Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([F:20])[CH:14]=2)=O)=[CH:7][CH:6]=1.[C:21]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(=O)[CH2:22][CH3:23]>>[Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([F:20])[CH:14]=2)=[C:21]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:22][CH3:23])=[CH:7][CH:6]=1
Reactant: CCC(=O)c1ccccc1
Reactant: O=C(c1ccc(OCCCl)cc1)c1ccc(O)c(F)c1
Product: CCC(=C(c1ccc(OCCCl)cc1)c1ccc(O)c(F)c1)c1ccccc1

Procedure:
Following general procedure of McMurry reaction as described in example 1, step B, (4-(2-chloroethoxy)phenyl)(3-fluoro-4-hydroxyphenyl)methanone (350 mg, 1.19 mmol) was reacted with propiophenone (319 mg, 2.38 mmol) to give the desired product (quant.) as a yellow solid.
Reaction SMILES: [C-:1]#[N:2].[K+].[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH:30]([CH3:32])[CH3:31])[C:12]([O:14][CH:15](Cl)[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:17]=2)=[O:13])=[CH:7][CH:6]=1>CCOCC>[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH:30]([CH3:32])[CH3:31])[C:12]([O:14][CH:15]([C:1]#[N:2])[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:17]=2)=[O:13])=[CH:7][CH:6]=1
Reactant: [C-]#N
Reactant: CC(C)C(C(=O)OC(Cl)c1cccc(Oc2ccccc2)c1)c1ccc(Cl)cc1
Agent: [K+]
Solvent: CCOCC
Product: CC(C)C(C(=O)OC(C#N)c1cccc(Oc2ccccc2)c1)c1ccc(Cl)cc1
Temperature: 20 °C
Reaction time: 72 h

Procedure:
1.5 g of potassium cyanide were added to a mixture of 80 ml of acetonitrileand the solution obtained in Example 9 and the mixture was stirred at 20° C. for 72 hours. Ether was added to the mixture which was then filtered to remove insolubles. The filtrate was evaporated to dryness under reduced pressure and the residue was chromatographed over silica gel. Elution with a 95-5 cyclohexane-acetone mixture yielded 6.5 g of RS α-cyano-3-phenoxy-benzyl 2-(p-chlorophenyl)-2-isopropyl-acetate.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]2[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][CH:14]=2)[N:3]=[CH:2]1.C([O-])(O)=O.[Na+].C1C=CC(OC(Cl)=[S:34])=CC=1>C1COCC1.O>[S:34]=[C:2]1[NH:3][C:4]([CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]2[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][CH:14]=2)=[CH:5][NH:1]1
Reactant: N#Cc1ccc(-c2ccccc2Cc2c[nH]cn2)cc1
Reactant: S=C(Cl)Oc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1ccc(-c2ccccc2Cc2c[nH]c(=S)[nH]2)cc1
Reaction time: 16 h

Procedure:
A solution of 2′-(1H-imidazol-4-ylmethyl)-biphenyl-4-carbonitrile (Intermediate D3) (0.36 g, 1.4 mmol) in THF (11 mL) and water (10 mL) was treated with NaHCO3 (1.2 g) at rt for 5 m. Phenyl chlorothionoformate (0.95 mL, 7.0 mmol) was added and stirring was continued for 16 h. The mixture was diluted with water (10 mL) and extracted with ether (4×15 mL). The organic portions were combined, dried over MgSO4, filtered and freed of solvent. The residue was dissolved in MeOH (15 mL) and treated with NEt3 (2.0 mL) for 18 h. The solvent was removed under vacuum and the product was washed on a glass frit with CH2Cl2 and pentane to give a solid 2′-(2-thioxo-2,3-dihydro-1H-imidazol-4-ylmethyl)-biphenyl-4-carbonitrile (Compound 6) in 40% yield. 1H NMR (300 MHz, DMSO-d6): δ 11.8 (s, 1H), 11.6 (s, 1H), 7.92 (d, J=9 Hz, 2H), 7.52 (d, J=9 Hz, 2H), 7.44-7.19 (m, 4H), 6.14 (s, 1H), 3.63 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.C([Mg]Br)C.[CH3:15][C:16]1([CH3:24])[C:18]([CH3:20])([CH3:19])[CH:17]1[C:21](Cl)=[O:22]>ClCCl.[Cl-].[Zn+2].[Cl-]>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:21]([CH:17]1[C:18]([CH3:20])([CH3:19])[C:16]1([CH3:24])[CH3:15])=[O:22]
Reactant: Clc1ccc2[nH]ccc2c1
Reactant: CC1(C)C(C(=O)Cl)C1(C)C
Agent: CC[Mg]Br
Agent: [Cl-]
Agent: [Zn+2]
Solvent: ClCCl
Product: CC1(C)C(C(=O)c2c[nH]c3ccc(Cl)cc23)C1(C)C
Yield: 42.5 %

