Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][C:3]=1[NH:9][C:10]([N:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:11].[N:17]1[CH:22]=[CH:21][CH:20]=[C:19](B(O)O)[CH:18]=1.C(=O)(O)[O-].[Na+]>C1COCC1.O.[Pd]>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:19]2[CH:18]=[N:17][CH:22]=[CH:21][CH:20]=2)=[CH:4][C:3]=1[NH:9][C:10]([N:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:11]
Reactant: Nc1ccc(Br)cc1NC(=O)N1CCCC1
Reactant: OB(O)c1cccnc1
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Nc1ccc(-c2cccnc2)cc1NC(=O)N1CCCC1
Temperature: 90 °C
Yield: 68.9 %

Procedure:
To a solution of N-(2-amino-5-bromophenyl)pyrrolidine-1-carboxamide (0.26 g, 0.72 mmol) in THF (10 mL) and water (5 mL) were added pyridin-3-ylboronic acid (0.13 g, 1.07 mmol, 1.5 equiv.), sodium bicarbonate (0.11 g, 1.07 mmol, 1.5 equiv.) and palladium(0) (0.08 g, 0.07 mmol, 0.1 equiv.). The reaction mass was stirred at 90° C. for sixteen hours. The reaction crude was filtered on a celite bed and diluted in ethyl acetate. The organic layers were washed with water and brine then dried over Na2SO4 and concentrated. The residue was purified by column chromatography on eluting ethyl acetate and hexane to allow N-(2-amino-5-(pyridin-3-yl)phenyl)pyrrolidine-1-carboxamide (0.14 g, 63% yield).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][C:12]([NH:14][C:15]3[CH:24]=[CH:23][C:18]([C:19](OC)=[O:20])=[CH:17][CH:16]=3)=[O:13])=[CH:9][C:4]=2[O:3][CH2:2]1.O.[NH2:26][NH2:27]>CCO>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][C:12]([NH:14][C:15]3[CH:24]=[CH:23][C:18]([C:19]([NH:26][NH2:27])=[O:20])=[CH:17][CH:16]=3)=[O:13])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: NN
Reactant: COC(=O)c1ccc(NC(=O)CCc2ccc3c(c2)OCO3)cc1
Solvent: CCO
Solvent: O
Product: NNC(=O)c1ccc(NC(=O)CCc2ccc3c(c2)OCO3)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 65 %

Procedure:
To a suspension of methyl 4-{[3-(1,3-benzodioxol-5-yl)propanoyl]amino}benzoate (200 mg, 0.61 mmol) in EtOH (3.5 mL) was added hydrazine hydrate (0.5 mL). After stirring for 15 hrs at reflux, the reaction mixture was cooled to rt and a white solid precipitated out. Filtration, washing with EtOH (2×1 mL) and water (3×1 mL), and drying under vacuo at 70° C. for 1 hr gave 130 mg of the title compound (65%) as a white solid in 95.5% purity by HPLC (MaxPlot detection between 230 and 400 nm).
Reaction SMILES: C[O:2]N=C1C2C(=CC=C(C(O)=O)C=2C)SCC1.[CH3:18][O:19][N:20]=[C:21]1[C:30]2[C:25](=[C:26](C)[CH:27]=[C:28]([C:32](C3C=NN(CC)C=3OS(CCC)(=O)=O)=[O:33])[C:29]=2[CH3:31])[S:24](=[O:50])(=[O:49])[CH2:23][CH2:22]1.OO.C(OCC)(=O)C>C(O)(=O)C>[CH3:18][O:19][N:20]=[C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([C:32]([OH:33])=[O:2])[C:29]=2[CH3:31])[S:24](=[O:50])(=[O:49])[CH2:23][CH2:22]1
Reactant: CCCS(=O)(=O)Oc1c(C(=O)c2cc(C)c3c(c2C)C(=NOC)CCS3(=O)=O)cnn1CC
Reactant: CON=C1CCSc2ccc(C(=O)O)c(C)c21
Agent: OO
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CON=C1CCS(=O)(=O)c2ccc(C(=O)O)c(C)c21
Yield: 97 %

