Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH3:16][O:17][C:18]([CH:20]1[CH2:24][C:23](=[O:25])[N:22]([C:26]2[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=2)[CH2:21]1)=[O:19]>CN(C1C=CN=CC=1)C.C1(C)C=CC=CC=1.CCOC(C)=O>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:32][C:29]1[CH:28]=[CH:27][C:26]([N:22]2[C:23](=[O:25])[CH2:24][CH:20]([C:18]([O:17][CH3:16])=[O:19])[CH2:21]2)=[CH:31][CH:30]=1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: COC(=O)C1CC(=O)N(c2ccc(O)cc2)C1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)C1CC(=O)N(c2ccc(Oc3ccnc4cc(OC)c(OC)cc34)cc2)C1
Temperature: 180 °C

Procedure:
A mixture of 4-chloro-6,7-dimethoxy-quinoline (1.0 g, 4.45 mmol), 1-(4-hydroxyphenyl)-5-oxo-pyrrolidine-3-carboxylic acid methyl ester (Step 1, 1.6 g, 6.7 mmol) and DMAP (0.55 g, 4.45 mmol) in 30 mL of toluene (in 5 microwave tubes) was heated in a microwave (Personal Chemistry, Emrys Optimizer) at 180° C. for 1 h. The mixture was cooled to RT and diluted with 60 mL of EtOAc. The solution was washed with 20 mL of satd. NaHCO3 followed by 20 mL of brine, dried over Na2SO4 and concentrated in vacuo. The residue was further purified with silica gel column chromatography (100% EtOAc to 15% MeOH in EtOAc) to provide the title compound as colorless glass. MS (ESI pos. ion) m/z: 423.2 (M+H). Calc'd Exact Mass for C23H22N2O6: 422.43.
Reaction SMILES: [CH2:1]([C:22]1[C:26]2[S:27][C:28]3[C:32]4[S:33][C:34](C(O)=O)=[C:35]([CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH3:56])[C:31]=4[S:30][C:29]=3[C:25]=2[S:24][C:23]=1C(O)=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].NCC(O)=O>COCCOCCOCCOCCOC>[CH2:1]([C:22]1[C:26]2[S:27][C:28]3[C:32]4[S:33][CH:34]=[C:35]([CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH3:56])[C:31]=4[S:30][C:29]=3[C:25]=2[S:24][CH:23]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCCCCCCCCCCCCCCCCCc1c(C(=O)O)sc2c1sc1c3sc(C(=O)O)c(CCCCCCCCCCCCCCCCCCCCC)c3sc21
Agent: COCCOCCOCCOCCOC
Agent: NCC(=O)O
Product: CCCCCCCCCCCCCCCCCCCCCc1csc2c1sc1c3scc(CCCCCCCCCCCCCCCCCCCCC)c3sc21
Temperature: 240 °C
Reaction time: 1.5 h

Procedure:
Decarboxylation (Step D) A mixture of the 3,7-diheneicosyl thieno[3,2-b]thieno[2′,3′:4,5]thieno[2,3-d]thiophene-2,6-dicarboxylic acid (1.0 mmol) product of Example 11, Cu2O (0.10 mmol), and glycine (0.16 mmol) in tetraethyleneglycol dimethylether is heated to about 240° C. in a flask fitted with an outlet bubbler to monitor gas evolution. As the decarboxylation proceeds the evolved gas is periodically monitored. After about 1.5 hr no further gas is observed to evolve and after 2 hr total the reaction is terminated. The hot reaction mixture is filtered quickly to remove the copper oxide and other solid residue. The filtered solution is then cooled to RT, to afford a pale yellow precipitate. This is filtered from the solution and subsequently recrystallized hot to cold from toluene to give the desired product, 3,7-diheneicosylthieno[3,2-b]thieno[2′,3′:4,5]thieno[2,3-d]thiophene (DC21FT4) 1H NMR (CD2Cl2) 0.91 (6H, t, J=6.8 Hz), 1.15-1.50 (76H, m), 1.74-1.90 (4H, m), 2.78 (4H, m), and 7.02 (2H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[NH:8]C(=O)[N:6]3[N:13]=[C:14]([CH3:16])[N:15]=[C:5]3[C:4]=2[CH:3]=1.BrC1C=CC2NC(=O)N3N=CN=C3C=2C=1>>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]([NH2:8])=[C:4]([C:5]2[NH:6][N:13]=[C:14]([CH3:16])[N:15]=2)[CH:3]=1
Reactant: Cc1nc2c3cc(Cl)ccc3[nH]c(=O)n2n1
Agent: O=c1[nH]c2ccc(Br)cc2c2ncnn12
Product: Cc1n[nH]c(-c2cc(Cl)ccc2N)n1
Yield: 76.4 %

