Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C)([O-])C.[K+].[NH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8]1.Br[CH2:17][C:18]([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=1)=[O:19]>O1CCOCC1.CN(C=O)C>[N:7]1([CH2:17][C:18]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:28])([F:29])[F:30])[CH:22]=2)=[O:19])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8]1
Reactant: O=C(CBr)Nc1cccc(C(F)(F)F)c1
Reactant: c1ccc2[nH]ccc2c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: O=C(Cn1ccc2ccccc21)Nc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.7 %

Procedure:
A solution of potassium tert-butoxide (0.25 mmol) in TBF (0.25 mL) was added to a solution of 1H-indole (30 mg, 0.25 mmol) in a mixture of dioxane (6 m]L) and DMF (1.5 mL) under argon atmosphere at ambient temperature. The solution was stirred for 5 min before a solution of 2-bromo-N-(3-trifluoromethyl-phenyl)-acetamide (0.2 mmol) in DMF (1 mL) was added dropwise. The reaction mixture was stirred overnight at ambient temperature and the solvents were-removed in vacuum. The crude product was purified on a preparative LC/MS (XTerra C8 column 19×100 mm, 0.1 M aqueous NH4Ac/CH3CN). The product-containing fractions were pooled and lyophilized to afford 24 mg (38%) of the title compound. Calculated for C17H13F3N2O m/z: 318.3, found 319.0 [M+H]+. 1H NMR (400 MHz, CDCl3) δ ppm 4.9 (s, 2H), 6.7 (d, J=3.0 Hz, 1H), 7.0 (s, 1H), 7.1 (d, J=3.0 Hz, 1H), 7.2-7.3 (m, 5 H), 7.4 (m, 1H), 7.6 (s, 1H), 7.7 (d, J=8.1 Hz, 1H).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([I:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[Hg](C#N)[C:16]#[N:17].N1C=CC=CC=1.Cl>CN(C)C=O>[I:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[CH:6]=[CH:7][C:2]([C:16]#[N:17])=[CH:3][CH:4]=2)=[CH:9][CH:10]=1
Reactant: Ic1ccc(-c2ccc(I)cc2)cc1
Reactant: N#C[Hg]C#N
Agent: Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: N#Cc1ccc(-c2ccc(I)cc2)cc1
Temperature: 200 °C
Yield: 86.8 %

Procedure:
A mixture of 15 g (33.2.10-3 mol) of 4,4'-diiodo-1,1'-biphenyl, 3.13 g (34.9.10-3 mol) of mercuric cyanide and 2.75 g (34.9.10-3 mol) of pyridine is heated at 200° C. for 15 minutes and 6 ml of dimethylformamide are then added to the mixture. After cooling, the reaction medium is hydrolyzed with a 1N aqueous solution of hydrochloric acid. The expected product is extracted with ethyl acetate. The organic phase obtained is washed with water until the pH of the washings is neutral, dried over magnesium sulfate and evaporated under vacuum. 3.28 g (yield: 33%) of a yellow solid are obtained after purification by flash chromatography using a chloroform/toluene mixture (1/1 v/v) as the eluent.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:24])[CH2:11][CH2:12][CH2:13][C:14]([O:16]N2C(=O)CCC2=O)=O)=[CH:5][CH:4]=1)#[CH:2].[NH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][OH:32]>C(Cl)Cl>[OH:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][NH:25][C:14](=[O:16])[CH2:13][CH2:12][CH2:11][C:10]([NH:9][C:6]1[CH:5]=[CH:4][C:3]([C:1]#[CH:2])=[CH:8][CH:7]=1)=[O:24]
Reactant: C#Cc1ccc(NC(=O)CCCC(=O)ON2C(=O)CCC2=O)cc1
Reactant: NCCCCCCO
Solvent: ClCCl
Product: C#Cc1ccc(NC(=O)CCCC(=O)NCCCCCCO)cc1

Procedure:
A solution of (2,5-dioxopyrrolidin-1-yl) 5-(4-ethynylphenyl)amino-5-oxo-pentanate (0.2 g, 0.6 mmol) in CH2Cl2 (10 ml) is added slowly to a solution of 1-amino-6-hexanol (0.35 g, 3.0 mmol) in CH2Cl2 (50 ml) with vigorous stirring. The crude reaction solution is concentrated by rotary evaporation and the mixture is purified by silica column chromatography (10% methanol/5% TEA/CH2Cl2).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:12]([F:13])=[CH:11][CH:10]=[CH:9][C:4]=2[S:5][C:6]=1[CH:7]=O.[BH4-].[Na+].[CH3:16][NH2:17]>CO>[Cl:1][C:2]1[C:3]2[C:12]([F:13])=[CH:11][CH:10]=[CH:9][C:4]=2[S:5][C:6]=1[CH2:7][NH:17][CH3:16]
Reactant: CN
Reactant: O=Cc1sc2cccc(F)c2c1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CNCc1sc2cccc(F)c2c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 48 %