Procedure:
1.0 Gram (4.0 mmol) of the 4-methoxyimino-5-methylthiochroman-6-carboxylic acid obtained in the above (2) was reacted with 1.3 g (12 mmol) of a 30% hydrogen peroxide aqueous solution in 5 ml of acetic acid at 100° C. for 1 hour. Ethyl acetate was added to the reaction product, and the mixture was washed with a saturated sodium chloride aqueous solution and then dried over sodium sulfate. The solvent was distilled off to give 1.1 g (yield 97%) of 4-methoxyimino-5-methylthiochroman-6-carboxylic acid-1,1-dioxide.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([CH2:13][S:14][C:15]2[NH:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[N:16]=2)[C:8]=1[CH3:24].[OH-:25].[Na+]>ClCCl>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([CH2:13][S:14]([C:15]2[NH:16][C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[N:19]=2)=[O:25])[C:8]=1[CH3:24]
Reactant: [OH-]
Reactant: COCCCOc1ccnc(CSc2nc3ccccc3[nH]2)c1C
Agent: [Na+]
Solvent: ClCCl
Product: COCCCOc1ccnc(CS(=O)c2nc3ccccc3[nH]2)c1C
Yield: 48.3 %

Procedure:
2-[{4-(3-Methoxypropoxy)-3-methylpyridin-2-yl}methylthio]-1H-benzimidazole (25.0 g (72.8 mmol)) was dissolved in dichloromethane, and then the solution was cooled, and mcpba (70.2% purity; 10.7 g (43.7 mmol)) was added little by little such that the internal temperature did not exceed −15° C. After the addition, a 10% sodium hydroxide aqueous solution (70.8 ml) was added, the mixture was stirred and then left to stand, and then the aqueous layer was separated off. The separated aqueous layer was washed twice with dichloromethane (48 ml). A 2N ammonium acetate aqueous solution was then put into the solution, and then extraction was carried out twice with dichloromethane (48 ml). The dichloromethane layers were washed twice with water (48 ml), vacuum concentration was carried out, crystallization was carried out using acetone (198 ml), and then filtration was carried out, thus obtaining 2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazole (12.6 g) (HPLC purity 99.3%, yield 48.3%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH:5]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)[C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1.[CH3:20][CH:21]([CH3:37])[C:22]([NH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)=[O:23]>>[F:12][C:9]1[CH:10]=[CH:11][C:6]([CH:5]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH2:4][CH2:3][CH2:2][N:34]2[CH2:35][CH2:36][CH:31]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[NH:24][C:22](=[O:23])[CH:21]([CH3:20])[CH3:37])[CH2:32][CH2:33]2)=[CH:7][CH:8]=1
Reactant: Fc1ccc(C(CCCCl)c2ccc(F)cc2)cc1
Reactant: CC(C)C(=O)Nc1ccccc1C1CCNCC1
Product: CC(C)C(=O)Nc1ccccc1C1CCN(CCCC(c2ccc(F)cc2)c2ccc(F)cc2)CC1

Procedure:
Prepared by Procedure G and Scheme AI using 1-[4-chloro-1-(4-fluorophenyl)butyl]-4-fluorobenzene and 2-methyl-N-[2-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 490.9 (M+H)+.
Reaction SMILES: [Na].C(OCC)(=O)[CH2:3][C:4](OCC)=[O:5].[Cl:13][C:14]1[C:22]2[O:21][C:20]([CH3:24])([CH3:23])[CH2:19][C:18]=2[C:17]([CH3:25])=[C:16]([CH3:26])[C:15]=1[CH:27]=[CH:28][C:29](=[O:31])[CH3:30].O>CO>[Cl:13][C:14]1[C:22]2[O:21][C:20]([CH3:23])([CH3:24])[CH2:19][C:18]=2[C:17]([CH3:25])=[C:16]([CH3:26])[C:15]=1[CH:27]1[CH2:3][C:4](=[O:5])[CH:30]=[C:29]([OH:31])[CH2:28]1
Reactant: CC(=O)C=Cc1c(C)c(C)c2c(c1Cl)OC(C)(C)C2
Reactant: CCOC(=O)CC(=O)OCC
Agent: [Na]
Solvent: CO
Solvent: O
Product: Cc1c(C)c(C2CC(=O)C=C(O)C2)c(Cl)c2c1CC(C)(C)O2
Temperature: 25 °C

