Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C:2]1([N+:21]([O-])=O)[C:7]([O:8][CH2:9][C:10]([F:13])([F:12])[F:11])=[CH:6][C:5]([CH3:14])=[N:4][CH:3]1[O:15][CH2:16][C:17]([F:20])([F:19])[F:18].CN(C)C1C=CC=CC=1.[Br:33][CH2:34][C:35](Br)=[O:36]>ClCCl>[Br:33][CH2:34][C:35]([NH:21][C:2]1[C:3]([O:15][CH2:16][C:17]([F:18])([F:19])[F:20])=[N:4][C:5]([CH3:14])=[CH:6][C:7]=1[O:8][CH2:9][C:10]([F:11])([F:12])[F:13])=[O:36]
Reactant: CC1=NC(OCC(F)(F)F)C(N)([N+](=O)[O-])C(OCC(F)(F)F)=C1
Reactant: O=C(Br)CBr
Solvent: CN(C)c1ccccc1
Solvent: ClCCl
Product: Cc1cc(OCC(F)(F)F)c(NC(=O)CBr)c(OCC(F)(F)F)n1
Yield: 85 %

Procedure:
3-Amino-2,4-bis(2,2,2-trifluoroethoxy)-6-methyl-3-nitropyridine (42.29 g, 139.0 mmol) was dissolved in dichloromethane (600 mL), followed by the addition of N,N-dimethylaniline (20.46 g, 16.8 mmol). While stirring the mixture in an ice bath, a solution of bromoacetyl bromide (28.73 g, 142.3 mmol) in dichloromethane (100 mL) was added dropwise, and the reaction mixture was stirred at room temperature for 10 minutes. The reaction mixture was extracted with chloroform-water. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized from chloroform-hexane to obtain the title compound (50.25 g, 85%) as colorless needles.
Reaction SMILES: C([O:4][CH2:5][CH2:6][O:7][C:8]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)=[C:11]([NH2:20])[N:10]([CH3:21])[N:9]=1)(=O)C.[H-].[Na+].[C:24]([C:29]1[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=1)([CH2:27][CH3:28])([CH3:26])[CH3:25]>CC(N(C)C)=O.O>[OH:4][CH2:5][CH2:6][O:7][C:8]1[C:12]([C:13]2[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][CH:18]=2)=[C:11]([NH:20][S:35]([C:32]2[CH:33]=[CH:34][C:29]([C:24]([CH2:27][CH3:28])([CH3:25])[CH3:26])=[CH:30][CH:31]=2)(=[O:37])=[O:36])[N:10]([CH3:21])[N:9]=1
Reactant: CCC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(=O)OCCOc1nn(C)c(N)c1-c1ccc(C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCC(C)(C)c1ccc(S(=O)(=O)Nc2c(-c3ccc(C)cc3)c(OCCO)nn2C)cc1
Reaction time: 2 h

Procedure:
To 2-{[5-amino-1-methyl-4-(4-methylphenyl)-1H-pyrazol-3-yl]oxy}ethyl acetate (Preparation 5) (1.0 g) in dimethylacetamide (10 ml) at 0° C. under an atmosphere of nitrogen was added sodium hydride (60% dispersion in oil, 415 mg) followed by 4-tert-amylbenzenesulphonyl chloride and (938 mg), the mixture was stirred for 2 hrs. The reaction was diluted with water (50 ml) and extracted with dichloromethane (5×30 ml). The crude mixture was dissolved in ethanol (50 ml) and sodium hydroxide (2N, 5 ml) was added, the mixture was stirred at room temperature for 48 hrs and then neutralised to pH 7 by addition of hydrochloric acid (2N) and extracted with dichloromethane (2×50 ml). The organic fractions were combined, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica, 10 g) eluted with ethyl acetate:hexane (1:1) to yield the title compound as a white solid (290 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][NH:7]2.[Br:12]N1C(=O)CCC1=O>C(Cl)Cl>[Br:12][C:11]1[C:2]([Cl:1])=[C:3]2[C:8](=[N:9][CH:10]=1)[NH:7][CH2:6][CH2:5][CH2:4]2
Reactant: Clc1ccnc2c1CCCN2
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: Clc1c(Br)cnc2c1CCCN2
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.6 %

