Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[C:2]1[N:9]=[C:8]([CH3:10])[C:7]([N+:11]([O-:13])=[O:12])=[CH:6][C:3]=1[C:4]#[N:5].P(Cl)(Cl)(Cl)(Cl)[Cl:15].C(O)C>P(Cl)(Cl)(Cl)=O>[Cl:15][C:2]1[N:9]=[C:8]([CH3:10])[C:7]([N+:11]([O-:13])=[O:12])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: Cc1nc(O)c(C#N)cc1[N+](=O)[O-]
Solvent: CCO
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1nc(Cl)c(C#N)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 37.9 %

Procedure:
A suspension of the compound prepared in Example 442 (5.00 g) and phosphorus pentachloride (6.97 g) in phosphorus oxychloride (25 mL) was stirred and heated in an oil bath set to 110° C. for 30 minutes. The resulting solution was cooled to ambient temperature and concentrated. The residual liquid was cooled in an ice bath, whereupon a solid formed. This solid was carefully treated with 50% aqueous ethanol (10 mL), and then the mixture was stirred and heated in the 110° C. oil bath for 5 minutes. This redissolved the solid, and then the flask was again placed in the ice bath. The solid reappeared on cooling, and it was collected by filtration, washed with water, and air-dried. The solid was then recrystallized by stirring it with methanol (20 mL), and heating to boiling until all solid dissolved. On cooling to ambient temperature crystallization began, and the mixture was stored in the refrigerator overnight. The crystals were collected by filtration, washed with cold methanol, and dried under vacuum to provide the title compound (2.09 g) with the following physical data.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[C:9]([Br:10])=[CH:8][C:7]([CH3:11])=[CH:6][N:5]=1.Cl[C:13]1[C:14](=[O:29])[N:15]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[CH:16]=[C:17]([Cl:19])[N:18]=1>O1CCCC1>[Br:10][C:9]1[C:4]([NH:3][C:13]2[C:14](=[O:29])[N:15]([CH2:20][C:21]3[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=3)[CH:16]=[C:17]([Cl:19])[N:18]=2)=[N:5][CH:6]=[C:7]([CH3:11])[CH:8]=1
Reactant: Cc1cnc(N)c(Br)c1
Reactant: COc1ccc(Cn2cc(Cl)nc(Cl)c2=O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(Cn2cc(Cl)nc(Nc3ncc(C)cc3Br)c2=O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 56 %

Procedure:
An oven dried, 2 L, three necked round bottom flask was charged with NaH (60% dispersion in oil, 11.9 g, 298.11 mmol), suspended in anhydrous tetrahydrofuran (500 mL) and cooled in an ice bath. To the cooled mixture, was added the solution of 2-amino-3-bromo-5-methylpyridine (39.4 g, 210.433 mmol, 150 mL of anhydrous THF). The ice bath was removed and the reaction was allowed to warm to room temperature over a 1 h period. Via addition funnel, the solution of 3,5-dichloro-1-(4-methoxybenzyl)pyrazin-2(1H)-one (50.0 g, 175.36 mmol, 150 mL anhydrous tetrahydrofuran) was added in a rapid, drop-wise fashion, attached a reflux condenser and stirred in an oil bath heated at 72° C. (exothermic reaction occurred upon heating). After 3 h, the flask was removed from the oil bath, cooled to room temperature, quenched with isopropanol (15 mL) and BHT (0.075 g), and concentrated in vacuo to a dark crude. Chromatography on silica gel plug with ethyl acetate/DCM (3/97) afforded the desired product as a light tan solid. The mix fractions were combined, concentrated and the desired product was purified by recrystallization in ethyl acetate/diethyl ether and isolated by vacuum filtration. The two solid pools were combined (43 g, 56% yield) and verified by 1H-NMR and analytical LCMS. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.30 (s, 3H) 3.74 (s, 3H) 5.00 (s, 2H) 6.93 (d, J=8.84 Hz, 2H) 7.39 (s, 2H) 7.42 (s, 1H) 8.01 (s, 1H) 8.28 (s, 1H) 9.50 (s, 1H). ESI-MS: m/z 437.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:34]=[CH:33][C:6]([C:7]([NH:9][C:10]2[CH:11]=[C:12]([CH:17]=[CH:18][C:19]=2[NH:20][C:21](=[O:32])[C:22]2[CH:27]=[CH:26][C:25]([C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:24][CH:23]=2)[C:13]([O:15]C)=[O:14])=[O:8])=[CH:5][CH:4]=1.[OH-].[Na+]>O1CCCC1.CO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:9][C:10]2[CH:11]=[C:12]([CH:17]=[CH:18][C:19]=2[NH:20][C:21](=[O:32])[C:22]2[CH:23]=[CH:24][C:25]([C:28]([CH3:30])([CH3:31])[CH3:29])=[CH:26][CH:27]=2)[C:13]([OH:15])=[O:14])=[O:8])=[CH:33][CH:34]=1
Reactant: COC(=O)c1ccc(NC(=O)c2ccc(C(C)(C)C)cc2)c(NC(=O)c2ccc(OC)cc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(C(=O)Nc2cc(C(=O)O)ccc2NC(=O)c2ccc(C(C)(C)C)cc2)cc1
Reaction time: 16 h
Yield: 84.2 %