Procedure:
To a solution of 1.0 g of sodium in 30 ml of absolute methanol was added 6.5 ml of diethyl malonate and 10 g of the 4-(7-chloro-2,3-dihydro-2,2,4,5-tetramethyl-benzofuran-6-yl)-3-buten-2-one in 20 ml of absolute methanol, and refluxed for 4 hours. The reaction mixture was added 100 ml of water and concentrated under reduced pressure and then added 17 g of 20% aqueous solution of sodium hydroxide. After refluxing 1 hour, the reaction mixture was cooled to room temperature and washed with benzene. Concentrated hydrochloric acid was added dropwise into the aqueous layer until the bubble of carbon dioxide ceased. And then, solid was dissolved in ethyl acetate and washed with water. The combined organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to afford 11.8 g of 5-(7-chloro-2,3-dihydro-2,2,4,5-tetramethylbenzofuran-6-yl)-3-hydroxycyclohex-2-en-1-one.
Reaction SMILES: Br.Br[CH:3]1[C:14](=[O:15])[C:7]2[N:8]3N=C[N:11]=[C:9]3S[C:6]=2[CH2:5][CH2:4]1.NC1[CH:22]=[CH:21][CH:20]=[CH:19]N=1>C(O)C>[CH:19]1[N:8]2[C:9](=[N:11][C:6]3[CH2:5][CH2:4][CH2:3][C:14](=[O:15])[C:7]=32)[CH:22]=[CH:21][CH:20]=1
Reactant: Nc1ccccn1
Reactant: O=C1c2c(sc3ncnn23)CCC1Br
Agent: Br
Solvent: CCO
Product: O=C1CCCc2nc3ccccn3c21
Yield: 32 %

Procedure:
2-Bromo-1,3-cyclohexadione (9.55 g) prepared in Example 1, Route 1 (A) and 2-aminopyridine (4.7 g) were dissolved into absolute ethanol (200 ml), and the reaction mixture was heated to reflux for 20 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the residue was dissolved into water. The solution was neutralized with sodium carbonate, extracted with chloroform three times, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluant:methylene chloride: acetonitrile=2:1) to give the titled compound (3.0 g, 32%).
Reaction SMILES: [CH2:1](NCCCC)CCC.C(O)(=O)C.C=O.[CH3:16][CH:17]([CH:21]([CH3:23])[CH3:22])[CH2:18][CH:19]=[O:20]>C1(C)C=CC=CC=1>[CH3:16][CH:17]([CH:21]([CH3:23])[CH3:22])[C:18](=[CH2:1])[CH:19]=[O:20]
Reactant: CC(C)C(C)CC=O
Reactant: CCCCNCCCC
Agent: C=O
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: C=C(C=O)C(C)C(C)C
Temperature: 70 °C

Procedure:
Dibutylamine (34 g), acetic acid (15.78 g), and formaldehyde (230 g) were charged to a reaction flask and heated to 70° C. 3,4-Dimethyl-pentanal (500 g) was fed over 2 hours and aged for another hour. The reaction mixture was cooled down and toluene (200 mL) was added. The reaction mixture was sequentially washed with water (2 L), sodium carbonate solution (1 L), and brine (1 L) to provide the crude product 3,4-dimethyl-2-methylene-pentanal.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[OH:22][CH2:23][CH2:24][NH:25][S:26]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]Cl)(=[O:28])=[O:27]>C(N(C(C)C)C(C)C)C>[OH:22][CH2:23][CH2:24][NH:25][S:26]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][N:12]1[CH2:11][CH2:10][N:9]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH2:14][CH2:13]1)(=[O:28])=[O:27]
Reactant: Clc1ccc(C(c2ccc(Cl)cc2)N2CCNCC2)cc1
Reactant: O=S(=O)(CCCCCCl)NCCO
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(CCCCCN1CCN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)CC1)NCCO
Yield: 97.5 %

