Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[CH2:5]([O:7][CH:8]([SiH2:12][CH2:13][CH2:14][CH2:15][NH2:16])[O:9][CH2:10][CH3:11])[CH3:6].CN(C)C1C=CC=CC=1.Cl.CN(C)C1C=CC=CC=1>C1(C)C=CC=CC=1>[CH2:10]([O:9][CH:8]([SiH2:12][CH2:13][CH2:14][CH2:15][N:16]=[C:1]=[O:2])[O:7][CH2:5][CH3:6])[CH3:11]
Reactant: O=C(Cl)Cl
Reactant: CCOC(OCC)[SiH2]CCCN
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CN(C)c1ccccc1
Product: CCOC(OCC)[SiH2]CCCN=C=O
Reaction time: 3 h
Yield: 71.9 %

Procedure:
In 150 ml of toluene was dissolved 9.9 g of carbonyl chloride, and a solution of 19.1 g of γ-diethoxymethylsilylpropylamine and 24.2 g of N,N-dimethylaniline in 50 ml of toluene was dropped into the above solution at -5° C. to -10° C. over a period of 3 hours to effect reaction. After the reaction, N,N-dimethylaniline hydrochloride was removed by filtration, the filtrate was distilled to recover toluene, and a fraction having a boiling point of 91° C. to 93° C. under 9 mmHg was collected. Then, 1 g of sodium benzoate was added to the fraction. The mixture was then stirred for 3 hours and the pH value became 7. Excessive sodium benzoate and the precipitate were removed by filtration, and the filtrate was distilled to obtain 15.6 g of γ-diethoxymethylsilylpropyl isocyanate as a fraction having a boiling point of 80° C. to 82° C. under 5 mmHg. The product remained stable, even when stored for more than 6 months.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[NH2:16][CH:17]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29]2[CH:38]=[CH:37][C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[N:30]=2)=[CH:24][CH:23]=1)[C:18]([OH:20])=[O:19]>>[C:18]([CH:17]([NH:16][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1)[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29]2[CH:38]=[CH:37][C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[N:30]=2)=[CH:24][CH:23]=1)([OH:20])=[O:19]
Reactant: NC(Cc1ccc(Nc2ccc3ccccc3n2)cc1)C(=O)O
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Product: O=C(O)c1cc2cc(Cl)ccc2nc1NC(Cc1ccc(Nc2ccc3ccccc3n2)cc1)C(=O)O

Procedure:
In close analogy to the procedure described in Example 104b, 2,6-dichloroquinoline-3-carboxylic acid is reacted with 2-amino-3-[4-(quinolin-2-ylamino)-phenyl]-propionic acid (prepared by reaction of 2-amino-3-(4-aminophenyl)-propionic acid with 2-chloro-quinoline as in Example 104a) to provide the title compound in good yield.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:16]=[CH:15][C:14]([O:17][CH2:18][CH:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])(C)C)=[O:26])[CH2:21][CH2:20]3)=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(O)(C(F)(F)[F:35])=O.C(N(C(C)C)CC)(C)C.ClC(OCCF)=O>C(Cl)Cl>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:16]=[CH:15][C:14]([O:17][CH2:18][CH:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][CH2:28][CH2:31][F:35])=[O:26])[CH2:21][CH2:20]3)=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCC(COc2ccc(-c3ccc(S(C)(=O)=O)cc3)nc2)CC1
Agent: O=C(Cl)OCCF
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)c1ccc(-c2ccc(OCC3CCN(C(=O)OCCF)CC3)cn2)cc1