Procedure:
To a solution of methyl 3-[(4-methoxybenzoyl)amino]-4-[(4-tert-butylbenzoyl)amino]benzoate (0.487 g, 1.00 mmol) in tetrahydrofuran (32 mL) and methanol (8 mL) was added 5 N aqueous sodium hydroxide (0.6 mL). The resulting mixture was stirred for 16 h, a second portion of 5 N aqueous sodium hydroxide (0.6 mL) added, and the mixture stirred for an additional 16 h. The solvent was concentrated in vacuo and the crude product acidified with dilute aqueous hydrochloric acid and diluted with ethyl acetate. The mixture was extracted with saturated aqueous potassium carbonate solution. The aqueous layer was acidified and extracted with ethyl acetate. The organic layer was dried (magnesium sulfate), filtered, and concentrated in vacuo. Crystallization of the residue from methylene chloride/-hexane provided 376 mg (100%) of the title product.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][O:12][C:13]2[CH:18]=[CH:17][N:16]3[C:19]([C:22]([O:24]CC)=[O:23])=[CH:20][N:21]=[C:15]3[CH:14]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].O.[OH-].[Li+:29].Cl>O>[CH:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][O:12][C:13]2[CH:18]=[CH:17][N:16]3[C:19]([C:22]([O-:24])=[O:23])=[CH:20][N:21]=[C:15]3[CH:14]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[Li+:29]
Reactant: CCOC(=O)c1cnc2cc(OCCN3CCN(C(C)C)CC3)ccn12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: CC(C)N1CCN(CCOc2ccn3c(C(=O)[O-])cnc3c2)CC1
Temperature: 95 °C
Reaction time: 0.17 h
Yield: 101.6 %

Procedure:
To ethyl 7-(2-(4-isopropylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxylate (5.68 g, 15.8 mmol) in H2O (30 mL) was added lithium hydroxide hydrate (0.67 g, 16.0 mmol). The reaction mixture was heated to 95° C. for 4 hours. The mixture was cooled to ambient temperature and hydrogen chloride (0.0394 mL, 4M in dioxane) was added. The mixture was stirred for 10 minutes. The H2O was removed under reduced pressure and the residue placed under high vacuum for 16 hours to give the product (5.43 g).
Reaction SMILES: C([O:3][C:4](=[O:31])[CH2:5][CH:6]([N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]([CH2:19][C:20]2[C:21]3[C:28]([CH3:29])=[CH:27][CH:26]=[CH:25][C:22]=3[S:23][CH:24]=2)[C:11]1=[O:30])[CH2:7][CH2:8][CH3:9])C.[OH-].[Na+].Cl.O>CO>[CH3:29][C:28]1[C:21]2[C:20]([CH2:19][N:12]3[C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=4[N:10]([CH:6]([CH2:7][CH2:8][CH3:9])[CH2:5][C:4]([OH:31])=[O:3])[C:11]3=[O:30])=[CH:24][S:23][C:22]=2[CH:25]=[CH:26][CH:27]=1
Reactant: CCCC(CC(=O)OCC)n1c(=O)n(Cc2csc3cccc(C)c23)c2ccccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCC(CC(=O)O)n1c(=O)n(Cc2csc3cccc(C)c23)c2ccccc21
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 91.4 %