Procedure:
As described for example 21c) 9-chloro-2-methyl-6H-[1,2,4]triazolo[1,5-c]quinazolin-5-one (9.67 g, 41.2 mmol), instead of 9-bromo-6H-[1,2,4]triazolo[1,5-c]quinazolin-5-one, was converted to the title compound (6.57 g, 76%) which was obtained as an off-white solid. MS: m/e=209.0 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[CH2:7][C:8]([C:10]1[CH:15]=[N:14][C:13]([NH:16][C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:12][N:11]=1)=[O:9])([CH3:4])([CH3:3])[CH3:2].[Br:24]N1C(=O)CCC1=O>[Br-].[Li+].CC(=O)CC>[C:1]([O:5][C:6](=[O:23])[CH:7]([Br:24])[C:8]([C:10]1[CH:15]=[N:14][C:13]([NH:16][C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:12][N:11]=1)=[O:9])([CH3:3])([CH3:2])[CH3:4]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)CC(=O)c1cnc(NC(=O)C(C)(C)C)cn1
Agent: [Br-]
Agent: [Li+]
Solvent: CCC(C)=O
Product: CC(C)(C)OC(=O)C(Br)C(=O)c1cnc(NC(=O)C(C)(C)C)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 1-L round bottomed flask equipped with a magnetic stirrer was charged with 73.00 mg (0.841 mmol) of lithium bromide and the butanone solution obtained in step 3 (ca. 100 mL), which theoretically contained 27.09 g (84.30 mmol) of 3-[5-(2,2-dimethyl-propionylamino)-pyrazin-2-yl]-3-oxo-propionic acid-tert-butyl ester and ca. 73 mL of butanone. To the resulting mixture was added a total of 15.16 g (85.17 mmol) of N-bromosuccinimide portionwise with careful reaction monitoring by HPLC. After stirring at room temperature for 1 h, HPLC analysis indicated complete reaction. The reaction mixture was concentrated at 25° C./25 mmHg to a volume of ca. 70 mL, then diluted with 130 mL of ethyl acetate and washed with 3×100 mL L of water. After concentration at 35° C./60 mmHg to a volume of ca. 90 mL, the resulting suspension was diluted with 200 mL of heptane, and re-concentrated to a volume of ca. 90 mL. Then, 200 mL of heptane was added, and the suspension was again concentrated to a volume of ca, 150 mL. The solid was then collected by filtration, washed with 2×50 mL of heptane and dried by suction to give 32.16 g of the title compound as a light yellow solid; 98.7% pure as determined by HPLC analysis (HPLC column Zorbax XDB-C8, 3×100 mm, 3.5 μm, eluent 20-100% acetonitrile/water+01. % TFA over 10 min at 0.5 mL/min, detection at UV 254 nm, retention time 9.52 min).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7](N)[C:8]=1[C:9]([OH:11])=[O:10].Cl.N([O-])=[O:15].[Na+]>O>[Cl:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([OH:15])[C:8]=1[C:9]([OH:11])=[O:10]
Reactant: O=N[O-]
Reactant: Nc1cccc(Cl)c1C(=O)O
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=C(O)c1c(O)cccc1Cl
Temperature: 5 °C
Reaction time: 0.17 h
Yield: 44.7 %