Procedure:
A mixture of 5-chloroindole (0.30 g. 2.0 mmol), ethylmagnesium bromide (1.0 M solution in THF, 2.4 mL, 2.4 mmol), zinc chloride (1.0 M solution in Et2O, 2.4 mL, 2.4 mmol) and the product of Example 1A (3.0 mmol) in 15 mL of dichloromethane was processed as described in Example 1B to provide the title compound (0.23 g, 0.85 mmol, 43% yield). MS (DCI/NH3) m/z 276 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][NH:6][N:5]=1)([O-:3])=[O:2].[CH:9]1([CH2:12]O)[CH2:11][CH2:10]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1.C(OCC)(=O)C>[CH:9]1([CH2:12][N:6]2[CH:7]=[CH:8][C:4]([N+:1]([O-:3])=[O:2])=[N:5]2)[CH2:11][CH2:10]1
Reactant: O=[N+]([O-])c1cc[nH]n1
Reactant: OCC1CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccn(CC2CC2)n1
Yield: 57.4 %

Procedure:
The 3-Nitro-1H-pyrazole (prepared in example 3, 255 mg, 2.26 mmol) was dissolved in tetrahydrofuran (11 mL) and cyclopropyl-methanol (163 mg, 2.26 mmol) was added followed by triphenylphosphine (592 mg, 2.26 mmol). While stirring, diisopropyl azodicarboxylate (667 μL, 3.39 mmol) was added dropwise. A mild exotherm was observed. The reaction continued to stir for 30 min. The solution was diluted with ethyl acetate (100 mL), washed with water (2×35 mL), 1.0 M aqueous hydrochloric acid solution (35 mL), saturated aqueous brine solution (35 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by flash column chromatography (Merck silica gel 60, 40-63 μm; 5% ethyl acetate/hexanes to 50% ethyl acetate/hexanes) afforded 1-cyclopropylmethyl-3-nitro-1H-pyrazole (217 mg, 58%) as a yellow oil: H1-NMR (400 MHz, CDCl3) δ 0.44 (2H, qt, J=5.6 Hz), 0.73 (2H, qt, J=6.8 Hz), 1.30-1.40 (1H, m), 4.07 (2H, d, J=7.6 Hz), 6.89 (1H, d, J=2.8 Hz), 7.57 (1H, d, J=2.4 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8](=[O:11])[NH:9][N:10]=2)[N:7]=1.[C:12](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8](=[O:11])[N:9]([CH3:12])[N:10]=2)[N:7]=1
Reactant: O=c1[nH]nc2ccc(Cl)nn12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1nc2ccc(Cl)nn2c1=O
Temperature: 25 °C
Yield: 67.2 %