Procedure:
To a solution of 5-chloro-1,2,3,4-tetrahydro-[1,8]naphthyridine (500 mg, 3.0 mmol) in DCM (40 mL) is added N-bromosuccinimide (530 mg, 3.0 mmol). The reaction mixture is stirred at room temperature for 2 hrs. The reaction mixture is concentrated to give the crude product. Purification by flash column chromatography affords 680 mg of 6-bromo-5-chloro-1,2,3,4-tetrahydro-[1,8]naphthyridine.
Reaction SMILES: CC(C)([O-])C.[Na+].[F:7][CH:8]([F:34])[O:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]([NH:19][CH:20]2[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]2)=[O:18])=[C:12](I)[CH:11]=1.ClCCl>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[F:7][CH:8]([F:34])[O:9][C:10]1[CH:15]=[CH:14][C:13]2[NH:16][C:17](=[O:18])[N:19]([CH:20]3[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]3)[C:12]=2[CH:11]=1
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)Nc2ccc(OC(F)F)cc2I)CC1
Agent: [Fe+2]
Agent: [Pd]
Agent: CC(C)(C)[O-]
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC(n2c(=O)[nH]c3ccc(OC(F)F)cc32)CC1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
A solution of tris(dibenzylideneacetone)dipalladium (0) (0.18 g), 1,1′-bis(diphenylphosphino)ferrocene (0.10 g), sodium tert-butoxide (0.6 g) in 1,4-dioxane (10 ml) was stirred under an atmosphere of argon for 10 minutes. 1,1-Dimethylethyl 4-{[({4-[(difluoromethyl)oxy]-2-iodophenyl}amino)carbonyl]amino}-1-piperidinecarboxylate (D52, 1.3 g) was added and the mixture was heated to 90° C. The mixture was stirred at this temperature overnight. The mixture was poured into dichloromethane which was washed with water and brine. The solvent was removed and the residue was chromatographed on silica gel eluted with ethyl acetate/hexane 0-50% to give the title compound as a off-white solid. (0.54 g).
Reaction SMILES: [N:1]1[N:5]2[CH:6]=[C:7](O)[CH:8]=[CH:9][C:4]2=[CH:3][CH:2]=1.[O-]S(C(F)(F)F)(=O)=O.[CH2:19](N(CC)CC)[CH3:20]>ClCCl>[C:19]([C:7]1[CH:8]=[CH:9][C:4]2[N:5]([N:1]=[CH:2][CH:3]=2)[CH:6]=1)#[CH:20]
Reactant: CCN(CC)CC
Reactant: Oc1ccc2ccnn2c1
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: ClCCl
Product: C#Cc1ccc2ccnn2c1

