Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[N:15]=[C:14]2[C:10]([C:11]([C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=3)=[C:12]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[NH:13]2)=[CH:9][CH:8]=1.CN(C1C=CC=CN=1)C.[OH-].[Na+]>C(Cl)(Cl)Cl>[CH3:1][S:2]([NH:6][C:7]1[N:15]=[C:14]2[C:10]([C:11]([C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=3)=[C:12]([C:16]3[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=3)[NH:13]2)=[CH:9][CH:8]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccc2c(-c3ccncc3)c(-c3ccc(F)cc3)[nH]c2n1
Agent: CN(C)c1ccccn1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CS(=O)(=O)Nc1ccc2c(-c3ccncc3)c(-c3ccc(F)cc3)[nH]c2n1
Reaction time: 24 h

Procedure:
Methanesulfonyl chloride (5 ml, 0.07 mmol) was added dropwise to 6-amino-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole (17) (20 mg, 0.066 mmol), dimethylamino pyridine (1 mg, 0.007 mmol), and chloroform (3 mL). After 24 h at 23° C., an additional 4 equivalents of methanesulfonyl chloride was added. After 4 h at 23° C., NaOH (10N, 3 mL) was added. After 3 h, the mixture was extracted with ethyl acetate (50 mL), washed with water (3×15 mL), and dried (Na2SO4). After concentration in vacuo, the residue was purified by application of preparative plate chromatography (two 2 mm silica gel plates, ethyl acetate) to afford 6-(methylsulfonyl amino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole (56): Mass Spectrum (CI) 383 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH2:25][C:26]1[N:27]=[C:28]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[S:29][C:30]=1[CH3:31])[CH2:6][O:7][C:8]1[C:12]([CH:13]=O)=[CH:11][N:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:9]=1.[CH2:38]([P:47](=[O:54])([O:51][CH2:52][CH3:53])[O:48][CH2:49][CH3:50])P(=O)(OCC)OCC.CN(C)C=O.[H-].[Na+]>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH2:25][C:26]1[N:27]=[C:28]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[S:29][C:30]=1[CH3:31])[CH2:6][O:7][C:8]1[C:12](/[CH:13]=[CH:38]/[P:47](=[O:54])([O:48][CH2:49][CH3:50])[O:51][CH2:52][CH3:53])=[CH:11][N:10]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:9]=1
Reactant: COc1cc(COc2nn(-c3ccccc3)cc2C=O)ccc1OCc1nc(-c2ccccc2)sc1C
Reactant: CCOP(=O)(CP(=O)(OCC)OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOP(=O)(/C=C/c1cn(-c2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccccc3)sc2C)c(OC)c1)OCC
Reaction time: 15 h
Yield: 55.5 %

Procedure:
To a mixture of 3-({3-methoxy-4-[(5-methyl-2-phenyl-1,3-thiazol-4-yl)methoxy]benzyl}oxy)-1-phenyl-1H-pyrazole-4-carbaldehyde (0.30 g), tetraethyl methylenediphosphonate (0.19 g) and N,N-dimethylformamide (10 mL) was added sodium hydride (60% in oil, 0.03 g) at room temperature, and the mixture was stirred at the same temperature for 15 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give diethyl (E)-2-[3-({3-methoxy-4-[(5-methyl-2-phenyl-1,3-thiazol-4-yl)methoxy]benzyl}oxy)-1-phenyl-1H-pyrazol-4-yl]ethenylphosphonate as colorless crystals (0.21 g, yield 55%) from a fraction eluted with ethyl acetate-hexane (9:1, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 110-111° C.
Reaction SMILES: [CH2:1](I)[CH3:2].[NH:4]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@@H:5]([C:7]([OH:9])=[O:8])[CH3:6]>>[C:13]([O:12][C:10]([NH:4][C@@H:5]([C:7]([O:9][CH2:1][CH3:2])=[O:8])[CH3:6])=[O:11])([CH3:14])([CH3:15])[CH3:16]
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CCI
Product: CCOC(=O)[C@@H](C)NC(=O)OC(C)(C)C
Yield: 48.8 %