Procedure:
To a solution of 3-[3-(4-Methyl-benzo[b]thiophen-3-ylmethyl)-2-oxo-2,3-dihydro-benzimidazol-1-yl]-hexanoic acid ethyl ester (65 mg, 0.15 mmol) in MeOH (3.0 mL) is added 2.0 N NaOH (0.5 mL). The reaction mixture is stirred at room temperature for 3.5 h and then 1.0M HCl (1.5 mL) and water (50 mL) are added. The mixture is extracted with EtOAc (3×50 mL). The organic layers are combined, dried over MgSO4 and concentrated to give crude product. Purification by flash column chromatography affords 56 mg (92%) of 3-[3-(4-Methyl-benzo[b]thiophen-3-ylmethyl)-2-oxo-2,3-dihydro-benzimidazol-1-yl]-hexanoic acid.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH2:6][C:5](=[O:7])[O:4][C:3]1=[O:8].[Cl:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15]([CH3:20])=[CH:14]2>ClCCCl>[Cl:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15]([CH3:20])=[C:14]2[C:5](=[O:7])[CH2:6][C:2]([CH3:9])([CH3:1])[C:3]([OH:4])=[O:8]
Reactant: Cc1cc2cc(Cl)ccc2[nH]1
Reactant: CC1(C)CC(=O)OC1=O
Solvent: ClCCCl
Product: Cc1[nH]c2ccc(Cl)cc2c1C(=O)CC(C)(C)C(=O)O

Procedure:
3,3-Dimethyl-dihydro-furan-2,5-dione (7.8 mmol, 1.0 g), 5-chloro-2-methylindole (13.8 mmol, 2.28 g), and AlC3 (9.0 mmol, 1.2 g) were stirred in 100 mL DCE overnight at 65° C. The reaction was cooled and quenched with 10 mL water. The resultant precipitate was filtered and washed with a small amount of DCE giving 1.06 g of the sub-titled compound.
Reaction SMILES: [CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]([O:17][CH3:18])=[O:16])[CH:13]=2)[N:8]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:7][C:6]1=O)[CH2:2][CH2:3][CH3:4].C12CCCC(CCC1)B12[H]B2(C3CCCC2CCC3)[H]1.C(CN)O>O1CCCC1>[CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]([O:17][CH3:18])=[O:16])[CH:13]=2)[N:8]([C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20])[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN1C(=O)CN(C(=O)OC(C)(C)C)c2ccc(C(=O)OC)cc21
Solvent: NCCO
Solvent: C1CCOC1
Product: CCCCN1CCN(C(=O)OC(C)(C)C)c2ccc(C(=O)OC)cc21
Temperature: 25 °C
Yield: 37.4 %