Procedure:
A stirred suspension of 10.0 grams (0.048 mole) of 6-chloroanthranilic acid hydrochloride and 100 mL of concentrated hydrochloric acid in 200 mL of water was cooled to 5° C., and a solution of 3.5 grams (0.050 mole) of sodium nitrite in 50 mL of water was added dropwise during a 10 minute period. Upon completion of addition, the reaction mixture was warmed to 90° C. where it was stirred for about 10 minutes. The reaction mixture was cooled to ambient temperature and was filtered. The filter cake was washed with cold heptane and dried to yield 3.7 grams of 6-chlorosalicylic acid. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[C:16]2[C:12]([CH:13]=[CH:14][NH:15]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:18]1[O:21][C@H:19]1[CH3:20]>>[OH:21][C@@H:19]([CH3:20])[CH2:18][N:15]1[C:16]2[C:12](=[CH:11][CH:10]=[C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:17]=2)[CH:13]=[CH:14]1
Reactant: C[C@H]1CO1
Reactant: c1ccc(COc2ccc3cc[nH]c3c2)cc1
Product: C[C@H](O)Cn1ccc2ccc(OCc3ccccc3)cc21

Procedure:
Alternatively, compound 1 is reacted with (R)-propylene oxide according to the foregoing method to yield (R)-1-(2-hydroxypropyl)-6-benzyloxyindole (R-2). Alternatively, compound 1 is reacted with (S)-propylene oxide according to the foregoing method to yield (S)-1-(2-hydroxypropyl)-6-benzyloxyindole (S-2).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:12][C:13]1([F:28])[CH2:18][CH2:17][C:16]([CH2:26][NH2:27])([C:19]2[CH:20]=[N:21][C:22]([F:25])=[CH:23][CH:24]=2)[CH2:15][CH2:14]1>>[F:28][C:13]1([F:12])[CH2:14][CH2:15][C:16]([CH2:26][NH:27][C:4](=[O:6])[C:3]2[CH:7]=[C:8]([F:11])[CH:9]=[CH:10][C:2]=2[F:1])([C:19]2[CH:20]=[N:21][C:22]([F:25])=[CH:23][CH:24]=2)[CH2:17][CH2:18]1
Reactant: NCC1(c2ccc(F)nc2)CCC(F)(F)CC1
Reactant: O=C(O)c1cc(F)ccc1F
Product: O=C(NCC1(c2ccc(F)nc2)CCC(F)(F)CC1)c1cc(F)ccc1F

Procedure:
From 2,5-difluorobenzoic acid and C-[4,4-difluoro-1-(6-fluoro-pyridin-3-yl)-cyclohexyl]-methylamine. LCMS (MH+): m/z=385.2, tR (minutes, Method D)=0.71
Reaction SMILES: [C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][C:4]([C:7](Cl)=O)=[CH:3][CH:2]=1.[C:16](#[N:19])[CH:17]=C>>[C:10]1([C:1]2[CH:6]=[CH:5][C:4]([CH:7]=[CH:17][C:16]#[N:19])=[CH:3][CH:2]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: C=CC#N
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Product: N#CC=Cc1ccc(-c2ccccc2)cc1
Reaction time: 2 h

Procedure:
This compound is prepared from 10.83 g (50 millimols) of biphenyl-4-carboxylic acid chloride and 3.31 g (62.5 millimols) of acrylonitrile, the mixture being stirredfor 2 hours at 120° C. The crude product is extracted, in a Soxhlet extractor, with 100 ml of n-hexane, and is recrystallised from methanol. 3.83 g (37% of theory) of yellow crystals, melting point 43.7° C., are obtained. Analysis for C15H11N: calculated C 87.77%, H 5.40%, N 6.82%; found C 87.64%, H 5.34%, N 6.76%.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[NH:4][N:3]=1.C(O)(=O)C.[NH:23]1[CH:27]=[CH:26][N:25]=[C:24]1[CH:28]=O>CO>[Cl:18][C:14]1[CH:13]=[C:12]([NH:11][C:9]2[N:8]=[CH:7][N:6]=[C:5]3[NH:4][N:3]=[C:2]([N:1]=[CH:28][C:24]4[NH:23][CH:27]=[CH:26][N:25]=4)[C:10]=23)[CH:17]=[CH:16][CH:15]=1
Reactant: Nc1n[nH]c2ncnc(Nc3cccc(Cl)c3)c12
Reactant: O=Cc1ncc[nH]1
Solvent: CC(=O)O
Solvent: CO
Product: Clc1cccc(Nc2ncnc3[nH]nc(N=Cc4ncc[nH]4)c23)c1