Procedure:
1-[Bis(4-chlorophenyl)methyl]piperazine (642.5 mg, 2.00 mmol) and N-(2-hydroxyethyl)-5-chloropentanesulfonamide (459.5 mg, 2.00 mmol) were refluxed in N-ethyldiisopropylamine (2 ml) for 6 hours. The reaction mixture was concentrated in vacuo, and water was added thereto. The mixture was extracted with chloroform. The chloroform layer was washed with water, and dried over anhydrous magnesium sulfate. Subsequently, the solvent was removed by evaporation in vacuo. The resulting crude product was purified by column chromatography on silica gel with chloroform-methanol (20:1), to give N-(2-hydroxyethyl)-5-[4-[bis(4-chlorophenyl)methyl]-1-piperazinyl]pentanesulfonamide (1003.0 mg) as a pale brown oil (97.5%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11][C:12]2[C:20]3[C:15](=[CH:16][C:17]([Cl:21])=[CH:18][CH:19]=3)[NH:14][C:13]=2[CH3:22])[CH:6]=1)[CH3:2].Cl[C:25]1[N:26]=[N:27][C:28]([CH3:31])=[CH:29][CH:30]=1>>[CH2:1]([O:3][C:4](=[O:23])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11][C:12]2[C:20]3[C:15](=[CH:16][C:17]([Cl:21])=[CH:18][CH:19]=3)[N:14]([C:25]3[N:26]=[N:27][C:28]([CH3:31])=[CH:29][CH:30]=3)[C:13]=2[CH3:22])[CH:6]=1)[CH3:2]
Reactant: Cc1ccc(Cl)nn1
Reactant: CCOC(=O)c1cccc(Sc2c(C)[nH]c3cc(Cl)ccc23)c1
Product: CCOC(=O)c1cccc(Sc2c(C)n(-c3ccc(C)nn3)c3cc(Cl)ccc23)c1

Procedure:
Prepared according to the procedure described in Example 55, Step 2 using the following starting materials: 3-(6-chloro-2-methyl-1H-indol-3-ylsulfanyl)-benzoic acid ethyl ester and 3-chloro-6-methyl-pyridazine.
Reaction SMILES: [N+](=[CH:3][C:4](=[O:9])[CH2:5][CH2:6][CH:7]=[CH2:8])=[N-].[C:10]([OH:13])(=[O:12])[CH3:11]>>[C:10]([O:13][CH2:3][C:4](=[O:9])[CH2:5][CH2:6][CH:7]=[CH2:8])(=[O:12])[CH3:11]
Reactant: C=CCCC(=O)C=[N+]=[N-]
Reactant: CC(=O)O
Product: C=CCCC(=O)COC(C)=O
Yield: 90 %