Procedure:
A solution of 1-tert-butyl 6-methyl 4-butyl-3-oxo-3,4-dihydroquinoxaline-1,6(2H)-dicarboxylate (440 mg) and 9-BBN dimer (600 mg) in tetrahydrofuran (10 mL) was heated at 65° C. for 10 h. The mixture was cooled to room temperature, ethanolamine (0.15 mL) was added and the resulting solution was concentrated under reduced pressure. The residue was washed with hexanes, filtered, and the filtrate was concentrated under reduced pressure. Purification by flash column chromatography (silica, 1:9 ethyl acetate/hexanes) afforded 158 mg of the title compound: 1H NMR (300 MHz, CDCl3) δ 7.50, 7.34, 7.28, 3.88, 3.77, 3.38-3.30, 1.65-1.51, 1.42-1.34, 0.99-0.94.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH2:5][CH2:6][C:7]1([CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[S:11][CH:10]([CH2:12][SH:13])[CH2:9][S:8]1)[CH3:2].[CH2:22]([C:25]1[C:35]([OH:36])=[C:34]([C:37](=[O:39])[CH3:38])[CH:33]=[CH:32][C:26]=1[O:27][CH2:28][CH:29]1[O:31][CH2:30]1)[CH2:23][CH3:24].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[CH2:1]([O:3][C:4](=[O:21])[CH2:5][CH2:6][C:7]1([CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[S:11][CH:10]([CH2:12][S:13][CH2:30][CH:29]([OH:31])[CH2:28][O:27][C:26]2[CH:32]=[CH:33][C:34]([C:37](=[O:39])[CH3:38])=[C:35]([OH:36])[C:25]=2[CH2:22][CH2:23][CH3:24])[CH2:9][S:8]1)[CH3:2]
Reactant: CCCc1c(OCC2CO2)ccc(C(C)=O)c1O
Reactant: CCOC(=O)CCC1(CCC(=O)OCC)SCC(CS)S1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCc1c(OCC(O)CSCC2CSC(CCC(=O)OCC)(CCC(=O)OCC)S2)ccc(C(C)=O)c1O

Procedure:
The title compound was prepared according to the procedure of Example 2 using the mercaptan produced in Example 31 (1.5 g, 0.004 mol), 3-(2-n-propyl-3-hydroxy-4-acetylphenoxy)-1,2-epoxypropane (described in U.S. Pat. No. 4,565,882) (1.1 g, 0.004 mol) and anhydrous potassium carbonate (1.75 g) in methyl ethyl ketone (15 ml). The crude product was chromatographed on silica gel using 30% ethyl acetate/hexane as eluent to give 1.9 g (60%) of the product as an oil.
Reaction SMILES: [C:1]([C:3]1[C:4]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=2)=[C:5]([C:14](O)=[O:15])[S:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)#[N:2].[CH3:26][S:27]([NH2:30])(=[O:29])=[O:28].Cl.CN(C)CCCN=C=NCC>C(Cl)Cl.Cl.O>[C:1]([C:3]1[C:4]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=2)=[C:5]([C:14]([NH:30][S:27]([CH3:26])(=[O:29])=[O:28])=[O:15])[S:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)#[N:2]
Reactant: N#Cc1c(N2CCOCC2)sc(C(=O)O)c1Cc1ccc(Cl)c(Cl)c1
Reactant: CS(N)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: CS(=O)(=O)NC(=O)c1sc(N2CCOCC2)c(C#N)c1Cc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 20.2 %