Procedure:
Analogously to Example 32, 261 mg (1.00 mmol) of 3-amino-4-(3-chlorophenylamino)-1H-pyrazolo[3,4-d]pyrimidine (see Step 1.6) and 180 mg of acetic acid are dissolved in 26 ml of methanol and reacted with 144 mg (1.5 mmol) of imidazole-2-carbaldehyde to form 4-(3-chloro-phenylamino)-3-[(1H-imidazol-2-yl)-methyleneamino]-1H-pyrazolo[3,4-d]pyrimidine. Reduction of the above intermediate in 15 ml of DMEU with 8 ml (8 mmol) of DIBAL-H, analogous working-up and digestion in ethanol yield 4-(3-chlorophenylamino)-3-(1H-imidazol-2-yl)-methylamino]-1H-pyrazolo[3,4-d]pyrimidine; HPLC: tRet(grad20-100/20) 5.8; FABMS: (M+H)+=341.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][CH3:14])=[CH:9][C:8]=1[C:15]([F:18])([F:17])[F:16])[CH3:2].Cl[CH2:21][C:22]1[C:23]([CH3:38])=[N:24][C:25]([C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=2)=[CH:26][CH:27]=1.[Na+].[I-].C1CCN2C(=NCCC2)CC1>CS(C)=O>[CH2:1]([O:3][C:4](=[O:19])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]([CH3:14])[CH2:21][C:22]2[C:23]([CH3:38])=[N:24][C:25]([C:28]3[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=3)=[CH:26][CH:27]=2)=[CH:9][C:8]=1[C:15]([F:17])([F:18])[F:16])[CH3:2]
Reactant: CCOC(=O)COc1ccc(NC)cc1C(F)(F)F
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1CCl
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)COc1ccc(N(C)Cc2ccc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1C(F)(F)F
Reaction time: 4 h

Procedure:
To 0.080 g (0.29 mmol) of the above prepared (4-methylamino-2-trifluoromethyl-phenoxy)-acetic acid ethyl ester and 0.124 g (0.43 mmol) of 3-chloromethyl-2-methyl-6-(4-trifluoromethyl-phenyl)-pyridine (see example 1N], dissolved in 1.0 ml of abs. DMSO, were added successively 0.048 g (0.32 mmol) of NaI and 0.066 g (0.43 mmol) of DBU. The reaction was allowed to proceed for 4 h at ambient temperature, when TLC still indicated some starting amine. Therefore, another 33 mg (0.4 eq.) of 3-chloromethyl-2-methyl-6-(4-trifluoromethyl-phenyl)-pyridine was added and stirring continued for 3 h. Pouring onto crashed ice, extraction with AcOEt, filtration over Celite, washing of the organic layer with water, drying over sodium sulfate, and evaporation of the solvents, followed by flash chromatography (SiO2, hexane/AcOEt=8/2), afforded 0.046 g of the title compound as colorless oil.
Reaction SMILES: ClC(Cl)C.[CH3:5][O:6][C:7]1[CH:44]=[CH:43][C:10]([CH2:11][N:12]([CH2:34][C:35]2[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=2)[C:13]2[N:18]=[CH:17][C:16]([C:19]3[C:20]4[CH2:33][CH2:32][NH:31][C:21]=4[N:22]=[C:23]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)[N:24]=3)=[CH:15][N:14]=2)=[CH:9][CH:8]=1.C(N(CC)CC)C.[CH2:52]([N:54]=[C:55]=[O:56])[CH3:53].[Cl-].[NH4+]>>[CH2:52]([NH:54][C:55]([N:31]1[C:21]2[N:22]=[C:23]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[N:24]=[C:19]([C:16]3[CH:15]=[N:14][C:13]([N:12]([CH2:11][C:10]4[CH:9]=[CH:8][C:7]([O:6][CH3:5])=[CH:44][CH:43]=4)[CH2:34][C:35]4[CH:36]=[CH:37][C:38]([O:41][CH3:42])=[CH:39][CH:40]=4)=[N:18][CH:17]=3)[C:20]=2[CH2:33][CH2:32]1)=[O:56])[CH3:53]
Reactant: CCN=C=O
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4)cn2)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCNC(=O)N1CCc2c(-c3cnc(N(Cc4ccc(OC)cc4)Cc4ccc(OC)cc4)nc3)nc(N3CCOCC3)nc21
Temperature: 25 °C
Yield: 97.5 %