Procedure:
The title compound (0.105 g, 90%) was prepared as a white solid from 1,1-dimethylethyl 4-[({6-[4-(methylsulfonyl)phenyl]-3-pyridinyl}oxy)methyl]-1-piperidinecarboxylate (0.12 g, 0.27 mmol) and TFA (0.20 mL) in CH2Cl2 (6 mL) then diisopropylethylamine (1.2 mL) and 2-fluoroethyl chloroformate (42 μL, 0.32 mmol) in a manner similar to Example 74. The crude material was purified by chromatography on a silica gel column eluted with 1:7 acetone/CH2Cl2 to give the title compound as a white solid. 1H NMR (400 MHz, CDCl3): δ 8.39 (d, 1H, J=2.7 Hz), 8.13 (d, 2H, J=8.3 Hz), 8.00 (d, 2H, J=8.5 Hz), 7.73 (d, 1H, J=8.8 Hz), 7.35-7.25 (m, 1H, 4.70-4.55 (m, 2H), 4.40-4.15 (m, 4H), 3.91 (d, 2H, J=6.4 Hz), 3.06 (s, 3H), 2.84 (bs, 2H), 2.10-1.95 (m, 1H), 1.95-1.80 (m, 2H), 1.40-1.25 (m, 2H); LRMS (ESI), m/z 437 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13](I)=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.C([Mg]Br)(C)C.[Li]CCCC.[O:28]1[CH2:33][CH2:32][C:31](=[O:34])[CH2:30][CH2:29]1>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([C:31]4([OH:34])[CH2:32][CH2:33][O:28][CH2:29][CH2:30]4)=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(-n2ncc3cc(I)ccc32)cc1
Reactant: O=C1CCOCC1
Agent: CC(C)[Mg]Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OC1(c2ccc3c(cnn3-c3ccc(F)cc3)c2)CCOCC1
Reaction time: 0.5 h
Yield: 40 %

Procedure:
1-(4-Fluorophenyl)-5-iodo-1H-indazole (350 mg, 1.0 mmol) was dissolved in 10 mL dry THF and treated with isopropylmagnesium bromide (1.6 mL of 1 M THF solution) and then BuLi (1.6 M in hexanes, 0.72 mmol, 1.1 mmol) at room temp. After 30 min, tetrahydro-4H-pyran-4-one (270 mg, 2.7 mmol) was added. After 2 h, the reaction was quenched with water, then 1 M HCl, and extracted 2× EtOAc. The organic layers were dried over MgSO4, filtered, concentrated, and the residue was purified using 1:1 EtOAc/hexanes to give 125 mg (39%) of 4-(1-(4-fluorophenyl)-1H-indazol-5-yl)tetrahydro-2H-pyran-4-ol as a clear oil that solidified upon standing. (M+H)+=313.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[C:6]([N:10]([CH2:14][CH2:15][CH3:16])[CH2:11][CH2:12][CH3:13])[N:5]2[CH:17]=1.[Li]C(C)(C)C.[CH3:23][C:24]1[CH:32]=[C:31]([CH3:33])[CH:30]=[CH:29][C:25]=1[C:26](Cl)=[O:27]>C1COCC1>[CH3:23][C:24]1[CH:32]=[C:31]([CH3:33])[CH:30]=[CH:29][C:25]=1[C:26]([C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[C:6]([N:10]([CH2:14][CH2:15][CH3:16])[CH2:11][CH2:12][CH3:13])[N:5]2[CH:17]=1)=[O:27]
Reactant: CCCN(CCC)c1cccc2nc(Br)cn12
Reactant: Cc1ccc(C(=O)Cl)c(C)c1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CCCN(CCC)c1cccc2nc(C(=O)c3ccc(C)cc3C)cn12
Temperature: 25 °C
Reaction time: 1 h
Yield: 24 %