Procedure:
0.853 g of 6-chloro[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one was dissolved in 5 ml of N,N-dimethylformamide; 0.83 g of potassium carbonate was added; with stirring at room temperature, 0.5 ml of methyl iodide was added. After stirring at room temperature for 15 hours, ice water and saline were added; the reaction mixture was extracted with ethyl acetate-tetrahydrofuran (1:1); the extract was washed with saline and dried over magnesium sulfate. After concentration under reduced pressure, the crystal obtained was collected by filtration, washed with diethyl ether, and dried, to yield 0.62 g of the title compound.
Reaction SMILES: [C:1]([O:4][C@@H:5]([C@H:9]([O:40][C:41](=[O:43])[CH3:42])[C@H:10]([O:36][C:37](=[O:39])[CH3:38])[C@@H:11]([NH:17][C:18](=[O:35])[C@H:19]([CH2:31][CH:32]([CH3:34])[CH3:33])[NH:20][C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])[CH2:12][O:13][C:14](=[O:16])[CH3:15])[C:6](O)=[O:7])(=[O:3])[CH3:2].C1(N=C=NC2CCCCC2)CCCCC1.[NH2:59][C@H:60]([C:67]1[CH:72]=[CH:71][C:70]([CH3:73])=[CH:69][CH:68]=1)[CH2:61][C:62]([O:64][CH2:65][CH3:66])=[O:63].C(N(CC)CC)C>C(#N)C>[C:1]([O:4][C@@H:5]([C@H:9]([O:40][C:41](=[O:43])[CH3:42])[C@H:10]([O:36][C:37](=[O:39])[CH3:38])[C@@H:11]([NH:17][C:18](=[O:35])[C@H:19]([CH2:31][CH:32]([CH3:34])[CH3:33])[NH:20][C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])[CH2:12][O:13][C:14](=[O:16])[CH3:15])[C:6]([NH:59][C@H:60]([C:67]1[CH:68]=[CH:69][C:70]([CH3:73])=[CH:71][CH:72]=1)[CH2:61][C:62]([O:64][CH2:65][CH3:66])=[O:63])=[O:7])(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1)[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)C(=O)O
Reactant: CCOC(=O)C[C@H](N)c1ccc(C)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)C[C@H](NC(=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H](OC(C)=O)[C@H](COC(C)=O)NC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.2 %

Procedure:
To a solution of [(2S,3R,4R,5S)-2,3,4,6-tetraacetoxy-5-(N-benzyloxycarbonyl-L-leucyl)aminohexanoic acid (250 mg) in acetonitrile (10 ml) were added N-hydroxy-5-norbornene-2,3-dicarboxyimide (110 mg) and N,N′-dicyclohexylcarbodimide (110 mg) and the mixture was stirred at room temperature for 1 hour. After addition of a solution of ethyl (S)-3-amino-3-(4-methylphenyl)propionate (150 mg) and triethylamine (0.13 ml) in acetonitrile (10 ml), the whole was stirred at room temperature for 18 hours. The formed insoluble solid was filtrated off and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (100 ml) and washed with saturated brine (50 ml×2), followed by drying over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was passed through silica gel column chromatography, followed by elution with ethyl acetate-hexane (2:1). The effective fractions were combined and concentrated under reduced pressure to afford the title compound (184 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[CH:14][N:13]=[C:12]2[CH2:17]C(OCC)=O)=[O:5].[OH-].[Na+]>C(O)C.O>[Cl:27][C:23]1[CH:24]=[CH:25][CH:26]=[C:2]([Cl:1])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[CH:14][N:13]=[C:12]2[CH3:17])=[O:5]
Reactant: CCOC(=O)Cc1ncnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1ncnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc12
Yield: 94.7 %

Procedure:
A mixture of 8-(2,6-dichlorobenzoylamino)-4-ethoxycarbonylmethylquinazoline (90 mg) and 1N sodium hydroxide solution (1 ml) in ethanol (5 ml) was refluxed for 30 minutes. The mixture was diluted with water, and the resulting precipitate was collected by filtration and washed with water to give 8-(2,6-dichlorobenzoylamino)-4-methylquinazoline (70 mg).
Reaction SMILES: [CH3:1][C:2]([C:5]1[N:6]=[C:7]([CH3:16])[O:8][C:9]=1[C:10](=O)[C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:4])[CH3:3].[OH-].[NH4+:18]>>[CH3:1][C:2]([C:5]1[C:9]([OH:8])=[C:10]([C:11]([CH3:14])([CH3:13])[CH3:12])[N:18]=[C:7]([CH3:16])[N:6]=1)([CH3:4])[CH3:3]
Reactant: Cc1nc(C(C)(C)C)c(C(=O)C(C)(C)C)o1
Reactant: [NH4+]
Agent: [OH-]
Product: Cc1nc(C(C)(C)C)c(O)c(C(C)(C)C)n1
Yield: 75 %