Procedure:
The title compound was prepared by the method of Example 8 using ethyl iodide (2.4 mL, 30 mmol) instead of methyl iodide and BOC-D-Ala-OH (5.0 g,26.4 mmol) instead of the product of Example 1. Concentration afforded the title compound (2.8 g) as a pale yellow oil and the structure verified by NMR.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([Cl:11])[N:8]=[C:7]2[C:3]=1[NH:4][CH:5]=[N:6]2.C(=O)([O-])[O-].[K+].[K+].[F:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Cl)=[CH:21][CH:20]=1>CN(C=O)C>[NH2:1][C:2]1[N:10]=[C:9]([Cl:11])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:23][C:22]1[CH:25]=[CH:26][C:19]([F:18])=[CH:20][CH:21]=1
Reactant: Fc1ccc(CCl)cc1
Reactant: Nc1nc(Cl)nc2nc[nH]c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1nc(Cl)nc2c1ncn2Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 1970.7 %

Procedure:
6-Amino-2-chloropurine (5.02 g) and potassium carbonate (5 g, 36 mmol) were suspended in DMF (200 ml) and thereto was added 4-fluorobenzyl chloride (5 ml, 42 mmol). The mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated in vacuo to dryness, and to the residue was added water. The mixture was extracted with chloroform and the organic layer was washed with water, dried on sodium sulfate and concentrated in vacuo to dryness. The residue was purified with silica gel chromatography (2% methanol/chloroform) to give the subject compound (162 g).
Reaction SMILES: O.[C:2]([O:6][C:7]([NH:9][C@H:10]([C:15]([OH:17])=O)[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:8])([CH3:5])([CH3:4])[CH3:3].C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.[N:34]1([O:43][C:44](N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.Cl.CONC>CN(C=O)C.C(OCC)C>[C:2]([O:6][C:7](=[O:8])[NH:9][C@H:10]([C:15](=[O:17])[NH:34][O:43][CH3:44])[CH2:11][CH:12]([CH3:13])[CH3:14])([CH3:3])([CH3:4])[CH3:5]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CNOC
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CONC(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 88.3 %

Procedure:
N-tert-Butoxycarbonyl-L-leucine monohydrate (2.5 g, 10 mmol, Bachem Inc., Torrance, Calif.) was dissolved in dry DMF (15 mL) under nitrogen atmosphere and cooled to 5° C. To this solution were added, in succession, N,N-diisopropylethylamine (5.3 mL, 30 mmol) and solid O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (3.8 g, 10 mmol). The resulting reaction mixture was stirred at that temperature for 30 minutes; O,N-dimethylhydroxylamine hydrochloride (1.1 g, 11 mmol, Aldrich, Milwaukee, Wis.) was then added. After additional 30 minutes stirring at 0° C., the reaction mixture was mixed with 75 mL of diethyl ether; the resulting mixture was successively washed with 5% aqueous HCl solution (50 mL), brine (50 mL), saturated aqueous NaHCO3 solution (50 mL), brine (2×50 mL), and was dried over Na2SO4. The solution was concentrated in vacuo affording 2.3 g of desired product as a clear oil which was used in the subsequent reaction without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH2:5][NH2:6].C([O:16][C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]1[CH:30]=[CH:29][C:28]([CH2:31][N:32]2[C:40]3[C:35](=[CH:36][C:37]([C:41](O)=[O:42])=[CH:38][CH:39]=3)[C:34]([CH3:44])=[C:33]2[CH3:45])=[CH:27][CH:26]=1)=[O:18])(C)(C)C>>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH2:5][NH:6][C:41]([C:37]1[CH:36]=[C:35]2[C:40](=[CH:39][CH:38]=1)[N:32]([CH2:31][C:28]1[CH:27]=[CH:26][C:25]([C:20]3[C:19]([C:17]([OH:18])=[O:16])=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:30][CH:29]=1)[C:33]([CH3:45])=[C:34]2[CH3:44])=[O:42]
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Reactant: COc1ccc(CN)cc1F
Product: COc1ccc(CNC(=O)c2ccc3c(c2)c(C)c(C)n3Cc2ccc(-c3ccccc3C(=O)O)cc2)cc1F