Procedure:
2-Bromo-N,N-dipropylimidazo[1,2-a]pyridin-5-amine (prepared in example 61) (0.136 g, 0.46 mmol) was dissolved in THF (1 mL). The solution was cooled to −78° C. t-BuLi (1.7M, 0.57 mL, 0.96 mmol) was added dropwise and the solution stirred for 1 hr. at −78° C. 2,4-Dimethylbenzoyl chloride (0.097 g, 0.57 mmol) diluted in 0.5 mL THF was added to the reaction mixture. After 0.5 hr, the solution was quenched with water and warmed to room temperature. Extraction occurred with EtOAc and the organic layer was dried over magnesium sulfate and concentrated. Flash chromatography (30-40% EtOAc/hexanes) gave the title compound. 0.039 g obtained (24% yield).
Reaction SMILES: [F:1][C@:2]1([CH3:18])[C@H:6]([OH:7])[C@@H:5]([CH2:8][OH:9])[O:4][C@H:3]1[N:10]1[CH:17]=[CH:16][C:14](=[O:15])[NH:13][C:11]1=[O:12].COC1C=CC(C(Cl)(C2C=CC=CC=2)C2C=CC(OC)=CC=2)=CC=1.N1C=CN=C1.[Si:48](Cl)([C:51]([CH3:54])([CH3:53])[CH3:52])([CH3:50])[CH3:49].FC(F)(F)C(O)=O.[OH-].[NH4+]>N1C=CC=CC=1.ClCCl.CO.O>[Si:48]([O:7][C@@H:6]1[C@@H:5]([CH2:8][OH:9])[O:4][C@@H:3]([N:10]2[CH:17]=[CH:16][C:14](=[O:15])[NH:13][C:11]2=[O:12])[C@@:2]1([F:1])[CH3:18])([C:51]([CH3:54])([CH3:53])[CH3:52])([CH3:50])[CH3:49]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C[C@@]1(F)[C@H](O)[C@@H](CO)O[C@H]1n1ccc(=O)[nH]c1=O
Agent: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CC(C)(C)[Si](C)(C)O[C@@H]1[C@@H](CO)O[C@@H](n2ccc(=O)[nH]c2=O)[C@]1(C)F
Temperature: 0 °C
Reaction time: 5 h
Yield: 52.1 %

Procedure:
To a solution of 3 (10.0 g, 38.43 mmol) in pyridine (50 mL) were added dichloromethane (50 mL). The solution was cooled to 0° C. To the solution was added 4,4′-dimethoxytrityl chloride (14.32 g, 42.27 mmol) and the solution was stirred at 0° C. for 5 h. Methanol (5 mL) was added to quench the reaction. The solution was concentrated to dryness under reduced pressure and the residue was partitioned between ethyl acetate (500 mL) and water (50 mL). The organic solution was washed with brine (50 mL) and dried (sodium sulfate, 4 g). The solvent was removed under reduced pressure and the residue was dissolved in dichloromethane (100 mL). To the solution were added imidazole (7.83 g, 115 mmol) and t-butyldimethylsilyl chloride (8.68 g, 57.6 mmol). The solution was stirred at ambient temperature for 16 h. Methanol was added to quench the reaction (5 mL) and the solvent was removed under reduced pressure and the residue was partitioned between ethyl acetate (500 mL) and water (50 mL). The organic solution was dried (sodium sulfate, 4 g) and evaporated under reduced pressure. The residue was purified by column chromatography (10-40% EtOAc in Hexane) to give 5′-β-DMT-3′-O-tBDMS intermediate product. This is turn was treated with 1% trifluoroacetic acid in dichloromethane (200 mL). The solution was stirred at ambient temperature for 1 h. Water (20 mL) was added and the solution was stirred at ambient for another 1 h. Methanol (5 mL) was slowly added and the solution was stirred at ambient for another 1 h. Ammonium hydroxide was added to adjust the solution pH to 7. The organic solution was separated, dried (sodium sulfate, 4 g) and evaporated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (1-5% methanol in dichloromethane) to give 12 as a white solid 7.5 g in 50% yield over the three steps. 1H NMR (DMSO-d6) δ (ppm) 11.48 (br s, 1H, NH), 7.94 (d, 1H, H-6), 6.00 (d, 1H, H-1′), 5.69 (d, 1H, H-5), 4.06 (dd, 1H, 3′-H), 3.85 (m, 2H, H-5′a, H-4′), 3.58 (br d, 1H, H-5′ b), 1.27 (d, 3 H, 2-CH3), 0.89 (s, 9H, C(CH3)3), 0.12 (s, 6H, Si(CH3)2).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:40]#[N:41])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:33][CH:34]3[CH2:36][C:35]3([F:38])[F:37])[C:17]([NH:19][C:20]3[CH:32]=[CH:31][C:23]([C:24]([O:26]C(C)(C)C)=[O:25])=[CH:22][CH:21]=3)=[O:18])[C:10](=[O:39])[CH:9]=2)[CH:7]=1.C(O)(C(F)(F)F)=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:40]#[N:41])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:33][CH:34]3[CH2:36][C:35]3([F:38])[F:37])[C:17]([NH:19][C:20]3[CH:32]=[CH:31][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=3)=[O:18])[C:10](=[O:39])[CH:9]=2)[CH:7]=1
Reactant: COc1cn(C(CC2CC2(F)F)C(=O)Nc2ccc(C(=O)OC(C)(C)C)cc2)c(=O)cc1-c1cc(Cl)ccc1C#N
Solvent: O=C(O)C(F)(F)F
Product: COc1cn(C(CC2CC2(F)F)C(=O)Nc2ccc(C(=O)O)cc2)c(=O)cc1-c1cc(Cl)ccc1C#N
Reaction time: 0.58 h