Procedure:
A 6-ethynyl-pyrazolo[1,5-a]pyridine of formula ID can be obtained by decarboxylation of an appropriately substituted 6-methoxy-pyrazolo[1,5-a]pyridine-3-carboxylic acid ester 22 with hydrobromic acid, yielding the corresponding pyrazolo[1,5-a]pyridin-6-ol derivative 23, which is converted to the triflate derivative 25 using trifluoromethanesulfonic anhydride 24 and a base such as triethylamine in a solvent such as dichloromethane. Sonogashira coupling of 25 with an aryl-acetylene of formula 3 yields the desired 6-ethynyl-pyrazolo[1,5-a]pyridine of formula ID (scheme 5).
Reaction SMILES: C(OC([NH:8][CH:9]1[CH2:14][CH2:13][C:12](=[O:15])[NH:11][C:10]1=[O:16])=O)(C)(C)C.[C:17]([OH:23])([C:19]([F:22])([F:21])[F:20])=[O:18]>C(Cl)Cl>[F:20][C:19]([F:22])([F:21])[C:17]([OH:23])=[O:18].[NH2:8][CH:9]1[CH2:14][CH2:13][C:12](=[O:15])[NH:11][C:10]1=[O:16]
Reactant: CC(C)(C)OC(=O)NC1CCC(=O)NC1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC1CCC(=O)NC1=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Compound 203 (1.14 g, 5 mmol) was suspended in CH2Cl2 (100 mL). To the mixture was added CF3COOH (10 mL) and this then was stirred at room temperature for 4 h. The solvent was evaporated to give crude 204 (1.25 g): 1H NMR (DMSO-d6) δ 11.42 (s, 1H), 8.70 (br, 2H), 4.31 (dd, J=5.4 Hz, J=13 Hz), 2.88-2.72 (m, 2H), 2.25-2.09 (m, 2H). A mixture of crude 204 (1.25 g) and phthalic anhydride (0.89 g, 6 mmol) and Et3N (1.39 ml, 10 mmol) in THF (150 mL) was refluxed for two days. The reaction mixture was concentrated and the residue was crystallized from ethyl acetate to give thalidomide (201) (0.89 g, 69%) as white crystals; mp 276° C. (lit. 276-279° C.). A mixture of thalidomide 201 (258 mg, 1 mmol) and Lawesson's reagent (222 mg, 0.55 mmol) in toluene (50 ml) was stirred at reflux for 12 h; thereafter, solvent was removed under vacuum. The resulting residue was purified by column chromatography using CH2Cl2 as the eluent to afford compound 205 (200 mg, 73%) as a yellow solid: mp 225-226° C.; 1H NMR (DMSO-d6) δ 12.83 (s, 1H, NH), 8.00-7.92 (m, 4H, Ph), 5.32 (dd, J=5.6 Hz, J=12.9 Hz, 1H, H-3′), 3.28-3.25 (m, 2H, H-5′), 2.60-2.54 (m, 1H, H-4′), 2.17-2.10 (m, 1H, H-4′); 13C NMR (DMSO-d6) δ 208.7 (C-6′), 165.3 (C-2′), 165.2 (C-1 & C-3), 133.1 (C-5 & C-6), 129.3 (C-3a, C-7a), 121.7 (C-4 & C-7), 46.9 (C-3′), 38.9 (C-5′), 21.79 (C-4′); MS (CI/CH4) m/z 274 (M+); Anal. (C13H10N2O3S) C, H, N.
Reaction SMILES: [C:1]1([N:7]2[C:11]3([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[C:10](=[O:17])[NH:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH2:19][C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>CC(=O)CC>[C:20]1([CH2:19][N:14]2[CH2:13][CH2:12][C:11]3([N:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH2:8][NH:9][C:10]3=[O:17])[CH2:16][CH2:15]2)[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: O=C1NCN(c2ccccc2)C12CCNCC2
Reactant: ClCc1cccc2ccccc12
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: O=C1NCN(c2ccccc2)C12CCN(Cc1cccc3ccccc13)CC2
Yield: 67.7 %

