CH:16][CH:15]=[C:14]([CH3:25])[N:13]=2)=[O:11])=[N:6][C:7]=1[CH3:8].Br[C:27]1C(C)=NC=CC=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:9][C:10]([C:12]2[C:17]([NH:18][C:19]3[C:20]([CH3:27])=[N:21][CH:22]=[CH:23][CH:24]=3)=[CH:16][CH:15]=[C:14]([CH3:25])[N:13]=2)=[O:11])=[N:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(Nc2cccnc2)c(C(=O)Nc2ccc(F)c(C)n2)n1
Reactant: Cc1ncccc1Br
Product: Cc1ccc(Nc2cccnc2C)c(C(=O)Nc2ccc(F)c(C)n2)n1

Procedure:
The title compound, was prepared from 3-Amino-6-methyl-pyridine-2-carboxylic acid (5-fluoro-6-methyl-pyridin-2-yl)-amide (example 11) in accordance with the general method of example 20 using 3-Bromo-2-methylpyridine instead of 3-Bromo-4-methylpyridine to yield the final compound as a light yellow crystalline solid, MS (ISP): m/e=352.1 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5](Cl)=[O:6].Cl.[NH2:13][CH:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]([CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:15]1=[O:28].C(=O)([O-])O.[Na+].C(Cl)(Cl)Cl>C(Cl)Cl.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([NH:13][CH:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]([CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:15]1=[O:28])=[O:6]
Reactant: CCCCCN1C(=O)C(N)c2ccccc21
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCCCCN1C(=O)C(NC(=O)c2ccc(Cl)c(Cl)c2)c2ccccc21
Reaction time: 0.5 h
Yield: 93.1 %

Procedure:
Under argon atmosphere and ice cooling, a solution of 2.80 g of 3,4-dichlorobenzoyl chloride in 20 ml of methylene chloride was added dropwise to a mixture of 2.84 g of 3-amino-1-pentyl-2,3-dihydro-1H-indol-2-one hydrochloride, 2.24 g of sodium hydrogen carbonate, 30 ml of chloroform and 30 ml of water. The reaction mixture was stirred under ice cooling for 30 minutes and then at room temperature for 30 minutes, diluted with water and extracted with chloroform. After the chloroform layer was washed and dried, the solvent was removed by evaporation. The residue was recrystallized from ethyl acetate-hexane to afford 4.06 g of 3,4-dichloro-N-(2,3-dihydro-2-oxo-1-pentyl-1H-indol-3-yl)benzamide as colorless crystals. Melting point: 125° to 126° C., IR (Nujol) (cm-1): 3280, 1725, 1635, 1610, MS (m/z): 390 (M+), 374, 372, 217 (base).