Procedure:
To dichloroethane solution (2 ml) of bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (100 mg, 0.185 mmol), triethylamine (780 μl, 5.56 mmol) and ethylisocyanate (780 μl, 5.56 mmol) were added, followed by refluxing for 6 hours. This was cooled to room temperature, followed by addition of saturated aqueous ammonium chloride solution, and passed through Whatman tube. The resulting organic layer was concentrated under reduced pressure, followed by purification by silica gel column chromatography (dichloromethane/methanol=100/1), to obtain 4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidine-7-carboxylic acid ethylamide (110.1 mg, Yield 97%). To this, trifluoroacetic acid (1 ml) and concentrated sulfuric acid (2 drops) were added, followed by stirring at 40° C. for 3 hours. After concentration of TFA under reduced pressure, water was added, followed by neutralization with 1M aqueous sodium hydroxide solution. The solid was filtered, followed by purification by silica gel column chromatography (dichloromethane/2M ammonia methanol=50/1), to obtain the desired compound as a yellow solid (20.9 mg, Yield 31%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2/[CH:11]=[C:12]1\[O:13][C:14]2[C:21]([CH2:22][N:23]3[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24]3)=[C:20]([O:36][CH3:37])[CH:19]=[CH:18][C:15]=2[C:16]\1=[O:17].FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2/[CH:11]=[C:12]1\[O:13][C:14]2[C:21]([CH2:22][N:23]3[CH2:24][CH2:25][NH:26][CH2:27][CH2:28]3)=[C:20]([O:36][CH3:37])[CH:19]=[CH:18][C:15]=2[C:16]\1=[O:17]
Reactant: COc1ccc2c(c1CN1CCN(C(=O)OC(C)(C)C)CC1)O/C(=C\c1n[nH]c3ccc(Cl)cc13)C2=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc2c(c1CN1CCNCC1)O/C(=C\c1n[nH]c3ccc(Cl)cc13)C2=O
Reaction time: 8 h
Yield: 44.9 %

Procedure:
A solution of tert-butyl (Z)-4-({2-[(5-chloro-1H-indazol-3-yl)methylene]-6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.0330 g, 0.0629 mmol) in methylene chloride (2 mL) was added with trifluoroacetic acid (2 mL) at room temperature, and the mixture was stirred overnight. The reaction mixture was concentrated, then the residue was added with saturated aqueous sodium hydrogencarbonate (10 mL), and the mixture was extracted three times with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and then the solvent was evaporated to obtain (Z)-2-[(5-chloro-1H-indazol-3-yl)methylene]-6-methoxy-7-(piperazin-1-ylmethyl)benzofuran-3(2H)-one (0.0120 g, 44%).
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[C:19]([C:26]2[CH:31]=[CH:30][C:29]([C:32](=[O:34])[CH3:33])=[CH:28][CH:27]=2)=[CH:20][CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)(=O)=O)C=CC=CC=1.[OH-].[Na+]>C(O)C.O1CCCC1.C(OCC)(=O)C>[CH:21]1([CH:20]=[C:19]([C:26]2[CH:27]=[CH:28][C:29]([C:32](=[O:34])[CH3:33])=[CH:30][CH:31]=2)[C:11]2[NH:10][C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=2)[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: CC(=O)c1ccc(C(=CC2CCCC2)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: C1CCOC1
Product: CC(=O)c1ccc(C(=CC2CCCC2)c2cc3cccnc3[nH]2)cc1
Yield: 89 %