Procedure:
1-Phenyl-1,3,8-triaza-spiro[4.5]decan-4-one (185.04 g, 0.76 mol) was suspended in 2-butanone (3600 ml). 1-(Chloromethyl)naphthalene (169.21 g, 0.91 mol), dry potassium carbonate (345.42 g, 2.50 mol) and sodium iodide (113.91 g, 0.76 mol) were added and the mixture was heated at reflux temperature for 24 h. The solvent was evaporated in vacuo and the remainder was distributed between water (2000 ml) and diethyl ether (2000 ml). The formed precipitate was collected by filtration, washed successively with water (800 ml), toluene (600 ml) and ice cold acetone (2×200 ml) and dried affording the title compound as a powder (191.20 g, 68% yield).
Reaction SMILES: [CH2:1]([O:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][O:7]1)[CH2:2][C:3]#[CH:4].C([Li])CCC.[P:17](Cl)([O:22][CH2:23][CH3:24])([O:19][CH2:20][CH3:21])=[O:18].C(=O)(O)[O-].[Na+]>O1CCCC1>[O:7]1[CH2:8][CH2:9][CH2:10][CH2:11][CH:6]1[O:5][CH2:1][CH2:2][C:3]#[C:4][P:17](=[O:18])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21]
Reactant: C#CCCOC1CCCCO1
Reactant: CCOP(=O)(Cl)OCC
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOP(=O)(C#CCCOC1CCCCO1)OCC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of tetrahydro-2-(3-butynyloxy)2H-pyran (20 g, 0.13 mol) in anhydrous tetrahydrofuran (200 ml) is cooled in a dry ice-acetone bath and treated dropwise with n-butyllithium (2.5M in hexane, 0.13 mol) in tetrahydrofuran (20 ml). The anion is stirred for 30 minutes and treated with diethyl chlorophosphate in tetrahydrofuran added via a slow stream. The reaction mixture is stirred 15 minutes and then warmed to room temperature overnight. A saturated aqueous solution of sodium bicarbonate (125 ml) is added and the mixture extracted with ethyl acetate (2×150 ml). The organic layer is separated, dried (magnesium sulfate), filtered and evaporated. The residue is chromatographed over silica gel and eluted with ethyl acetate in chloroform to give the title compound.
Reaction SMILES: C(OC(N1CC[C@H](C2C=CC=CC=2)[C@H](C(O)=O)C1)=O)(C)(C)C.C(OC(N1CC[C@H](C2C=CC=CC=2)[C@H](C([N:44]2[CH2:49][CH2:48][N:47]([C:50]3[CH:55]=[C:54]([CH3:56])[CH:53]=[CH:52][C:51]=3[CH3:57])[CH2:46][CH2:45]2)=O)C1)=O)(C)(C)C>>[CH3:57][C:51]1[CH:52]=[CH:53][C:54]([CH3:56])=[CH:55][C:50]=1[N:47]1[CH2:46][CH2:45][NH:44][CH2:49][CH2:48]1
Reactant: Cc1ccc(C)c(N2CCN(C(=O)[C@@H]3CN(C(=O)OC(C)(C)C)CC[C@@H]3c3ccccc3)CC2)c1
Agent: CC(C)(C)OC(=O)N1CC[C@H](c2ccccc2)[C@H](C(=O)O)C1
Product: Cc1ccc(C)c(N2CCNCC2)c1

Procedure:
In analogy to example 1, step 1, from (3S,4S)-4-phenyl-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester (CAS Reg. No.: [197900-77-9]) and 1-(2,5-dimethylphenyl)piperazine was prepared (3S,4S)-3-[4-(2,5-dimethyl-phenyl)-piperazine-1-carbonyl]-4-phenyl-piperidine-1-carboxylic acid tert-butyl ester as a white foam, MS: 478.28 ([M+H])+.
Reaction SMILES: [CH3:1][C:2]1([CH3:33])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[C:8]2[CH:7]=[C:6]([C:19]([NH:21][C:22]3[CH:32]=[CH:31][C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:24][CH:23]=3)=O)[CH:5]=[CH:4][C:3]1=2.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:43]2)=CC=1>C1C=CC=CC=1>[CH3:1][C:2]1([CH3:33])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[C:8]2[CH:7]=[C:6]([C:19]([NH:21][C:22]3[CH:32]=[CH:31][C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:24][CH:23]=3)=[S:43])[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)c1ccc(NC(=O)c2ccc3c(c2)C(c2ccc(C)cc2)=CCC3(C)C)cc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: c1ccccc1
Product: CCOC(=O)c1ccc(NC(=S)c2ccc3c(c2)C(c2ccc(C)cc2)=CCC3(C)C)cc1
Temperature: 25 °C