Procedure:
Into 35 ml of glacial acetic acid at 60°-70° C. is dropped slowly 12.4 g. (0.1 mole) of 1-diazo-5-hexen-2-one. After the nitrogen evolution stops, the reaction mixture is heated to reflux for one hour. The resulting mixture is extracted with 3×50 ml of methylene chloride. The organic layer is dried over anhydrous magnesium sulfate. Concentration of the filtrate gives 1-acetoxy-5-hexen-2-one as a brown oil in 90% yield, based on the starting 4-pentenoyl chloride.
Reaction SMILES: [N+:1]([CH:3](S(C1C=CC(C)=CC=1)(=O)=O)[CH2:4][CH2:5][CH2:6][CH3:7])#[C-:2].[C:18]([O:22][CH2:23][CH3:24])(=[O:21])[CH:19]=[CH2:20].CC(C)([O-])C.[K+]>O1CCCC1.O>[CH2:4]([C:3]1[NH:1][CH:2]=[C:19]([C:18]([O:22][CH2:23][CH3:24])=[O:21])[CH:20]=1)[CH2:5][CH2:6][CH3:7]
Reactant: C=CC(=O)OCC
Reactant: [C-]#[N+]C(CCCC)S(=O)(=O)c1ccc(C)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CCCCc1cc(C(=O)OCC)c[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
A solution (120 mL) of 1-[(1-isocyanopentyl)sulfonyl]-4-methylbenzene (10.8 g) and ethyl acrylate (4.78 mL) in tetrahydrofuran was added dropwise to a solution (80 mL) of potassium tert-butoxide (5.79 g) in tetrahydrofuran while stirring at room temperature over 1 hr. The mixture was further stirred at the same temperature for 30 min, and the reaction product was diluted with water, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=19:1→8:2) to give the title compound as a yellow oil (yield 6.56 g, 78%).
Reaction SMILES: [NH2:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]([CH2:13][O:14][CH3:15])[CH:7]=1)[C:3]([OH:5])=[O:4].Cl[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18].[OH-].[Na+]>O>[CH2:20]([O:19][C:17]([NH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]([CH2:13][O:14][CH3:15])[CH:7]=1)[C:3]([OH:5])=[O:4])=[O:18])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COCc1cc(C(N)C(=O)O)ccc1O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COCc1cc(C(NC(=O)OCc2ccccc2)C(=O)O)ccc1O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
α-Amino-4-hydroxy-3-(methoxymethyl)benzeneacetic acid (0.1 mole), is dissolved in water, the pH of which is about 8. This solution is cooled to 0° C. and benzyl chloroformate (0.1 mole) is added dropwise along with 1N sodium hydroxide so as to maintain the pH at 8 to 9. After the addition, the solution is stirred at 0° C. for 30 minutes and 30 minutes at room temperature. The solution is washed with ethyl ether and then acidified with hydrochloric acid. The title compound is then recovered from the aqueous solution.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]([NH:9][C:10]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[C:29]5[C:24](=[CH:25][C:26]([Cl:30])=[CH:27][CH:28]=5)[NH:23][N:22]=4)[N:19]=3)[N:14]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:13]=2)=[O:11])[CH3:8])[CH:2]=1.[H-].[Na+].Br[CH2:42][CH2:43][N:44]1[CH2:49][CH2:48][O:47][CH2:46][CH2:45]1>CN(C=O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]([NH:9][C:10]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[C:29]5[C:24](=[CH:25][C:26]([Cl:30])=[CH:27][CH:28]=5)[N:23]([CH2:42][CH2:43][N:44]5[CH2:49][CH2:48][O:47][CH2:46][CH2:45]5)[N:22]=4)[N:19]=3)[N:14]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:37])([CH3:36])[CH3:38])[CH:13]=2)=[O:11])[CH3:8])[CH:2]=1
Reactant: CC(NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3n[nH]c4cc(Cl)ccc34)nc12)c1cccnc1
Reactant: BrCCN1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(CCN4CCOCC4)c4cc(Cl)ccc34)nc12)c1cccnc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 33 %

Procedure:
2-(6-Chloro-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (1-pyridin-3-yl-ethyl)-amide (100 mg, 0.18 mmol) was combined with DMF (2 mL) at 0° C. to give a yellow solution. Sodium hydride (60% in mineral oil, 22 mg, 0.55 mmol) was added and the reaction was stirred at 0° C. for 10 min. 4-(2-Bromoethyl)morpholine hydrocholoride (63 mg, 0.27 mmol) was added and the reaction was stirred at 0° C. for 30 min then warmed to room temperature and stirred for 2 h. The reaction mixture was quenched with 5 mL of brine and 10 mL of water and extracted with ethyl acetate (2×30 mL). The combined organic layers were washed with water and brine then dried with MgSO4, filtered and concentrated in vacuo. The crude material was purified by silica gel chromatography (0-10% methanol in dichloromethane) to afford 40 mg (33%) of 2-[6-chloro-1-(2-morpholin-4-yl-ethyl)-1H-indazol-3-yl]-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (1-pyridin-3-yl-ethyl)-amide as a foaming solid. MS: (M+H)+=662.
Reaction SMILES: [Cu][C:2]#[N:3].Br[C:5]1[CH:14]=[CH:13][C:8]2[S:9][CH:10]=[C:11]([CH3:12])[C:7]=2[CH:6]=1>CN1CCCC1=O>[C:2]([C:5]1[CH:14]=[CH:13][C:8]2[S:9][CH:10]=[C:11]([CH3:12])[C:7]=2[CH:6]=1)#[N:3]
Reactant: N#C[Cu]
Reactant: Cc1csc2ccc(Br)cc12
Solvent: CN1CCCC1=O
Product: Cc1csc2ccc(C#N)cc12
Reaction time: 17 h
Yield: 90.1 %