Procedure:
A mixture of 1-{4-[1-(1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-cyclopentyl-vinyl]-phenyl}-ethanone (400 mg, 0.85 mmol) in ethanol (6 mL), tetrahydrofuran (4 mL) and an aqueous sodium hydroxide solution (10%, 1.5 mL) was heated at reflux for 48 h. The mixture was diluted with ethyl acetate (200 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 1-{4-[2-cyclopentyl-1-(1H-pyrrolo[2,3-b]pyridin-2-yl)-vinyl]-phenyl}-ethanone (250 mg, 89%) as a white solid: LC/MS m/e calcd for C22H22N2O [M+H]+ 331.43, observed 331.0.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[CH:6][CH-:5][B:4]1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:2].[Li+].[Cl-:15].[Cl-].[Cl-].[Cl-].[Zr+4:19]>CCOCC>[Cl-:15].[Cl-:15].[CH2:1]([N:3]1[CH:7]=[CH:6][CH:5]([Zr+2:19][CH:5]2[CH:6]=[CH:7][N:3]([CH2:1][CH3:2])[B:4]2[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[B:4]1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:2]
Reactant: CCN1C=C[CH-]B1c1ccccc1
Reactant: [Zr+4]
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOCC
Product: CCN1C=CC([Zr+2]C2C=CN(CC)B2c2ccccc2)B1c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59 %

Procedure:
A suspension of lithium (1-ethyl-2-phenyl-1,2-azaborolide) (1C), 0.80 g, 4.52 mmol) in 25 mL of ether was added to a suspension of ZrCl4 (0.51 g, 2.19 mmol) in 25 mL of ether at −50° C. The mixture was stirred for 8 h, during which time the mixture warmed to 25° C. The mixture was filtered through diatomaceous earth and the solvent was removed in vacuo. The residue was washed with ether and dried to obtain the desired product (0.65 g, 59 percent). The 1H NMR spectra indicated that the product is a mixture of two diasteromers in the ratio of 4:1. Spectral signals for the major isomer are reported.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]([O:15][C:16](=[O:24])[CH:17]([CH:19]1CCO[CH2:20]1)[CH3:18])[CH3:14].C(Br)=C.Cl.[O:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1>>[CH2:13]([O:15][C:16](=[O:24])[C:17]([CH3:18])([CH:31]1[CH2:32][CH2:33][O:29][CH2:30]1)[CH:19]=[CH2:20])[CH3:14]
Reactant: CCOC(=O)C(C)C1CCOC1
Reactant: C1CCOC1
Agent: C=CBr
Agent: Cl
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Product: C=CC(C)(C(=O)OCC)C1CCOC1
Temperature: -30 °C
Reaction time: 0.25 h
Yield: 24 %

Procedure:
A solution of N,N-diisopropylamine (1.28 mL, 9.1 mmol) in anhydrous tetrahydrofuran (15 mL) was cooled to −30° C. before adding n-butyllithium (3.22 mL, 8.08 mmol, 2.5 M in hexanes). The reaction mixture was stirred at −30° C. for 15 minutes before adding a solution of 2-(tetrahydro-furan-3-yl)-propionic acid ethyl ester (0.87 g, 5.05 mmol) in tetrahydrofuran (6 mL) dropwise over 3 minutes. The reaction mixture was stirred for a further 15 minutes at −30° C. before adding dibromobis(tributylphosphine)palladium(II) (40 mg, 50 μmol) and then a solution of vinylbromide (9.0 mL, 9.0 mmol, 1 M in tetrahydrofuran). The reaction mixture was stirred at −30° C. for 30 minutes then warmed to room temperature for 18 h. The reaction mixture was treated with hydrochloric acid (2 M, 20 mL). The mixture was extracted with diethyl ether (3×20 mL). The organics extract was dried over anhydrous sodium sulfate, filtered and evaporated. The residue was purified by silica gel chromatography using iso-hexanes/diethyl ether 3:2 to yield the title product (237 mg, 24%) as a yellow oil. 1H NMR (300 MHz, CDCl3) δ 1.14-1.30 (m, 6H), 1.61-1.75 (m, 1H), 1.84-1.99 (m, 1H), 2.68-2.82 (m, 1H), 3.52-3.95 (m, 4H), 4.10-4.21 (m, 2H), 5.09-5.23 (m, 2H), 5.95-6.07 (m, 1H). LCMS (m/z) 199.2 [M+H], Tr=2.17 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[C:4]([N+:11]([O-])=O)[C:3]=1[CH2:14][C:15]([O:17]C)=O.[Cl-].[NH4+].C(O)C>[Fe].O>[NH2:8][C:6]1[CH:5]=[C:4]2[C:3]([CH2:14][C:15](=[O:17])[NH:11]2)=[C:2]([Cl:1])[CH:7]=1
Reactant: COC(=O)Cc1c(Cl)cc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Nc1cc(Cl)c2c(c1)NC(=O)C2
Temperature: 120 °C
Reaction time: 3 h