Procedure:
A solution of 110.0 mg (0.25 mmol) ethyl 4-[[(5,6-dihydro-5,5-dimethyl-8-(4-methylphenyl)-2-naphthalenyl)carbonyl]amino]-benzoate (Compound 35) and 121.0 mg (0.30 mmol) of [2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide] (Lawesson's Reagent) in 12.0 ml of benzene was refluxed overnight. Upon cooling to room temperature, the mixture was filtered and the filtrate concentrated under reduced pressure. The title compound was isolated by column chromatography (10 to 25% EtOAc/hexanes) as a yellow solid. 1H NMR (CDCl3): δ 8.92 (1H, s), 8.06 (2H, t, J=8.5 Hz), 7.88-7.70 (3H, m), 7.42 (2H, d, J=8.1 Hz), 7.18 (4H, m), 6.03 (1H, t, J=4.7 Hz), 4.37 (2H, q, J=7.1 Hz), 2.38 (3H, s), 2,36 (2H, d, J=4.7 Hz), 1.56 (3H, t, J=7.1 Hz), 1.35 (6H, s).
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:27](Cl)(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.O>ClCCl>[C:27]([NH:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1)(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: Nc1ccc(C(=O)N2CCCc3ccccc32)cc1
Reactant: O=C(Cl)c1ccccc1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(C(=O)N2CCCc3ccccc32)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 34.7 %

Procedure:
To a solution of 1-(4-aminobenzoyl)-1,2,3,4-tetrahydroquinoline (0.5 g) in dichloromethane (20 ml) is added triethylamine (0.3 g), and thereto is added benzoyl chloride (0.28 g) under ice-cooling. The mixture is stirred at room temperature for 1 hour. To the reaction mixture is added water and extracted with dichloromethane. The extract is dried over magnesium sulfate and the solvent is distilled off under reduced pressure. The resulting residue is purified by silica gel column chromatography (eluent; dichloromethane:methanol=50:1) and recrystallized from methanol to give 1-[4-(benzoylamino)benzoyl]-1,2,3,4-tetrahydroquinoline (245 mg) as white powder, m.p. 202.5-203.5° C.
Reaction SMILES: [CH2:1]([P:3]([C:7]1[CH:12]=[C:11]([O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[Cl:24])[CH:10]=[CH:9][C:8]=1[N+:25]([O-:27])=[O:26])(=O)[O:4]C)[CH3:2].S(Cl)([Cl:30])=O>>[CH2:1]([P:3]([Cl:30])([C:7]1[CH:12]=[C:11]([O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[Cl:24])[CH:10]=[CH:9][C:8]=1[N+:25]([O-:27])=[O:26])=[O:4])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CCP(=O)(OC)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Product: CCP(=O)(Cl)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]

Procedure:
A mixture of methyl P-ethyl-2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenylphosphinate (700 mg, 1.65 mmol) and thionyl chloride (5 ml) is heated under reflux for 2 hours. The reaction mixture is concentrated to dryness to give P-ethyl-2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenylphosphinic chloride. To a solution of the phosphinic chloride in methylene chloride (8 ml) is added methyl 2-hydroxyimino-3-methylbutanoate (320 mg, 2.48 mmol) in one portion. The mixture is stirred at RT for 3 hours. The reaction is then worked up in methylene chloride, washed, dried, evaporated to dryness and purified by prep. TLC to yield methyl 2-[P-ethyl-2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenylphosphinyloxyimino]-3-methylbutanoate.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1.[N:28]1([C:34]2[CH:42]=[CH:41][C:37]([C:38](O)=[O:39])=[CH:36][CH:35]=2)[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>>[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:38](=[O:39])[C:37]5[CH:36]=[CH:35][C:34]([N:28]6[CH2:33][CH2:32][O:31][CH2:30][CH2:29]6)=[CH:42][CH:41]=5)[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1
Reactant: O=C(O)c1ccc(N2CCOCC2)cc1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1)c1ccc(N2CCOCC2)cc1