Procedure:
A solution of 3-chloro-4-fluoro-benzo[b]thiophene-2-carbaldehyde (880 mg, 4.04 mmol) in CH3NH2 (20 mL of a 2.0 M solution in MeOH, 40 mmol) was stirred at room temperature overnight. The mixture was concentrated. The residue was dissolved in EtOH (30 mL), and after cooling in an ice bath, NaBH4 (153 mg, 4.04 mmol) was added. The mixture was slowly warmed to room temperature and then stirred overnight. The mixture was concentrated. The residue was taken up in NaOH (30 mL) and the mixture was extracted with Et2O (3×). The combined organics were washed with satd NaCl, dried (Na2SO4) and concentrated. Purification by column chromatography (silica gel, 95:5 CH2Cl2/MeOH) gave the title compound (443 mg, 48%) as a yellow oil: 1H NMR (300 MHz, CDCl3) δ 7.54 (dd, J=8.0, 0.6 Hz, 1H), 7.27 (ddd, J=8.0, 8.0, 4.6 Hz, 1H), 7.03 (ddd, J=11.4, 8.0, 0.6 Hz, 1H), 4.05 (s, 2H), 2.53 (s, 3H), 1.55 (s, 1H).
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][CH3:12])=[CH:7][CH:6]=1)(=O)C.[Br:13][C:14]1[CH:24]=[CH:23][C:17]2[N:18]=[C:19](SC)[O:20][C:16]=2[CH:15]=1>C(O)(=O)C>[CH3:12][N:11]([C:8]1[CH:9]=[CH:10][C:5]([OH:4])=[CH:6][CH:7]=1)[C:19]1[O:20][C:16]2[CH:15]=[C:14]([Br:13])[CH:24]=[CH:23][C:17]=2[N:18]=1
Reactant: CSc1nc2ccc(Br)cc2o1
Reactant: CNc1ccc(OC(C)=O)cc1
Solvent: CC(=O)O
Product: CN(c1ccc(O)cc1)c1nc2ccc(Br)cc2o1
Temperature: 180 °C
Yield: 43.9 %

Procedure:
An intimate mixture of 4-(N-methylamino)phenol acetate (7.3 g, 0.04 mole) and 6-bromo-2-(methylthio)benzoxazole (6.0 g, 0.025 mole) was prepared and heated on an oil bath to a temperature of 180° C. The mixture was heated at this temperature for a period of 4 hours during which time acetic acid distilled from the mixture and methyl mercaptan was evolved and was trapped in aqueous sodium hydroxide. The mixture was cooled to form a solid and the solid was extracted with hot toluene (4×100 ml). The toluene solution was filtered hot and the solvent removed by distillation to give a brown solid. The solid was recrystallised from toluene to give the title compound as a grey solid (3.5 g), mp 195° C.
Reaction SMILES: C(OC(=[N:6][O:7][CH2:8][CH2:9][C:10](=[O:14])[NH:11][CH2:12][CH3:13])C)C.[ClH:15]>>[ClH:15].[NH2:6][O:7][CH2:8][CH2:9][C:10]([NH:11][CH2:12][CH3:13])=[O:14]
Reactant: CCNC(=O)CCON=C(C)OCC
Agent: Cl
Product: CCNC(=O)CCON
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To N-(2-ethylcarbamoyl-ethoxy)-acetimidic acid ethyl ester (180 mg, 0.890 mmol) obtained in Step A was added 2 M hydrochloric acid (2 ml), and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated to give a crude product of 3-aminooxy-N-ethyl-propionamide hydrochloride as a residue. To this residue, a mixed solvent of tetrahydrofuran/methanol (3:1, 20 ml) and 3,4-difluoro-2-(2-fluoro-4-iodophenylamino-5-formyl-N-(2-hydroxy-ethoxy)-benzamide (500 mg, 1.078 mmol) obtained in Step F of Example 1 were added, and the mixture was stirred for 1 hour. The reaction mixture was poured into purified water, and the resultant mixture was extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give (E)-5-[(2-ethylcarbamoyl-ethoxyimino)-methyl]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-benzamide (200 mg, 31% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[C:7]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(C(OC)=O)[CH2:6][CH2:5]2.[Cl-].[Li+].O>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH:7]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:6][CH2:5]2
Reactant: COC(=O)C1(c2ccccc2)CCc2cc(F)ccc2C1=O
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1c2ccc(F)cc2CCC1c1ccccc1
Temperature: 150 °C
Yield: 87 %