Procedure:
A mixture of 1-[4-(1,1-dimethylethyl)-2-methyl-5-oxazolyl]-2,2-dimethyl-l-propanone (8.5 g, and concentrated ammonium hydroxide (100 mi) is heated at 180° C. for 36 hours in a steel bomb. The reaction mixture is cooled and the excess ammonia is evaporated on the rotovap. The pH of the resulting mixture is adjusted to pH 6 with concentrated HCl with ice bath cooling. The product is extracted into ether (3×250 mL) and the organic layer is dried (MgSO4) and evaporated. The residue is purified by flash chromatography (silica, 7% EtOAc/hexane) to give pure 4,6-bis(1,1-dimethylethyl)-5-hydroxy-2-methylpyrimidine (6.35g, 75%) as a partial hydrate; mp 62°-65° C.
Reaction SMILES: [CH3:1][C:2]1[C:10]([CH3:11])=[CH:9][C:5]2[NH:6][N:7]=[N:8][C:4]=2[CH:3]=1.[Br:12]Br>C(O)(=O)C>[Br:12][C:9]1[C:5]2[N:6]=[N:7][NH:8][C:4]=2[CH:3]=[C:2]([CH3:1])[C:10]=1[CH3:11]
Reactant: Cc1cc2nn[nH]c2cc1C
Reactant: BrBr
Solvent: CC(=O)O
Product: Cc1cc2[nH]nnc2c(Br)c1C
Temperature: 25 °C

Procedure:
To a solution of 25.0 grams of 5,6-dimethylbenzotriazole in 250 milliliters of acetic acid at 50° C. is slowly added 30.5 grams of bromine in 75 ml. of the same solvent over a 11/4 hour period. The temperature is held at 50° C. for an additional hour and then the reaction mixture is allowed to cool to room temperature. The product is collected by filtration, 19.2 grams (56%), m.p. 255°-262° C. The analytical sample has a m.p. of 259°-261° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=2)(=[O:14])=[O:13])=[C:6]([CH:10]=1)[C:7](Cl)=[O:8].[CH3:26][O:27][C:28]1[CH:35]=[CH:34][CH:33]=[CH:32][C:29]=1[CH2:30][NH2:31].C(N(CC)CC)C>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=2)(=[O:14])=[O:13])=[C:6]([CH:10]=1)[C:7]([NH:31][CH2:30][C:29]1[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=1[O:27][CH3:26])=[O:8]
Reactant: COc1ccccc1CN
Reactant: O=C(Cl)c1cc(Br)ccc1NS(=O)(=O)c1ccc(OC(F)(F)F)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccccc1CNC(=O)c1cc(Br)ccc1NS(=O)(=O)c1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Yield: 75 %