Procedure:
74.0 mg (127 μmol) of tert-butyl 4-({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-[2,2-difluorocyclopropyl]propanoyl}amino)benzoate (mixture of racemic diastereomers) and 195 μl (2.53 mmol) of TFA were reacted according to General Method 2. The crude product was purified by preparative HPLC [column: Chromatorex C18, 10 μm, 125 mm×30 mm, mobile phase: acetonitrile/water gradient (0 to 3 min 15% acetonitrile, to 35 min 90% acetonitrile and a further 3 min 90% acetonitrile)]. Yield: 45 mg (52% of theory)
Reaction SMILES: [N:1]([CH:4]([CH3:14])[CH2:5][C:6]1[S:10][C:9]([C:11]([NH2:13])=[O:12])=[CH:8][CH:7]=1)=[N+]=[N-].N.C(OCC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(#N)C>[NH2:1][CH:4]([CH3:14])[CH2:5][C:6]1[S:10][C:9]([C:11]([NH2:13])=[O:12])=[CH:8][CH:7]=1
Reactant: CC(Cc1ccc(C(N)=O)s1)N=[N+]=[N-]
Agent: N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: CC#N
Product: CC(N)Cc1ccc(C(N)=O)s1

Procedure:
For the preparation of the amine starting material of Example 10f, α-methyl-2-thiophenethanol, acetyl chloride and aluminum chloride were reacted in methylene chloride to give (RS)-2-(5-acetyl-2-thienyl)-1-methylethyl acetate. The resulting acetate was saponified with sodium hydroxide in methanol to give 5-[(RS)-2-hydroxypropyl]-2-thienyl methyl ketone which was subsequently reacted with p-toluenesulfonyl chloride to give (RS)-2-(5-acetyl-2-thienyl)-1-methylethyl-p-toluenesulfonate, m.p. 101°-103°. With sodium azide in dimethylsulfoxide there was obtained therefrom 5-[(RS)-2-azidopropyl]-2-thienyl methyl ketone which was oxidized with bromine in sodium hydroxide solution to give 5-[(RS)-2-azidopropyl]-2-thiophenecarboxylic acid. With thionyl chloride, there was obtained therefrom the corresponding acid chloride and from this there was prepared with ammonia 5-[(RS)-2-azidopropyl]-2-thiophenecarboxamide, m.p. 79°-80° C., from diethyl ether. Treatment with triphenylphosphine and hydrolysis gave 5-[(RS)-2-aminopropyl]-2-thiophenecarboxamide, m.p. 91°-92° from acetonitrile.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][C:11]=3[CH:12]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].C1C(=O)N([Br:31])C(=O)C1.Cl>CC#N>[Br:31][C:13]1[C:11]2[CH:12]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=3)[O:9][C:10]=2[CH:16]=[CH:15][C:14]=1[OH:17]
Reactant: O=C1CCC(=O)N1Br
Reactant: Oc1ccc(-c2cc3cc(O)ccc3o2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Oc1ccc(-c2cc3c(Br)c(O)ccc3o2)cc1
Reaction time: 0.5 h