Procedure:
The title compound was prepared following the same general protocol as described in Steps 8-9, Example 1, using 3-fluoro-4-methoxybenzylamine and 1-((2′-(tert-butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid. LC-MS 537 (M+H).
Reaction SMILES: [CH3:1][CH:2]([CH2:13][CH3:14])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11][CH3:12])=[CH:7][CH:6]=1)=[O:4].[OH-:15].[Na+]>C1(C)C=CC=CC=1.C(Cl)(Cl)(Cl)Cl.Cl.[NH4+].[Cl-]>[OH:15][C:2]([CH3:1])([CH2:13][CH3:14])[C:3]([C:5]1[CH:6]=[CH:7][C:8]([S:11][CH3:12])=[CH:9][CH:10]=1)=[O:4]
Reactant: CCC(C)C(=O)c1ccc(SC)cc1
Reactant: [OH-]
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClC(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: CCC(C)(O)C(=O)c1ccc(SC)cc1
Reaction time: 48 h

Procedure:
To a solution of the ketone from step 1 (33 g) in toluene (48 mL), CCl4 (23.5 mL) and Aliquat, 336 (10.5 mL), was added NaOH pellets (14.5 g) and the resulting mixture was vigorously stirred for 2 days. The reaction mixture was diluted with 5N HCl, aqueous NH4Cl and extracted with Et2O. The organic layer was dried over Na2SO4 and concentrated. The crude product was purified by flash chromatography eluted with EtOAc/Hexane 9% to give a yellow syrup.
Reaction SMILES: [OH-:1].[C:2]1(/[CH:8]=[CH:9]/B(O)O)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>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.O>[CH:9](/[C:4]1[CH:5]=[CH:6][C:7]2[O:1][C:9]3[CH:4]=[CH:3][C:2](/[CH:9]=[CH:8]/[C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:7][C:8]=3[C:2]=2[CH:3]=1)=[CH:8]\[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [OH-]
Reactant: OB(O)/C=C/c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Product: C(=C/c1ccc2oc3ccc(/C=C/c4ccccc4)cc3c2c1)\c1ccccc1
Temperature: 110 °C
Reaction time: 24 h
Yield: 71 %

Procedure:
Tetrethylamine hydroxide (13.6 g, 18.4 mmol), tetrakis(triphenylphosphine)palladium(0) (142 mg) and trans-2-phenylvinylboronic acid (2.3 g, 15.3 mmol) are added to a solution of the product from example 1a) (2.00 g, 6.14 mmol) in N,N′-Dimethylacetamide (DMA) (30 ml). The mixture is then stirred at 110° C. for 24 hours. The reaction mixture is cooled to room temperature and poured into H2O. A gray crude product is obtained after filtration and washing with n-hexane. The crude product is purified by silicagel column chromatography with CH2Cl2, which result in a white solid (71% yield, mp.: 226° C.).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:37])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26](Br)[CH:25]=[C:24](Br)[CH:23]=2)[C:10]=1[CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH3:2].[N:38]1[CH:43]=[CH:42][CH:41]=[C:40](B(O)O)[CH:39]=1>>[CH2:1]([O:3][C:4](=[O:37])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([C:40]3[CH:39]=[N:38][CH:43]=[CH:42][CH:41]=3)[CH:25]=[C:24]([C:40]3[CH:39]=[N:38][CH:43]=[CH:42][CH:41]=3)[CH:23]=2)[C:10]=1[CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH3:2]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(Br)cc(Br)c2)c1CCC(=O)OCC
Reactant: OB(O)c1cccnc1
Product: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(-c3cccnc3)cc(-c3cccnc3)c2)c1CCC(=O)OCC
Yield: 62.2 %