Procedure:
5-Bromo-2-(4-trifluoromethoxy-benzenesulfonylamino)-benzoyl chloride (5.124 g, 11.6 mmol) was dissolved in tetrahydrofuran (100 mL) and the mixture was cooled in an ice bath below 5° C. 2-Methoxy-benzyl amine (1.8 mL, 13.8 mmol, 1.2 equivalents) and triethyl amine (1.9 mL, 13.6 mmol, 1.2 equivalents) were added to the mixture keeping the temperature below 10° C. The mixture was warmed to room temperature and the solvent was removed to dryness. The residue was partitioned between aqueous HCl (1M, 50 mL) and ethyl acetate (100 mL). The organic solvent was collected and concentrated to dryness. The resulting solid was dissolved in ethyl acetate and the solvent removed (2×25 mL). The resulting mixture was purified by column chromatography on silica with an eluent of 20% ethyl acetate in hexane. The solid was suspended in a mixture of 5% ethyl acetate in hexane (90 mL). The mixture was centrifuged and the solid dried at 40° C. overnight in vacuum oven. Recovery=4.85 g (75% yield). M/Z of [M−H]−=557, 1H NMR (CDCl3) δ=3.85 (s, 3H), 4.5 (sd, 2H), 6.5–6.6 (1H), 6.9–7.05 (4H), 7.3–7.4 (2H), 7.45 (1H), 7.5 (1H), 7.6 (1H), 7.8 (2H), 10.8 (br, 1H).
Reaction SMILES: BrCC(N[C:6]1[CH:48]=[CH:47][C:9]([O:10][CH2:11][C:12]([NH:14][C@H:15]([C:20]([NH:22][C@@H:23]([CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C@H:24]([OH:39])[C:25]([N:27]2[CH2:38][CH2:37][CH2:36][C@H:28]2[C:29]([NH:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[O:26])=[O:21])[CH2:16][C:17](=[O:19])[NH2:18])=[O:13])=[CH:8][CH:7]=1)=O.[CH2:49]([N:56]1[CH2:61][CH2:60][NH:59][CH2:58][CH2:57]1)[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1>>[CH2:49]([N:56]1[CH2:61][CH2:60][N:59]([C:6]2[CH:48]=[CH:47][C:9]([O:10][CH2:11][C:12]([NH:14][C@H:15]([C:20]([NH:22][C@@H:23]([CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C@H:24]([OH:39])[C:25]([N:27]3[CH2:38][CH2:37][CH2:36][C@H:28]3[C:29]([NH:31][C:32]([CH3:34])([CH3:33])[CH3:35])=[O:30])=[O:26])=[O:21])[CH2:16][C:17](=[O:19])[NH2:18])=[O:13])=[C:8]([NH:14][C:12](=[O:13])[CH3:11])[CH:7]=2)[CH2:58][CH2:57]1)[C:50]1[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=1
Reactant: CC(C)(C)NC(=O)[C@@H]1CCCN1C(=O)[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)COc1ccc(NC(=O)CBr)cc1
Reactant: c1ccc(CN2CCNCC2)cc1
Product: CC(=O)Nc1cc(N2CCN(Cc3ccccc3)CC2)ccc1OCC(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](Cc1ccccc1)[C@H](O)C(=O)N1CCC[C@H]1C(=O)NC(C)(C)C

Procedure:
Following a procedure similar to that described in Example 38, but using 100 mg (0.137 mmol) of 1-{(2S,3S)-3-[N2 -(4-bromoacetamidophenoxy)acetyl-L-asparaginyl]amino-2-hydroxy-4-phenylbutyryl}-N-t-butyl-L-prolinamide and 1 ml of 1-benzylpiperazine, 60 mg of the title compound were obtained as a colorless powder, melting at 119°-127° C.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]2=[O:21].[NH2:22][C@@H:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:24][OH:25]>>[OH:25][CH2:24][C@@H:23]([NH:22][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]2=[O:21])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: N[C@H](CO)c1ccccc1
Reactant: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(F)cc2c1=O
Product: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(N[C@H](CO)c3ccccc3)cc2c1=O
Yield: 76 %