Procedure:
To a mixture of 4-cyano-3-(3,4-dichlorobenzyl)-5-morpholinothiophene-2-carboxylic acid (291 mg, 0.732 mmol), in DCM (5.0 mL) was added methanesulfonamide (87.1 mg, 0.916 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (176 mg, 0.916 mmol), and N,N-dimethylaminopyridine (103 mg, 0.842 mmol) and the resulting solution was stirred at room temperature overnight. The reaction was diluted with DCM (10 mL), 1N HCl (3 mL) and with water (3 mL). The organic layer was dried, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (MeOH/DCM=0/100→20/80) to give 250 mg of crude product. This material was purified by preparative reverse phase chromatography to give 70 mg (20% yield) of the title compound as a white solid. LC/MS (FA) ES+ 474, 476. 1H NMR (400 MHz, MeOH-d4) δ: 7.45 (d, 1H, J=2.0 Hz)), 7.38 (d, 1H, J=8.4 Hz), 7.25 (dd, 1H, J=8.0, 2.0 Hz), 4.38 (s, 2H), 3.82-3.80 (m, 4H), 3.57-3.55 (m, 4H), 3.18 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8](N(OC)C)=[O:9])=[CH:6][C:5]([Cl:14])=[N:4][CH:3]=1.[C:15]1([Mg]Br)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(OCC)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[NH2:1][C:2]1[C:7]([C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:9])=[CH:6][C:5]([Cl:14])=[N:4][CH:3]=1
Reactant: Br[Mg]c1ccccc1
Reactant: CON(C)C(=O)c1cc(Cl)ncc1N
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCOCC
Solvent: C1CCOC1
Product: Nc1cnc(Cl)cc1C(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To 5-Amino-2-chloro-N-methoxy-N-methyl-isonicotinamide (1.50 g, 6.608 mmol) in THF (25 mL) under argon is added phenylmagnesium bromide in diethyl ether (6.00 mL, 2M, 18 mmol) at 0° C. The mixture is stirred for 30 minutes at 0° C. Aqueous citric acid solution (1 M, 25 mL) is added to the reaction and the mixture is extracted with ethyl acetate, the organic phase is dried over magnesium sulfate. The drying agent is removed by filtration and the solvent is concentrated to dryness. This provides the desired compound which is used without further purification.
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[CH2:12]([OH:15])[C:13]#[CH:14]>C(NCC)C.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[OH:15][CH2:12][C:13]#[C:14][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(I)cc1
Reactant: C#CCO
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCNCC
Product: COC(=O)c1ccc(C#CCO)cc1
Yield: 83.1 %

Procedure:
Methyl 4-iodobenzoate (9.0 g, 34.4 mmol) was dissolved in 90 ml of diethylamine. The solution was stirred vigorously and, sequentially, 121 milligrams of bis(triphenylphosphine) palladium chloride and 65 milligrams of cuprous iodide were added, each in a single portion, followed by 1.93 grams of propargyl alcohol. The resultant mixture was stirred for about 20 hours at room temperature in an argon atmosphere. At the end of this period, diethylamine was removed by concentration in vacuo. The residue was diluted with 200 ml of water and extracted three times with 100 ml of benzene and 75 ml of ethyl acetate. The organic extracts were combined, dried over Na2SO4, and concentrated in vacuo, yielding a brown solid. This crude residue was purified by flash chromatography. Elution with a 2 to 1 (V:V) mixture of hexane and ethyl acetate yielded 5.44 grams (83% yield) of a pale yellow solid melting at 81° to 82° C.
Reaction SMILES: [C:1]([C:5]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:6]=1[C:7]1[C:8](=[O:18])[CH2:9][CH2:10][CH2:11][C:12]=1[NH:13]2)([O:3][CH3:4])=[O:2].[CH:19]1[CH:24]=[C:23]([Cl:25])[C:22]([CH2:26]Br)=[C:21]([Cl:28])[CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[Cl:25][C:23]1[CH:24]=[CH:19][CH:20]=[C:21]([Cl:28])[C:22]=1[CH2:26][N:13]1[C:12]2[CH2:11][CH2:10][CH2:9][C:8](=[O:18])[C:7]=2[C:6]2[C:14]1=[CH:15][CH:16]=[CH:17][C:5]=2[C:1]([O:3][CH3:4])=[O:2]
Reactant: COC(=O)c1cccc2[nH]c3c(c12)C(=O)CCC3
Reactant: Clc1cccc(Cl)c1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc2c1c1c(n2Cc2c(Cl)cccc2Cl)CCCC1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 55.9 %