Procedure:
A similar procedure as described in Example 1, step 2 was used, starting from 4-{3-[6-(3,5-dibromo-phenoxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy}-butyric acid ethyl ester (250 mg, 0.39 mmol) and pyridin-3-ylboronic acid (201 mg, 1.55 mmol) to give 4-{3-[6-(3,5-di-pyridin-3-yl-phenoxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy}-butyric acid ethyl ester (155 mg, 62%) as a colorless oil: ES(+)-HRMS m/e calculated for C39H46N2O6 (M+H)+ 639.3429, found 639.3416.
Reaction SMILES: [C:1]([C:3]1[C:8]([C:9]2[CH:14]=[CH:13][C:12]([S:15]([CH2:18][CH3:19])(=[O:17])=[O:16])=[CH:11][C:10]=2[O:20][CH3:21])=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1)#[N:2].Cl[C:26]1[C:27]2[N:34]=[CH:33][N:32]([CH2:35][CH3:36])[C:28]=2[N:29]=[N:30][CH:31]=1>>[CH2:35]([N:32]1[C:28]2[N:29]=[N:30][CH:31]=[C:26]([C:6]3[CH:7]=[C:8]([C:9]4[CH:14]=[CH:13][C:12]([S:15]([CH2:18][CH3:19])(=[O:17])=[O:16])=[CH:11][C:10]=4[O:20][CH3:21])[C:3]([C:1]#[N:2])=[CH:4][CH:5]=3)[C:27]=2[N:34]=[CH:33]1)[CH3:36]
Reactant: CCn1cnc2c(Cl)cnnc21
Reactant: CCS(=O)(=O)c1ccc(-c2cc(B(O)O)ccc2C#N)c(OC)c1
Product: CCn1cnc2c(-c3ccc(C#N)c(-c4ccc(S(=O)(=O)CC)cc4OC)c3)cnnc21
Yield: 10 %

Procedure:
Prepared according to the method described for Example 45 using (6-cyano-4′-(ethylsulfonyl)-2′-methoxy-[1,1-biphenyl]-3-yl)boronic acid (Preparation 67) and 4-chloro-7-ethyl-7H-imidazo[4,5-c]pyridazine (Preparation 8) to afford the title compound as a white solid in 10% yield, 10.1 mg.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6].C(Cl)Cl.N1C=CC=CC=1.[N:20]1([C:26](Cl)=[O:27])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>O>[N:20]1([C:26]([O:10][C:9]2[CH:8]=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=2[F:1])=[O:27])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1
Reactant: O=Cc1ccc(O)c(F)c1
Reactant: O=C(Cl)N1CCOCC1
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: O=Cc1ccc(OC(=O)N2CCOCC2)c(F)c1
Temperature: 25 °C
Yield: 86.5 %

Procedure:
To a 250 mL dry round bottom flask were added 3-fluoro-4-hydroxybenzaldehyde (4.76 g, 34.0 mmol), anhydrous CH2Cl2 (40 mL) and pyridine (3.6 mL, 44.2 mmol). The mixture was stirred in an ice-water bath, then 4-morpholinecarbonyl chloride (4.4 mL, 37.4 mmol) was added. The mixture was stirred and warmed slowly to room temperature, then at room temperature overnight. Water (80 mL) was added to the reaction mixture. The CH2Cl2 layer was separated, and the aqueous layer was extracted continually with CH2Cl2 (50 mL×3). The combined CH2Cl2 solution was dried over Na2SO4. After removal of the solvent, the residue was purified with a silica gel chromatography (heptane/ethyl acetate, gradient eluting) to give 2-fluoro-4-formylphenyl morpholine-4-carboxylate (7.45 g) as white solid. Yield: 87%. 1H NMR (CDCl3, 300 MHz): δ=9.97 (s, 1H), 7.74-7.70 (m, 2H), 7.45 (t, J=7.8 Hz, 1H), 3.81-3.61 (m, 8H). 13C NMR (CDCl3, 75.5 MHz, mixture of two isomers): δ=189.9, 156.5, 153.1, 151.8, 144.0, 143.8, 135.0, 134.9, 126.7, 126.6, 124.8, 116.7, 116.4, 66.4, 66.3, 45.2, 44.4.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([C:12]2[C:17](Br)=[CH:16][CH:15]=[CH:14][N:13]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1.C([O-])([O-])=O.[Na+].[Na+].O>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([C:12]2[C:17]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:16][CH:15]=[CH:14][N:13]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC(c2ncccc2Br)C1
Reactant: Cc1cccc(B(O)O)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CC(c2ncccc2-c2ccccc2)C1
Temperature: 80 °C
Reaction time: 12 h
Yield: 87.3 %