Procedure:
N-(6-Fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl) -methanesulfonamide (30 mg, 0.0943 mmol) is reacted with (S)-2-amino-2-phenyl-ethanol according to the GPA affording 25.8 mg (76%) of a red powder. Rt=4.10 min.
Reaction SMILES: [O:1]1[CH2:5][C@@H:4]([OH:6])[C@H:3]2[O:7][CH2:8][C@@H:9]([OH:10])[C@@H:2]12.N12CCCN=C1CCCCC2.[Cl:22][C:23]1[CH:24]=[C:25]2[N:32]=[C:31](S(C)(=O)=O)[N:30]([CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:44])([CH3:43])[CH3:42])[C:26]2=[N:27][C:28]=1[I:29]>CN(C)C=O>[Cl:22][C:23]1[CH:24]=[C:25]2[N:32]=[C:31]([O:6][C@H:4]3[C@H:3]4[O:7][CH2:8][C@@H:9]([OH:10])[C@H:2]4[O:1][CH2:5]3)[N:30]([CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:44])([CH3:43])[CH3:42])[C:26]2=[N:27][C:28]=1[I:29]
Reactant: O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2O
Reactant: C[Si](C)(C)CCOCn1c(S(C)(=O)=O)nc2cc(Cl)c(I)nc21
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1c(O[C@@H]2CO[C@H]3[C@@H]2OC[C@H]3O)nc2cc(Cl)c(I)nc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(3R,3aR,6R,6aR)-Hexahydrofuro[3,2-b]furan-3,6-diol (1.84 g) is dissolved in N,N-dimethylformamide (10 mL) and treated with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU; 1.9 mL). A solution of 6-chloro-5-iodo-2-(methylsulfonyl)-3-(2-trimethylsilanyl-ethoxymethyl)-3H-imidazo[4,5-b]pyridine (2.05 g) in N,N-dimethylformamide (20 mL) is added dropwise and the mixture is stirred for 2 hours at room temperature. The mixture is partitioned between water and ethylacetate and the organic phase is washed with brine and dried (MgSO4). The solvents are evaporated in vacuo and the residue is chromatographed on silica gel (cyclohexane/ethyl acetate 80:20→0:100) to give the title compound. LC (method 1): tR=1.17 min; Mass spectrum (ESI+): m/z=554 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[C:8]([Br:10])[C:7]([Cl:11])=[CH:6][C:5]=1[NH:12][C:13]([O:15][CH:16]([CH3:18])[CH3:17])=[O:14].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:27][CH2:28][CH2:29][C:30]([O:32][CH3:33])=[O:31]>CN(C=O)C.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[C:8]([Br:10])[C:7]([Cl:11])=[CH:6][C:5]=1[N:12]([C:13]([O:15][CH:16]([CH3:17])[CH3:18])=[O:14])[CH2:27][CH2:28][CH2:29][C:30]([O:32][CH3:33])=[O:31]
Reactant: COC(=O)c1cc(Br)c(Cl)cc1NC(=O)OC(C)C
Reactant: COC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)CCCN(C(=O)OC(C)C)c1cc(Cl)c(Br)cc1C(=O)OC
Temperature: 60 °C
Yield: 85.8 %

Procedure:
To a mixture of 5-Bromo-4-chloro-2-isopropoxycarbonylamino-benzoic acid methyl ester (2.52 g, 7.19 mmol) and cesium carbonate (4.68 g, 14.4 mmol) in DMF (35 ml) under nitrogen was added methyl 4-bromobutyrate (2.60 g, 14.4 mmol) dropwise. The reaction mixture was heated to 60° C. for 4 hours and then cooled to room temperature. The mixture was diluted with ethyl acetate (100 ml), and then washed with 0.1N HCl(aq) (100 ml) and brine (3×100 ml). The organic layer was dried over Na2SO4 and concentrated under reduced pressure. Purification by silica gel chromatography (gradient eluent, 0-20% ethyl acetate in hexane) provided 5-Bromo-4-chloro-2-[isopropoxycarbonyl-(3-methoxycarbonyl-propyl)-amino]-benzoic acid methyl ester (2.78 g, 86%) as oil. MS (ES+): 450, 452 (M+H).
Reaction SMILES: FC(F)(F)C(O)=O.[N:8]1([C:14]2[N:19]3[N:20]=[C:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH:22]=[C:18]3[N:17]=[C:16]([NH:29][NH2:30])[CH:15]=2)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.[Cl:31][C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=1)[CH:35]=O>C(O)C>[Cl:31][C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=1)[CH:35]=[N:30][NH:29][C:16]1[CH:15]=[C:14]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:19]2[N:20]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:22]=[C:18]2[N:17]=1
Reactant: NNc1cc(N2CCOCC2)n2nc(-c3ccccc3)cc2n1
Reactant: O=Cc1cccc(Cl)c1
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: Clc1cccc(C=NNc2cc(N3CCOCC3)n3nc(-c4ccccc4)cc3n2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 34 %

Procedure:
There was dissolved, in ethanol (2 mL), trifluoroacetic acid salt of (7-morpholin-4-yl-2-phenyl-pyrazolo[1,5-a]pyrimidin-5-yl)-hydrazine (30.8 mg, 0.0572 mM), then 3-chloro-benzaldehyde (6.5 μL, 0.057 mM) was added to the solution and the mixture was stirred at room temperature for one hour. This reaction liquid was filtered and the resulting solid was purified by the NH-silica gel column chromatography (methylene chloride) to thus give the title compound (9.6 mg, yield: 34%).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[C:11]1[C:19]([O:21]CC1C=CC=CC=1)=[O:20])=[O:5])[CH3:2].[H][H]>C(O)C.[Pd]>[CH2:1]([O:3][C:4]([CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[C:11]1[C:19]([OH:21])=[O:20])=[O:5])[CH3:2]
Reactant: CCOC(=O)CCCCn1c(C(=O)OCc2ccccc2)cc2ccccc21
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCCCn1c(C(=O)O)cc2ccccc21
Yield: 23.1 %