Procedure:
A solution of 75 2-(4-Hydroxy-phenyl)-benzofuran-5-ol (0.65 g, 2.9 mmol) in CH3CN (40 mL) was treated with K2CO3 (1 g, 7.1 mmol) followed by portionwise addition of NBS (0.36 g, 2.0 mmol). After stirring for approximately 30 minutes, the reaction was worked up by addition of 2 N HCl followed by 10% Na2SO3aq. and then the CH3CN was stripped off. The aqueous layer was extracted with EtOAc and washed with brine and dried over MgSO4. The reaction mixture was concentrated and chromatographed on silica gel (EtOAc/hexanes; 1:4): Mp 196-198° C.; 1H NMR (DMSO-d6) δ 9.93 (br s, 2 H), 7.76 (d, 2H, J=8.5 Hz), 7.40 (d, 1 H, J=8.7 Hz), 7.04 (s, 1 H), 6.87 (dd, 2 H, J=9.0 Hz, 3.1 Hz); MS 305/307 (M+H)+.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N:11]2[N:15]=[CH:14][CH:13]=[N:12]2)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].IC1C=CC(OC)=CC=1[C:19](O)=[O:20].FC1C=CC(I)=C(C=1)C(O)=O>>[CH3:19][O:20][C:2]1[CH:3]=[CH:4][C:5]([N:11]2[N:15]=[CH:14][CH:13]=[N:12]2)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: COc1ccc(I)c(C(=O)O)c1
Reactant: O=C(O)c1cc(F)ccc1-n1nccn1
Agent: O=C(O)c1cc(F)ccc1I
Product: COc1ccc(-n2nccn2)c(C(=O)O)c1

Procedure:
The title compound was prepared in a manner analogous to Intermediate 1, substituting for 2-iodo-5-methoxy benzoic acid for 5-fluoro-2-iodo-benzoic acid in Step A. 1H NMR (400 MHz, CD3OD): 7.81 (s, J=6.4, 2H), 7.55 (d, J=8.8, 1H), 7.33 (d, J=2.9, 1H), 7.18 (dd, J=8.8, 2.9, 1H), 3.85 (s, 3H).
Reaction SMILES: [Cl-].COC[P+:5]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(OC)(=[O:31])CCCC=CC.C(O)(=O)C.[NH4+].[Cl-]>C1(C)C=CC=CC=1.CCOCC>[C:6]1([P:5](=[O:31])([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC=CCCCC(=O)OC
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: CCOCC
Solvent: CC(=O)O
Product: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 0 °C

Procedure:
Into a dry 100 ml round bottom 3-necked flask containing a stir bar is added dried methoxymethyltriphenylphosphonium chloride ((C6H5)3P+ --CH2OCH3Cl-) (12.9 g, 37.7 mmol) and 235 ml distilled toluene (stored over molecular sieves). The resulting suspension is stirred in an ice-bath, under argon, until cold and then a 1.55M solution of 18.3 ml (28.3 mmol) of potassium t-amylate in toluene was added dropwise. A bright red solution formed which is stirred at 0° C. for an additional 35 minutes. Thereafter, a solution of 4.8 g (18.8 mmol) of [1β,2α(5Z),3α,4β]-7-(3-formyl)-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid, methyl ester in 60 ml toluene is added by means of a dropping funnel over a 35 minute period with the ice-bath still in place. The reaction is then quenched by addition of 2.3 g (39 mmol) of acetic acid in 5 ml ether. The mixture is immediately poured into 200 ml saturated NH4Cl, and extracted with ether (4×200 ml). The combined ether phases are washed with NaCl saturated solution, and dried (MgSO4 anhydrous) and concentrated to yield a yellow oil in a white crystalline solid (triphenylphosphine oxide). This is washed with EtOAc and the material in the washings is purified by chromatography on an LPS-1 silica gel column. The fractions obtained are (A) [1α,2β(5Z), 3β,4α]-7-[[3-(2-oxo)ethyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid, methyl ester, (B) [1α,2β(5Z),3β,4α]-7-[3-(2-methoxy)ethendiyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid, methyl ester, and (C) [1α,2β(5Z),3β,4α]-7-[[3-(2,2-dimethoxy)ethyl]-7-oxabicylo[2.2.1]hept-2-yl]-5-heptenoic acid, methyl ester.
Reaction SMILES: [Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[CH:23]=[C:22]([CH3:24])[O:21][N:20]=3)[CH2:14][CH2:13]2)=[C:4]([N+:9]([O-])=O)[C:5]([NH2:8])=[N:6][CH:7]=1.CCO.[CH3:28][O:29][C:30]1[CH:37]=[CH:36][C:33]([CH:34]=O)=[CH:32][CH:31]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(OCC)C>[Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[CH:23]=[C:22]([CH3:24])[O:21][N:20]=3)[CH2:14][CH2:13]2)=[C:4]2[N:9]=[C:34]([C:33]3[CH:36]=[CH:37][C:30]([O:29][CH3:28])=[CH:31][CH:32]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Cc1cc(CN2CCN(c3c(Br)cnc(N)c3[N+](=O)[O-])CC2)no1
Reactant: COc1ccc(C=O)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CCO
Product: COc1ccc(-c2nc3c(N4CCN(Cc5cc(C)on5)CC4)c(Br)cnc3[nH]2)cc1
Temperature: 70 °C
Reaction time: 18 h