Procedure:
To copper (I) cyanide (0.569 g, 6.35 mmol) was added 5-bromo-3-methyl benzo[b]thiophene (1.179 g, 5.19 mmol) in N-methylpyrrolidinone (10 ml) and the mixture was stirred at 180°-90° C. for 17 h. This was then partitioned between ether (75 ml) and ammonia solution (75 ml). The ether layer was separated, washed with more ammonia solution (2×50 ml), dried (Na2SO4) and evaporated in vacuo to leave 0.81 g of an off-white solid. Chromatography on flash silica, eluting with 10% ethyl acetate/petroleum ether yielded 0.76 g (85%) of the title compound as a white solid. δ (CDCl3) 2.47 (3H, s), 7.23 (1H, s), 7.55 (1H, dd, J=8.3 and 1.5 Hz), 7.93 (1H, d, J=8.4 Hz), 8.03 (1H, d, J=1.4 Hz).
Reaction SMILES: C[O:2][C:3](=[O:24])[C@@H:4]1[CH2:8][CH:7]([O:9][Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11])[CH2:6][N:5]1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].[Li+].[OH-].Cl>CO>[C:17]([N:5]1[CH2:6][CH:7]([O:9][Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11])[CH2:8][C@H:4]1[C:3]([OH:24])=[O:2])([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18]
Reactant: COC(=O)[C@@H]1CC(O[Si](C)(C)C(C)(C)C)CN1C(=O)OC(C)(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC(O[Si](C)(C)C(C)(C)C)C[C@H]1C(=O)O
Reaction time: 0.5 h
Yield: 84.4 %

Procedure:
To a solution of 1.3 g (3.6 mmol) of N-Boc-4-(t-butyldimethylsilyloxy)proline methyl ester, prepared as described by Rosen et al., J. Med. Chem. 1988, 31, 1598, in 10 ml of methanol was added 5 ml (5 mmol) of 1 N LiOH in an ice bath. The reaction mixture was stirred for 30 min. The reaction mixture was adjusted to pH 2-3 with 1 N HCl at the same temperature and the solvent was evaporated. The resulting residue was partitioned between dichloromethane and water, and extracted 3 times with dichloromethane. The combined organic solution was washed with 1 N HCl and water, dried over anhydrous magnesium sulfate, and concentrated in vacuo to give 1.05 g (96%) of N-Boc-4-(t-butyldimethylsilyl-oxy)proline as a foamy solid which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:29]=[CH:28][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([N:13]=[C:14]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:8]=2[Cl:27])=[C:4]([F:30])[CH:3]=1.[F:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]2[C:39](=[O:47])[C:40]([C:44](O)=[O:45])=[CH:41][NH:42][CH:43]=2)=[CH:34][CH:33]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:27][C:8]1[C:9]([N:13]=[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[N:10][CH:11]=[CH:12][C:7]=1[O:6][C:5]1[CH:28]=[CH:29][C:2]([NH:1][C:44]([C:40]2[C:39](=[O:47])[C:38]([C:35]3[CH:36]=[CH:37][C:32]([F:31])=[CH:33][CH:34]=3)=[CH:43][NH:42][CH:41]=2)=[O:45])=[CH:3][C:4]=1[F:30]
Reactant: Nc1ccc(Oc2ccnc(N=C(c3ccccc3)c3ccccc3)c2Cl)c(F)c1
Reactant: O=C(O)c1c[nH]cc(-c2ccc(F)cc2)c1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(Oc2ccnc(N=C(c3ccccc3)c3ccccc3)c2Cl)c(F)c1)c1c[nH]cc(-c2ccc(F)cc2)c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 78 %