Procedure:
To a stirred solution of 3-(3-bromo-pyridin-2-yl)-azetidine-1-carboxylic acid tert-butyl ester (3) (150 mg, 0.48 mmol) in dioxane (10 mL) was added phenylboronic acid (78) (87 mg, 0.71 mmol), Na2CO3 (152 mg, 1.4 mmol) and H2O (2 mL). The reaction mixture was degassed with N2 and then PdCl2(dppf) (35 mg, 0.05 mmol) was added. The reaction mixture was stirred at 80° C. for 12 h. The reaction mixture was left to reach RT and filtered through a pad of CELITE® and the filter cake was washed with CH2Cl2 (20 mL×3). The combined filtrates were evaporated in vacuo and the residue was purified by column chromatography ((EtOAc:Petrol ether=3:1) to give the desired compound (79) (130 mg, 87% yield). ESI-MS (M+1): 311 calc. for C19H22N2O2 310.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:10][C:9]=1[N+:22]([O-])=O)([CH3:4])([CH3:3])[CH3:2].O.O.Cl[Sn]Cl>>[C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:10][C:9]=1[NH2:22])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(C#Cc2ccccc2)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Solvent: O
Product: CC(C)(C)OC(=O)Nc1ccc(C#Cc2ccccc2)cc1N
Yield: 64.6 %

Procedure:
Prepared from (2-nitro-4-phenylethynyl-phenyl)-carbamic acid tert.-butyl ester (Example F3) (403 mg, 1.19 mmol) by reduction with SnCl2.2H2O (1.34 g, 5.96 mmol) according to the general procedure G (method b). Obtained as an orange solid (237 mg).
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[S:13]1[CH2:17][CH2:16][NH:15][CH2:14]1>C(Cl)(Cl)Cl>[NH:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:4]([CH2:3][CH2:2][N:15]2[CH2:16][CH2:17][S:13][CH2:14]2)=[CH:5]1
Reactant: BrCCc1c[nH]c2ccccc12
Reactant: C1CSCN1
Solvent: ClC(Cl)Cl
Product: c1ccc2c(CCN3CCSC3)c[nH]c2c1
Temperature: 25 °C

Procedure:
3-(2-Bromo-ethyl)-indole (3.00 g, 13.4 mmol) and thiazolidine (2.38 g, 26.8 mmol) were stirred in abs. CHCl3 (25 ml) at a bath temperature of 75° C. for 5 h. The mixture was cooled to RT and extracted with dilute sulfuric acid (2×30 ml). The acidic aqueous phase was rendered alkaline with 5N NaOH, while cooling with ice, and extracted with ether (3×30 ml). The organic phase was dried over Na2SO4 and concentrated i. vac. and the residue was purified by flash chromatography with CHCl3/MeOH (20:1→4:1→MeOH).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Br:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])=[CH:14][CH:13]=1.[C:29]([O:33][C:34](=[O:37])[CH2:35]Br)([CH3:32])([CH3:31])[CH3:30].[Cl-].[NH4+]>C1COCC1>[Br:11][C:12]1[CH:13]=[CH:14][C:15]([CH:18]([CH2:35][C:34]([O:33][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:37])[C:19]([O:21][CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[O:20])=[CH:16][CH:17]=1
Reactant: O=C(Cc1ccc(Br)cc1)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CC(C(=O)OCc1ccccc1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.7 %