Procedure:
To a mixture of 5-bromo-4-[4-(5-methyl-isoxazol-3-ylmethyl)-piperazin-1-yl]-3-nitro-pyridin-2-ylamine (0.044 g, 0.11 mmol) and EtOH (3 ml) was added 4-methoxybenzaldehyde (0.023 g, 0.17 mmol) with the aid of EtOH (1 ml), followed by a freshly prepared aqueous solution of Na2S2O4 (1M; 0.44 ml, 0.44 mmol). The reaction mixture was stirred at 70° C. for 18 h, then allowed to cool to room temperature and concentrated in vacuo. The resulting residue was absorbed on silica, and the free-running powder was placed on a 10 g isolute silica column. Elution with ethyl acetate/dichloromethane (v:v; 3:7) and then 2.5% methanol in ethyl acetate/dichloromethane (v:v; 1:1) afforded a yellow solid. The title compound was obtained as a pale yellow solid after trituration with diethyl ether (0.023 g, 43%); 1H-NMR (500 MHz, DMSO-d6) 2.40 (s, 3H, isoxazole 5-CH3), 2.64 (br s, 4H, piperazine N(CH2)2), 3.60 (s, 2H, NCH2), 3.65 (br s, 4H, piperazine N(CH2)2), 3.84 (s, 3H, OCH3), 6.25 (s, 1H, isoxazole 4-H), 7.10 (d, J=8.9 Hz, 2H) and 8.13 (d, J=8.8 Hz, 2H) (3,5-C6H4 OMe and 2,6-C6H4OMe), 8.20 (s, 1H, imidazo[4,5-b]pyridine 5-H), 13.35 (br s, 1H, imidazo[4,5-b]pyridine N—H);
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8][CH3:9])[NH:5][C:4]2=[N:10][CH:11]=[CH:12][C:3]=12.[CH2:13]([NH2:18])[CH2:14][CH:15]([CH3:17])[CH3:16]>>[CH3:16][CH:15]([CH3:17])[CH2:14][CH2:13][NH:18][C:2]1[N:7]=[C:6]([S:8][CH3:9])[NH:5][C:4]2=[N:10][CH:11]=[CH:12][C:3]=12
Reactant: CSc1nc(Cl)c2ccnc-2[nH]1
Reactant: CC(C)CCN
Product: CSc1nc(NCCC(C)C)c2ccnc-2[nH]1