Procedure:
A suspension of 5-carbomethoxy-1,2-dihydro-9H-carbazol-4(3H)-one (973 mg, 4.0 mM), a-bromo-2,6-dichlorotoluene (1.19 g, 4.8 mM), and potassium carbonate (553 mg, 4.0 mM) in 10 mL DMF was stirred at room temperature for 24 hours. The mixture was diluted with ethyl acetate, washed with H2O, 1 N HCl, H2O, saturated NaHCO3, H2O, and saturated brine, dried over anhydrous magnesium sulfate, filtered, concentrated. The residue was purified by column chromatography on silica gel (elution with methylene chloride/ethyl acetate) to afford 900 mg (56%) of the 9-[(2,6-dichlorophenyl)methyl]-5-carbomethoxy-1,2-dihydrocarbazol-4(3H)-one as a white foam. 1H NMR (CDCl3) δ 7.4-7.2 (m, 6H), 5.6 (s, 2H), 4.0 (s, 3H), 2.9 (t, 2H, J=6 Hz), 2.55 (t, 2H, J=6 Hz), and 2.2 (m, 2H). IR (KBr, cm−1) 1725 and 1652. MS (ES) m/e 400, 402, 404.
Reaction SMILES: C([N:4]1[C:8]2=[N:9][C:10](Br)=[CH:11][CH:12]=[C:7]2[C:6]([C:14]#[N:15])=[CH:5]1)(=O)C.C(N(CC)CC)C.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.[F:57][C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][C:59]=1B(O)O>O1CCOCC1>[F:57][C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][C:59]=1[C:10]1[N:9]=[C:8]2[NH:4][CH:5]=[C:6]([C:14]#[N:15])[C:7]2=[CH:12][CH:11]=1
Reactant: CC(=O)n1cc(C#N)c2ccc(Br)nc21
Reactant: OB(O)c1ccccc1F
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: N#Cc1c[nH]c2nc(-c3ccccc3F)ccc12
Temperature: 100 °C
Yield: 97.9 %

Procedure:
In a 100 mL round-bottomed flask, 1-acetyl-6-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (250 mg, 947 μmol, Eq: 1.00), triethylamine (575 mg, 792 μl, 5.68 mmol, Eq: 6) and X-PHOS (181 mg, 379 μmol, Eq: 0.40) were combined with dioxane (25.0 ml) to give a colorless solution. [1,1′-bis(diphenylphosphino)ferrocene]dichloropaladium(II) (173 mg, 237 μmol, Eq: 0.25) and 2-fluorophenylboronic acid (265 mg, 1.89 mmol) were added and the resultant mixture was degassed for 5 minutes under Nitrogen. The reaction mixture was heated to 100° C. and microwaved for 1 hr. The reaction mixture was poured into 50 mL EtOAc and washed with H2O. The organic layers were dried over MgSO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 40 g, 20% to 30% EtOAc in hexanes) to give 6-(2-fluorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (220 mg, 98%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8]/[C:9](=[CH:14]\[C:15]([CH3:18])([CH3:17])[CH3:16])/[C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].O1CCOCC1.[H][H]>C(O)C>[CH3:13][O:12][C:10](=[O:11])[C@@H:9]([CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7]
Reactant: COC(=O)/C(=C/C(C)(C)C)NC(=O)OC(C)(C)C
Reactant: [H][H]
Solvent: C1COCCO1
Solvent: CCO
Product: COC(=O)[C@@H](CC(C)(C)C)NC(=O)OC(C)(C)C

Procedure:
Methyl (2Z)-2-[(tert-butoxycarbonyl)amino]-4,4-dimethylpent-2-enoate (example 4A, 60 g, 233.2 mmol) is dissolved in ethanol p.a./dioxane 3:1 (1000 ml). An argon protective gas atmosphere is passed through with a needle (˜10 min). The solution is placed in an ultrasonic bath (about 5 min) and (+)-1,2-bis[(2R,5R)-diethylphospholano]benzene(cyclooctadiene)rhodium(I) triflate (600 mg, 1% by weight) is added. The mixture is hydrogenated under a pressure of 3.5 bar of hydrogen and at RT for 3 days. The reaction mixture is filtered through kieselguhr, and the eluate is concentrated. The crude product is chromatographed (silica gel, eluent: cyclohexane/ethyl acetate 4:1). 60 g (99% of theory) of the title compound are obtained.
Reaction SMILES: [C:1]([O-:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:10]([OH:17])(=[O:16])/[CH:11]=[CH:12]\[C:13]([OH:15])=[O:14]>C(OCC)(=O)C>[C:10]([OH:17])(=[O:16])/[CH:11]=[CH:12]\[C:13]([OH:15])=[O:14].[C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C([O-])c1ccccc1
Agent: O=C(O)/C=C\C(=O)O
Solvent: CCOC(C)=O
Product: O=C(O)c1ccccc1