Procedure:
The title compound, off-white solid (104 mg, 80%), MS (ISP) m/z=520.5 [(M+H)+], mp 228.5° C., was prepared in accordance with the general method of example 32 from trans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanamine trihydrochloride (intermediate C) (110 mg, 0.25 mmol) and 4-morpholin-4-yl-benzoic acid.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[NH2:8][C:9]1[CH:10]=[CH:11][C:12]([O:22][CH2:23][CH:24]([OH:31])[CH2:25][NH:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[C:13]([C:15]2[CH:16]=[CH:17][C:18](=[S:21])[NH:19][N:20]=2)[CH:14]=1>>[C:1]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([O:22][CH2:23][CH:24]([OH:31])[CH2:25][NH:26][C:27]([CH3:28])([CH3:30])[CH3:29])=[C:13]([C:15]2[CH:16]=[CH:17][C:18](=[S:21])[NH:19][N:20]=2)[CH:14]=1)(=[O:3])[CH3:2]
Reactant: CC(C)(C)NCC(O)COc1ccc(N)cc1-c1ccc(=S)[nH]n1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1ccc(OCC(O)CNC(C)(C)C)c(-c2ccc(=S)[nH]n2)c1

Procedure:
Addition of acetic anhydride to a stirred suspension of 6-[5-amino-2-(3-t-butylamino-2-hydroxypropoxy)phenyl]-3(3H)-pyridazinethione in an aqueous buffer solution at pH 5.5 gave 6-[5-acetamido-2-(3-t-butylamino-2-hydroxypropoxy)phenyl]-3(2H)-pyridazinethione.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([C@H:7]2[O:9][C@@H:8]2[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:5][CH:6]=1.[OH:16][CH:17]([CH2:20][NH2:21])[CH2:18][NH2:19]>>[OH:16][CH:17]([CH2:20][NH:21][CH:8]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[CH:7]([C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1)[OH:9])[CH2:18][NH:19][CH:7]([C:4]1[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1)[CH:8]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[OH:9]
Reactant: NCC(O)CN
Reactant: c1ccc([C@H]2O[C@@H]2c2ccccc2)cc1
Product: OC(CNC(c1ccccc1)C(O)c1ccccc1)CNC(c1ccccc1)C(O)c1ccccc1
Yield: 55 %

Procedure:
A mixture of trans-stilbene oxide (3.93 g, 0.020 mol) and 2-hydroxy-1,3-propanediamine (0.90 g, 0.010 mol) was heated on a steam bath for 18 hours, giving a white solid. The material was triturated with boiling toluene and allowed to cool. The white solid that formed was collected, washed with toluene, and dried under ambient conditions for 18 hours. The solid was then vacuum dried over refluxing toluene for 4 hours to obtain 2.60 g (55% yield); mp 155°-175° C. (undefined).
Reaction SMILES: C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:53]([NH2:57])[CH2:54][CH2:55][CH3:56].[N+:58]([C:61]1[CH:70]=[CH:69][C:64]([C:65]([O:67][CH3:68])=[O:66])=[CH:63][C:62]=1OS(C(F)(F)F)(=O)=O)([O-:60])=[O:59]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:53]([NH:57][C:70]1[CH:69]=[C:64]([CH:63]=[CH:62][C:61]=1[N+:58]([O-:60])=[O:59])[C:65]([O:67][CH3:68])=[O:66])[CH2:54][CH2:55][CH3:56]
Reactant: COC(=O)c1ccc([N+](=O)[O-])c(OS(=O)(=O)C(F)(F)F)c1
Reactant: CCCCN
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CCCCNc1cc(C(=O)OC)ccc1[N+](=O)[O-]
Temperature: 80 °C