Procedure:
Lithium bis(trimethylsilyl)amide (1.06 M in THF; 20.6 mL, 21.9 mmol) was added dropwise over 10 min to a stirred solution of benzyl (4-bromophenyl)acetate (6.07 g, 19.9 mmol) in THF (60 mL) at −78° C. under nitrogen. On completion of addition stirring was continued at −78° C. for 30 min then t-butylbromoacteate (4.65 g, 3.52 mL, 23.9 mmol) was added dropwise over 5 min. The reaction was allowed to warm slowly to room temperature over 4 h then saturated ammonium chloride solution (50 mL) was added and the resulting suspension extracted with ethyl acetate (3×100 mL). The organic phases were combined, dried (magnesium sulfate) and evaporated to dryness. The residue was chromatographed on silica gel (10% diethyl ether: cyclohexane) to give the title compound as a colourless oil (6.82 g, 82%). LC/MS: 3.90 min; z/e 419 and 421, calcd (M+1) 419 and 421. 1H NMR (400 MHz: CDCl3): 7.40 (2H), 7.30 (5H), 7.15 (2H), 5.10 (2H), 4.05 (1H), 3.05 (1H), 1.35 (9H).
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([C:23]4[S:24][C:25]([C:28](=[O:30])[CH3:29])=[CH:26][CH:27]=4)=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:31].[NH2:32][C:33]1[CH:34]=[CH:35][C:36]([CH3:40])=[C:37]([OH:39])[CH:38]=1>C1COCC1>[OH:39][C:37]1[CH:38]=[C:33]([NH:32][CH:2]=[C:3]2[C:11]3[C:6](=[CH:7][C:8]([C:12]([C:14]4[CH:15]=[C:16]([NH:20][C:21]([C:23]5[S:24][C:25]([C:28](=[O:30])[CH3:29])=[CH:26][CH:27]=5)=[O:22])[CH:17]=[CH:18][CH:19]=4)=[O:13])=[CH:9][CH:10]=3)[NH:5][C:4]2=[O:31])[CH:34]=[CH:35][C:36]=1[CH3:40]
Reactant: Cc1ccc(N)cc1O
Reactant: CC(=O)c1ccc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CO)c2)s1
Solvent: C1CCOC1
Product: CC(=O)c1ccc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CNc3ccc(C)c(O)c3)c2)s1
Temperature: 65 °C
Reaction time: 24 h
Yield: 71.9 %

Procedure:
A small screw cap test tube was charged with 5-Acetyl-thiophene-2-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (as prepared in Example 54, 100 mg, 0.231 mmol) and THF (2 mL). To the resulting solution was added 5-amino-2-methylphenol (31.33 mg, 0.254 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature. Hexanes were added to the reaction mixture. The solid precipitate that formed was washed with ˜1 mL of i-prOH yielding 72% (89 mg, 0.166 mmol) of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:15]=[C:14]([OH:16])[C:13]2[C:8](=[CH:9][C:10]([CH3:17])=[CH:11][CH:12]=2)[N:7]=1)=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[C:24]([O:28][C:29](=[O:32])[CH2:30]Br)([CH3:27])([CH3:26])[CH3:25]>CN(C=O)C.O>[CH2:1]([O:3][C:4]([C:6]1[CH:15]=[C:14]([O:16][CH2:30][C:29]([O:28][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:32])[C:13]2[C:8](=[CH:9][C:10]([CH3:17])=[CH:11][CH:12]=2)[N:7]=1)=[O:5])[CH3:2]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CCOC(=O)c1cc(O)c2ccc(C)cc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc(OCC(=O)OC(C)(C)C)c2ccc(C)cc2n1
Reaction time: 16 h