Procedure:
To 100 mg of 4-chloro-2-methylthiopyrrolo[2,3-d]-pyrimidine was added 2 ml of isopentylamine. The solution was heated at reflux under nitrogen for 2 hours. The resulting dark oil was purified by chromatography on 30 g of Sephadex LH-20, elution with H2O and then with increasing concentrations of EtOH up to 40% EtOH. The appropriate fractions were combined and evaporated to dryness and the solid residue was crystallized from EtOH/H2O to afford white crystals of product, yield 39 mg (38%), m.p. 157°-158° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[CH:10]([C:12]1[C:20]2[C:15](=[N:16][CH:17]=[C:18]([C:21]3[CH2:22][CH2:23][NH:24][CH2:25][CH:26]=3)[CH:19]=2)[NH:14][CH:13]=1)[CH3:11].C[Si]([N:31]=[C:32]=[O:33])(C)C.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[CH:10]([C:12]1[C:20]2[C:15](=[N:16][CH:17]=[C:18]([C:21]3[CH2:22][CH2:23][N:24]([C:32]([NH2:31])=[O:33])[CH2:25][CH:26]=3)[CH:19]=2)[NH:14][CH:13]=1)[CH3:11]
Reactant: CC(c1c(Cl)ccc(F)c1Cl)c1c[nH]c2ncc(C3=CCNCC3)cc12
Reactant: C[Si](C)(C)N=C=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(c1c(Cl)ccc(F)c1Cl)c1c[nH]c2ncc(C3=CCN(C(N)=O)CC3)cc12
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A mixture of 3-[1-(2,6-dichloro-3-fluorophenyl)-ethyl]-5-(1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridine (12.0 mg, 0.0307 mmol), trimethylsilyl isocyanate (8.32 μL, 0.0615 mmol), DIPEA (26.8 μL, 0.154 mmol) and DMF (0.5 mL) was stirred at rt for 20 min. The solution was concentrated in vacuo, redissolved in MeOH (0.5 mL) and purified via HPLC. The fractions containing the pure product were concentrated in vacuo to afford the title compound as a white solid. 1H NMR (400 MHz, CD3OD): δ=1.87 (d, J=7.1 Hz, 3 H), 2.28-2.51 (m, 2 H), 3.60 (t, J=5.8 Hz, 2 H), 4.02 (q, J=2.5 Hz, 2 H), 5.26 (q, J=7.1 Hz, 1 H), 5.88-5.94 (m, 1 H), 7.18 (t, J=8.6 Hz, 1 H), 7.29 (d, J=2.0 Hz, 1 H), 7.32-7.55 (m, 2 H), 8.23 (br. s., 1 H). MS (ES+): m/z 433.02 (100) [MH+]. HPLC: tR=3.15 min (ZQ3, polar—5 min).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]=O.[CH3:14][NH:15][CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[BH4-].[Na+]>CO.S(=O)(=O)(O)O>[CH3:1][O:2][C:3](=[O:13])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][N:15]([CH3:14])[CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COC(=O)CCCCCCCC=O
Reactant: CNCCc1ccccc1
Agent: O=S(=O)(O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)CCCCCCCCN(C)CCc1ccccc1

Procedure:
To a solution of 9-oxononanoic acid methyl ester (J. Org. Chem. 2007, 72, 9471; 303 mg, 1.63 mmol) and N-methyl-2-phenylethylamine (220 mg, 1.63 mmol) in methanol (10 mL) was added concentrated sulfuric acid (5 drops) at room temperature, then after 40 h the solution was heated at reflux for 2 h. After cooling sodium borohydride (123 mg, 3.25 mmol) was added, then after 1 h the reaction mixture was partitioned between water and dichloromethane. The organic layer was dried over sodium sulfate, filtered, and evaporated to afford 9-(methyl-phenethyl-amino)-nonanoic acid methyl ester as a light yellow liquid.
Reaction SMILES: [C:1]1([CH3:23])[CH:6]=[CH:5][C:4]([NH:7][C:8](=[O:22])[NH:9][C:10]2[S:11][CH:12]=[C:13]([C:15](=O)[C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:14]=2)=[CH:3][CH:2]=1.[S:24]1[CH2:30][C:28](=[O:29])[N:27]([CH2:31][C:32]([OH:34])=[O:33])[C:25]1=[S:26].[Cl-].[NH4+].N>C(O)C>[CH2:19]([O:18][C:16]([C:15](=[C:30]1[S:24][C:25](=[S:26])[N:27]([CH2:31][C:32]([OH:34])=[O:33])[C:28]1=[O:29])[C:13]1[N:14]=[C:10]([NH:9][C:8]([NH:7][C:4]2[CH:5]=[CH:6][C:1]([CH3:23])=[CH:2][CH:3]=2)=[O:22])[S:11][CH:12]=1)=[O:17])[CH3:20]
Reactant: O=C(O)CN1C(=O)CSC1=S
Reactant: CCOC(=O)C(=O)c1csc(NC(=O)Nc2ccc(C)cc2)n1
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: CCOC(=O)C(=C1SC(=S)N(CC(=O)O)C1=O)c1csc(NC(=O)Nc2ccc(C)cc2)n1

Procedure:
Following a procedure similar to that described in Example 1, the desired compound was prepared using 4.8 g of ethyl 2-(3-p-tolylureido)thiazol-4-ylglyoxylate, 2.5 g of rhodanine-3-acetic acid, 1.5 g of ammonium chloride, 1.5 ml of 20% v/v aqueous ammonia and 50 ml of ethanol. The resulting product was a yellow powder having the following physical properties.