Procedure:
In 3 mL of ethyl acetate was dissolved 0.25 g 5 of 1-{3-[2-(1-benzothiophen-5-yl)ethoxy]propyl}-3-azetidinyl=benzoate, and 0.07 g of maleic acid was added thereto, after which the resulting mixture was heated to effect dissolution. The reaction mixture was cooled and the crystals precipitated were collected by filtration to obtain 0.15 g of 1-{3-[2-(1-benzothiophen-5-yl)ethoxy]propyl}-3-azetidinyl=benzoate maleate.
Reaction SMILES: Cl.[Cl:2][CH2:3][CH2:4][NH:5][CH2:6][CH2:7]Cl.[CH3:9][C:10]1([CH3:30])[CH:14]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[C:13]2[C:22]([CH3:29])=[C:23]([NH2:28])[C:24]([CH3:27])=[C:25]([CH3:26])[C:12]=2[O:11]1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)CCC>[ClH:2].[CH3:9][C:10]1([CH3:30])[CH:14]([C:15]2[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=2)[C:13]2[C:22]([CH3:29])=[C:23]([N:28]3[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]3)[C:24]([CH3:27])=[C:25]([CH3:26])[C:12]=2[O:11]1
Reactant: ClCCNCCCl
Reactant: Cc1ccc(C2c3c(C)c(N)c(C)c(C)c3OC2(C)C)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCCO
Product: Cc1ccc(C2c3c(C)c(N4CCNCC4)c(C)c(C)c3OC2(C)C)cc1
Temperature: 25 °C

Procedure:
Bis(2-chloroethyl)amine hydrochloride (18.7 g, 105 mmol) was added to a suspension of 2,2,4,6,7-pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-amine (29.5 g, 100 mmol) in 1-butanol (300 mL) and the mixture was refluxed for 24 hours under argon atmosphere. The reaction mixture was cooled to room temperature and then sodium carbonate (12.7 g, 120 mmol) was added. The resulting mixture was refluxed for 24 hours and concentrated under reduced pressure. The residue was diluted with water (500 ml) and extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified on basic silica gel column chromatography (hexane/ethyl acetate=10/1) to obtain a free base of the title compound as an oil residue.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([OH:13])=[O:12])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[Br:14]Br.N1C=CC=CC=1.[OH-].[Na+]>C(Cl)(Cl)(Cl)Cl>[Br:14][C:3]1[CH:2]=[N:1][C:10]2[C:5]([CH:4]=1)=[CH:6][C:7]([C:11]([OH:13])=[O:12])=[CH:8][CH:9]=2
Reactant: O=C(O)c1ccc2ncccc2c1
Reactant: BrBr
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: O=C(O)c1ccc2ncc(Br)cc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.3 %

Procedure:
To a suspension of quinoline-6-carboxylic acid (2.77 g, 16.0 mmol) in CCl4 (20 ml) in a flask wrapped with Al foil was added bromine (987 uL, 19.2 mmol) dropwise. The resulting mixture was stirred at rt for 30 min, then heated under reflux for 30 min. A solution of pyridine (1.55 mL, 19.2 mmol) in CCl4 (4 mL) was added dropwise at refluxing temperature. Then the reaction mixture was heated under reflux for 4 h. The reaction mixture was treated with 3 N NaOH until all the precipitates were dissolved. The aqueous layer was separated and washed with DCM once more, then acidified with 3 N HCl. The resulting orange precipitates were filtered, and washed with H2O, and a small amount of MeOH to afford the titled compound as an off-white solid (3.36 g).