Procedure:
A mixture of methyl (2-chloro-4,6-dinitrophenyl)acetate, ammonium chloride, iron powder, ethanol and water was stirred at 120° C. for 3 hours. The reaction liquid was filtered, trifluoroacetic acid was added to the filtrate, followed by stirring overnight at room temperature. The reaction liquid was concentrated under a reduced pressure, 1 M sodium hydroxide was added to the residue, and this was post-treated to obtain 6-amino-4-chloro-1,3-dihydro-2H-indol-2-one.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)=[CH:5][C:4]=1[O:18][CH3:19].O.[C-:21]#[N:22].[Na+]>CN(C)C=O>[O:10]1[C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=2[N:13]=[C:9]1[C:6]1[CH:7]=[CH:8][C:3]([CH2:2][C:21]#[N:22])=[C:4]([O:18][CH3:19])[CH:5]=1
Reactant: [C-]#N
Reactant: COc1cc(-c2nc3ccccc3o2)ccc1CBr
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(-c2nc3ccccc3o2)ccc1CC#N
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of, 2-[4-(bromomethyl)-3-methoxyphenyl]-1,3-benzoxazole (318 mg, 1 mmol), dimethylformamide (7.5 mL) and deionzed water (2.5 mL) was stirred at rt. Sodium cyanide (150 mg, 3.0 mmol) was added to reaction. After 3 h, dimethylformamide (10 mL) was added to help dissolve solids in reaction mixture. Let reaction mixture stir overnight at rt. Workup was done by washing reaction with brine (3×30 mL), extraction with EtOAc, combined organic extracts, dried (Na2SO4), filtered and removed solvent in vacuo. Flash chromatography of resulting orange solid on silica gel using a gradient elution of 1:9 EtOAc:hexanes to 1:3 EtOAc:hexanes afforded the desired intermediate, [4-(1,3-benzoxazol-2-yl)-2-methoxyphenyl]acetonitrile, as a light yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[N:14]=[C:13]2[C:15]([I:18])=[CH:16][NH:17][C:12]2=[CH:11][CH:10]=1.[C:19]1([CH3:29])[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1.[OH-].[Na+]>C1COCC1.CCOC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[N:14]=[C:13]2[C:15]([I:18])=[CH:16][N:17]([S:25]([C:22]3[CH:23]=[CH:24][C:19]([CH3:29])=[CH:20][CH:21]=3)(=[O:27])=[O:26])[C:12]2=[CH:11][CH:10]=1
Reactant: Fc1cccc(F)c1-c1ccc2[nH]cc(I)c2n1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2cc(I)c3nc(-c4c(F)cccc4F)ccc32)cc1
Temperature: 23 °C
Reaction time: 0.75 h

Procedure:
A solution of 5-(2,6-difluorophenyl)-3-iodo-1H-pyrrolo[3,2-b]pyridine (657 mg, 1.845 mmol) in THF (18 mL) was treated with 4-toluenesulfonyl chloride (387 mg, 2.029 mmol, Aldrich) and solid NaOH (89 mg, 2.214 mmol, VWR). The reaction was stirred at 23° C. under N2. After 45 min, the solution was diluted with EtOAc (200 ml) and washed with brine (150 mL), dried over MgSO4, concentrated in vacuo and purified by silica gel chromatography (eluent: 10-30% EtOAc/hexane), affording 5-(2,6-difluorophenyl)-3-iodo-1-tosyl-1H-pyrrolo[3,2-b]pyridine.