Procedure:
To a stirred solution of Pd2(dba)3 (139 mg), BINAP (284 mg), and cesium carbonate (2.0 g) in toluene (50 mL) was added butylamine (0.45 mL), and the reaction mixture was heated at 80° C. for 15 min. A solution of methyl 4-nitro-3-{[(trifluoromethyl)sulfonyl]oxy}benzoate (1.0 g) in toluene (15 mL) was added dropwise over 1 h. The mixture was cooled to room temperature, filtered through diatomaceous earth, and concentrated under reduced pressure. Purification by flash column chromatography (silica, 3:1 ethyl acetate/hexanes) provided 670 mg of the title compound as a yellow oil: ESI MS m/z 550 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:12]=[C:11]([O:23][C:24]2[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=2)[C:10]=1[C:33](=[O:42])[CH2:34][C:35](=O)[C:36]([O:38][CH2:39][CH3:40])=[O:37])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:44]O>C(O)C>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:12]=[C:11]([O:23][C:24]2[CH:25]=[CH:26][C:27]([N+:30]([O-:32])=[O:31])=[CH:28][CH:29]=2)[C:10]=1[C:33]1[O:42][N:44]=[C:35]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH:34]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(=O)CC(=O)c1c(OCc2ccccc2)cc(OCc2ccccc2)cc1Oc1ccc([N+](=O)[O-])cc1
Reactant: NO
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1cc(-c2c(OCc3ccccc3)cc(OCc3ccccc3)cc2Oc2ccc([N+](=O)[O-])cc2)on1
Yield: 80.4 %

Procedure:
A stirred solution of ethyl 4-[2,4-bis(benzyloxy)-6-(4-nitrophenoxy)phenyl]-2,4-dioxobutanoate (5 g, 9 mmol) and hydroxylamine hydrochloride (0.74 g, 15 mmol, 1.2 eq) in ethanol (mL 50) was refluxed for 2 hours. The solution was concentrated to a small volume and diluted with ethyl acetate. After washing with brine and drying, the solvent was removed and the residue was carefully chromatographed on silica gel eluting with hexane/ethyl acetate 6/1, to provide the title compound (4.1 g, 82% yield).
Reaction SMILES: ClCCl.CO[C:6]1[N:16]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]3[NH:34][N:33]=[N:32][N:31]=3)=[CH:20][CH:19]=2)[C:9]2=[N:10][C:11](C)=[CH:12][C:13]([CH3:14])=[C:8]2[N:7]=1.B(Br)(Br)Br.[CH3:39][OH:40]>>[OH:40][CH2:39][C:6]1[N:16]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]3[NH:34][N:33]=[N:32][N:31]=3)=[CH:20][CH:19]=2)[C:9]2=[N:10][CH:11]=[CH:12][C:13]([CH3:14])=[C:8]2[N:7]=1
Reactant: COc1nc2c(C)cc(C)nc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Reactant: CO
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1ccnc2c1nc(CO)n2Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
30 ml of a dichloromethane solution of 410 mg (1 mmol) of 2-methoxy-methyl-7-methyl-3[(2'-(1H-tetrazol-5-yl)-biphenyl-4-yl)-methyl]-3H-imidazo[4.5-b]pyridine was stirred, cooled with ice. During this step, 10 ml (10 mmol) of dichloromethane solution of 1M boron tribromide was added little by little thereto dropwise. The mixture was further agitated at a room temperature for 12 hours. The reaction product mixture was cooled, while stirred. During this step, methanol was added little by little. The solvent was distilled out at a reduced pressure. The residue was mixed with water, neutralized with sodium bicarbonate, adjusted to a weak acidity with acetic acid and decanted to remove the water. The residue was mixed with methanol. The solvent was distilled out at a reduced pressure. The residue was treated with isopropylether for re-crystallization to obtain 330 mg of the intended compound.