Procedure:
To a solution of 4-(4-amino-2-fluorophenoxy)-3-chloro-N-(diphenylmethylene)pyridin-2-amine (836 mg, 2.0 mmol) and 5-(4-fluorophenyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid (490 mg, 2.0 mmol) in DMF (10 mL) at room temperature were added HATU (913 mg, 2.4 mmol) and DIPEA (1.05 ml, 6.0 mmol). The reaction mixture was stirred at room temperature for 3 h prior to being quenched by the addition of cold water (50 mL). The solid that formed was collected by filtration, and washed with water and ether. The solid was dissolved in DCM and purified by flash column chromatography (SiO2, DCM to 10% MeOH in DCM) to give the desired product (987 mg, 78%) as a light yellow solid. MS (ESI+) m/z 633 (M+H)+.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1.[CH3:13][Sn:14](Cl)([CH3:16])[CH3:15].C1COCC1>CCOCC>[CH3:13][Sn:14]([CH3:16])([CH3:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1
Reactant: C[Sn](C)(C)Cl
Reactant: Brc1ccccn1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: C[Sn](C)(C)c1ccccn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 51 %

Procedure:
A solution of 15.7 mL of 1.6 M n-butyllithium (25.1 mmol) in anhydrous ether (25 mL) was stirred under Ar at −78° C. and to this was added a solution of 2-bromopyridine (3.97 g, 25.1 mmol) in anhydrous ether (12.5 mL). The resulting orange solution was stirred for 2 h, and trimethyltin chloride in THF (26.0 mmol, 26 and, 1.0 M) added over 30 min. The reaction was stirred for 1 h at −78° C. then warmed to room temperature over 1 h, filtered and the filtrate evaporated. Distillation afforded 3.1 g (51%) of the title compound as a colorless liquid which solidified in the receiver flask. B.p. 65° C./2 mm Hg; Literature B.p. 75° C./4 mm Hg.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH2:9][C:10]#[CH:11])=[CH:6][C:5]([N+:12]([O-])=O)=[C:4]([F:15])[CH:3]=1.O>C(O)(=O)C.[Fe]>[Cl:1][C:2]1[C:7]([O:8][CH2:9][C:10]#[CH:11])=[CH:6][C:5]([NH2:12])=[C:4]([F:15])[CH:3]=1
Reactant: C#CCOc1cc([N+](=O)[O-])c(F)cc1Cl
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Product: C#CCOc1cc(N)c(F)cc1Cl
Temperature: 90 °C
Yield: 72.6 %

Procedure:
A suspension of electrolytic iron powder (3.5 g) in a 5% aqueous acetic acid solution was heated to 90° C., and a solution of 4-chloro-2-fluoro-5-(2-propynyloxy)nitrobenzene (5.7 g) in acetic acid (40 ml) was dropwise added thereto at the same temperature. The resultant mixture was stirred at 90°-105° C. for 1 hour and allowed to cool to room temperature. Water (200 ml) was added thereto. Insoluble materials were filtered, and the filtrate was neutralized, followed by extraction with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated. The residue was washed with petroleum ether and carbon tetrachloride to obtain 3.6 g of 4-chloro-2-fluoro-5-(2-propynyloxy)aniline. M.P. 61.0°-61.5° C.
Reaction SMILES: [C:1]1([C:7]2[O:8][CH:9]=[C:10]3[C:18]4[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=4[N:12](S(C4C=CC=CC=4)(=O)=O)[C:11]=23)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+].Cl>CS(C)=O.O>[C:1]1([C:7]2[O:8][CH:9]=[C:10]3[C:18]4[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=4[NH:12][C:11]=23)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=S(=O)(c1ccccc1)n1c2ccccc2c2coc(-c3ccccc3)c21
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: c1ccc(-c2occ3c2[nH]c2ccccc23)cc1
Temperature: 25 °C

Procedure:
45 g (123 mmol) of 3-phenyl-4-(phenylsulfonyl)-4H-furo[3,4-b]indole and 48 g (856 mmol) of potassium hydroxide in 65 ml of DMSO and 21 ml of water are heated under reflux for 1 h. The mixture is subsequently cooled to room temperature, neutralised using 1M HCl solution and extracted with dichloromethane. The solvent is evaporated in vacuo, and the residue is purified by chromatography (heptane/ethyl acetate 10:1). Yield: 22.4 g (96 mmol), 80%.