Procedure:
To a solution of 3.0 g of 4-Hydroxy-7-methyl-quinoline-2-carboxylic acid ethyl ester in 20 ml of DMF, 3.0 g of potassium carbonate and 3.8 g of Bromo-acetic acid tert-butyl ester was added and stirred for 16 h. Then, the reaction mixture was diluted with water and extracted with ethyl acetate (3×150 ml). The combined organic phases were dried over MgSO4 and the solvents were removed under reduced pressure. The crude product was pure enough for the next reaction step. Yield: 4.9 g.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[N:11]1[C:14](=[O:15])[C:13]([CH3:17])([CH3:16])[NH:12]1)[CH2:8]2.[N+:18]([C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH2:24]Br)([O-:20])=[O:19]>>[CH3:16][C:13]1([CH3:17])[N:12]([CH2:24][C:23]2[CH:26]=[CH:27][CH:28]=[C:21]([N+:18]([O-:20])=[O:19])[CH:22]=2)[N:11]([CH:2]2[CH:3]3[CH2:4][CH:5]4[CH2:6][CH:7]([CH2:8][CH:1]2[CH2:10]4)[CH2:9]3)[C:14]1=[O:15]
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Reactant: CC1(C)NN(C2C3CC4CC(C3)CC2C4)C1=O
Product: CC1(C)C(=O)N(C2C3CC4CC(C3)CC2C4)N1Cc1cccc([N+](=O)[O-])c1

Procedure:
2-(Adamantan-2-yl)-4,4-dimethyl-1,2-diazetidin-3-one and 3-nitrobenzyl bromide were used for a similar reaction and treatment as Process 6 of Example 1, and the title compound was obtained as a yellow oil.
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC([N:15]1[CH2:20][CH2:19][N:18]([C:21]2[CH:26]=[CH:25][C:24]([C:27](=[O:37])[NH:28][C:29]3[CH:34]=[CH:33][C:32]([CH3:35])=[C:31]([I:36])[CH:30]=3)=[CH:23][N:22]=2)[CH2:17][CH2:16]1)=O)(C)(C)C.C(C1C=CC(NC(=O)C2C=CC(N3CCNCC3)=NC=2)=CC=1)(C)(C)C>>[I:36][C:31]1[CH:30]=[C:29]([NH:28][C:27](=[O:37])[C:24]2[CH:25]=[CH:26][C:21]([N:18]3[CH2:17][CH2:16][NH:15][CH2:20][CH2:19]3)=[N:22][CH:23]=2)[CH:34]=[CH:33][C:32]=1[CH3:35]
Reactant: Cc1ccc(NC(=O)c2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)nc2)cc1I
Agent: CC(C)(C)c1ccc(NC(=O)c2ccc(N3CCNCC3)nc2)cc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(NC(=O)c2ccc(N3CCNCC3)nc2)cc1I

Procedure:
N-(3-Iodo-4-methyl-phenyl)-6-piperazin-1-yl-nicotinamide was prepared by the TFA deprotection of 4-[5-(3-iodo-4-methyl-phenylcarbamoyl)-pyridin-2-yl]-piperazine-1-carboxylic acid tert-butyl ester in a manner similar to the one described in the synthesis of N-(4-tert-butyl-phenyl)-6-piperazin-1-yl-nicotinamide above. LCMS calcd for C17H19IN4O (m/e) 422, obsd 423 (M+H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]#[N:10])=[CH:5][CH:4]=1.[NH:11]1[CH:15]=[N:14][CH:13]=[N:12]1>C(Cl)(Cl)Cl.C(#N)C>[CH:8]1[C:3]([CH2:2][N:11]2[N:12]=[CH:13][N:14]=[CH:15]2)=[CH:4][CH:5]=[C:6]([C:9]#[N:10])[CH:7]=1
Reactant: c1nc[nH]n1
Reactant: N#Cc1ccc(CBr)cc1
Solvent: ClC(Cl)Cl
Solvent: CC#N
Product: N#Cc1ccc(Cn2cncn2)cc1

Procedure:
A solution containing alpha-bromo-4-tolunitrile (19.6 g) and 1,2,4-triazole (30.5 g) in a mixture of chloroform (250 mL) and acetonitrile (50 mL) is stirred at reflux for 15 hours. The solution is cooled and washed with 3% aqueous sodium bicarbonate (200 mL) and the organic solution is then dried (MgSO4) and evaporated. The residue is chromatographed on silica gel (300 g). Elution with chloroform/isopropanol (10:1) affords 4-[1-(1,2,4-triazolyl)methyl]-benzontrile, m.p. 77°-79°, which forms a hydrochloride salt, m.p. 200°-205°, when its solution in ethyl acetate is treated with ethereal HCl.