Procedure:
Benzyl 1-(4-ethoxycarbonylbutyl)indole-2-carboxylate (12.44 g) was dissolved in ethanol (120 ml). The mixture was subjected to catalytic reduction by blowing a hydrogen gas in the presence of 10% palladium/carbon. The reaction mixture was filtered through Celite to remove catalyst. The solvent was evaporated, and the residue was purified by silica gel column chromatography using a mixed solvent of ethyl acetate and hexane as an eluent to give 2.19 g of 1-(4-ethoxycarbonylbutyl)indole-2-carboxylic acid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:18])[CH3:17])=[CH:11][CH:10]=2)=[O:8])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]([OH:42])([C:38]([F:41])([F:40])[F:39])[C:34]([F:37])([F:36])[F:35])=[CH:29][CH:28]=1.CO>CN1CCCC1=O>[F:35][C:34]([F:36])([F:37])[C:33]([C:30]1[CH:31]=[CH:32][C:27]([CH2:26][N:1]2[CH2:2][CH2:3][CH:4]([C:7]([C:9]3[CH:10]=[CH:11][C:12]([NH:15][C:16](=[O:18])[CH3:17])=[CH:13][CH:14]=3)=[O:8])[CH2:5][CH2:6]2)=[CH:28][CH:29]=1)([OH:42])[C:38]([F:39])([F:41])[F:40]
Reactant: OC(c1ccc(CBr)cc1)(C(F)(F)F)C(F)(F)F
Reactant: CC(=O)Nc1ccc(C(=O)C2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CN1CCCC1=O
Product: CC(=O)Nc1ccc(C(=O)C2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1
Temperature: 25 °C
Yield: 78.7 %

Procedure:
To a stirred mixture of N-(4-(piperidine-4-carbonyl)phenyl)acetamide (3.82 mmol, 0.94 g) and potassium carbonate (11.45 mmol, 1.582 g) in N-methyl-2-pyrrolidinone (5 mL) was added 2-(4-(bromomethyl)phenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (3.82 mmol, 1.286 g). The reaction was stirred at room temperature over the weekend. Methanol (30 mL) was added and the reaction was filtered. The filtrate was purified by strong cation exchange column chromatography to afford the title compound (1.51 g).
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[C:8]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=3)[CH:9]=[C:10]([NH:11][CH:12]3[CH2:14][CH2:13]3)[C:5]2=[N:4][CH:3]=1.B(O)(O)[C:27]1[S:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[S:35]1[C:27]([C:2]2[N:6]3[N:7]=[C:8]([NH:15][C:16]4[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=4)[CH:9]=[C:10]([NH:11][CH:12]4[CH2:14][CH2:13]4)[C:5]3=[N:4][CH:3]=2)=[CH:28][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:34]1=2
Reactant: OB(O)c1cc2ccccc2s1
Reactant: COc1ccc(Nc2cc(NC3CC3)c3ncc(Br)n3n2)cc1OC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: COc1ccc(Nc2cc(NC3CC3)c3ncc(-c4cc5ccccc5s4)n3n2)cc1OC
Yield: 34.9 %

Procedure:
To a solution of 3-bromo-N8-cyclopropyl-N6-(3,4-dimethoxyphenyl)imidazo[1,2-b]pyridazine-6,8-diamine (66 mg, 0.163 mmol, 1.0 equiv) in acetonitrile (1.63 mL), was added benzo[b]thiophen-2-yl-2-boronic acid (58 mg, 0.327 mmol, 2.0 equiv), bis(triphenylphosphine)palladium(II) chloride (11 mg, 0.0163 mmol, 0.1 equiv), then sodium carbonate (1.63 mL, 1.0 M aqueous solution, 10 equiv). The reaction mixture was irradiated at 150° C. for 10 min. Purification by column chromatography gave 26 mg of the brown solid, 34%.