Procedure:
The tetralone from Step B (2.8 g, 9.4 mmole) was dissolved in 45 ml of dimethylformamide. To this solution was added lithium chloride (2.0 g, 47 mmole) and water (0.42 ml, 23 mmole). The reaction mixture was heated to 150° C. for 2.5 hrs and then cooled and partitioned between ether and water. The aqueous phase was separated and extracted three times with ether. The combined organic phases were washed once with water, dried (MgSO4), and concentrated (1.96 g, 87% yield). 1H NMR (CDCl3) δ: 8.13 (1H, dd, J=6,10 Hz), 7.31 (5H, m) 6.99 (2H, m), 3.80 (1H, m), 3.07 (2H, m), 2.43 (2H, m).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.Cl[C:15]1[C:16](=[O:34])[N:17]([CH2:27][C:28]2[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=2)[C:18](=[O:26])[C:19]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>CC#N>[N:4]1([C:7]2[CH:13]=[CH:12][C:10]([NH:11][C:15]3[C:16](=[O:34])[N:17]([CH2:27][C:28]4[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=4)[C:18](=[O:26])[C:19]=3[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:9][CH:8]=2)[CH2:3][CH2:2][O:1][CH2:6][CH2:5]1
Reactant: Nc1ccc(N2CCOCC2)cc1
Reactant: O=C1C(Cl)=C(c2ccccc2)C(=O)N1Cc1cccnc1
Solvent: CC#N
Solvent: O
Product: O=C1C(Nc2ccc(N3CCOCC3)cc2)=C(c2ccccc2)C(=O)N1Cc1cccnc1
Temperature: 130 °C
Yield: 27 %

Procedure:
4-Morpholinoaniline (0.94 mmol, 178 mg) dissolved in dry CH3CN (2 mL) was added to crude 3-chloro-4-phenyl-1-(pyridin-3-ylmethyl)-1H-pyrrole-2,5-dione (0.47 mmol, 140 mg) and the reaction mixture was subjected to microwave heating single node 130° C. for 10 min. 0.3 mL water was added and the reaction mixture was purified using HPLC (57% 0.1M ammonium acetate buffer: 43% CH3CN→100% CH3CN, 20 mL/min) to give 56 mg (27%) of the title compound. 1H NMR (400 MHz, CD3CN) δ 8.63 (d, 1H), 8.51 (dd, 1H), 7.81-7.73 (m, 1H), 7.36-7.31 (m, 1H), 7.16-7.11 (m,1H), 7.10-7.04 (m, 2H), 6.99-6.93 (m, 2H), 6.69-6.64 (m, 2H), 6.59-6.53 (m, 2H), 4.75 (s, 2H), 3.74 (t, J=4.8 Hz, 4H), 2.97 (t, J=4.8 Hz, 4H).
Reaction SMILES: [CH2:1]([N:5]1[CH2:10][CH2:9][N:8]([CH:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:12]([O:14]C)=[O:13])[C:7](=[O:22])[C:6]1=[O:23])[CH2:2][CH2:3][CH3:4].[Li+].[OH-].Cl>CO.C1COCC1>[CH2:1]([N:5]1[CH2:10][CH2:9][N:8]([CH:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:12]([OH:14])=[O:13])[C:7](=[O:22])[C:6]1=[O:23])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN1CCN(C(C(=O)OC)c2ccccc2)C(=O)C1=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCCN1CCN(C(C(=O)O)c2ccccc2)C(=O)C1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 100 %

Procedure:
To a solution of methyl (4-butyl-2,3-dioxopiperazin-1-yl)(phenyl)acetate (2.5 g, 9.1 mmol) in 1:1 methanol/THF (40 ml) was added 1N LiOH (18.2 ml, 18.2 mmol). The reaction was warmed to rt and allowed to stir for 18 h. The reaction mixture was cooled to 0° C., adjusted to pH 2 with conc HCl, and concentrated in vacuo. The residue was dissolved in EtOAc, washed with brine, dried over sodium sulfate, filtered, and concentrated to yield (4-butyl-2,3-dioxopiperazin-1-yl)(phenyl)acetic acid (100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[N:11][C:12](Cl)=[CH:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[CH:5][CH:4]=1.[F:24][C:25]1[CH:26]=[C:27]([OH:32])[CH:28]=[CH:29][C:30]=1[F:31]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[N:11][C:12]([O:32][C:27]3[CH:28]=[CH:29][C:30]([F:31])=[C:25]([F:24])[CH:26]=3)=[CH:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2cc(Cl)nnc2-c2ccc(OC)cc2)cc1
Reactant: Oc1ccc(F)c(F)c1
Product: COc1ccc(-c2cc(Oc3ccc(F)c(F)c3)nnc2-c2ccc(OC)cc2)cc1

Procedure:
In a similar manner as in Example 2, 3,4-bis(4-methoxyphenyl)-6-chloropyridazine (150 mg, 0.459 mmol) and 3,4-difluorophenol were reacted as starting materials at 150° C. for 14 hours and post-treatment was then conducted, whereby the title compound was obtained as a pale yellow amorphous solid (190.2 mg, 99.1%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@@:9]2([CH3:23])[N:18]([CH2:19][C:20]#[CH:21])[C:17](=[O:22])[C:12]3([CH2:16][CH2:15][CH2:14][CH2:13]3)[NH:11][CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.Br[C:25]1[CH:26]=[C:27]2[C:40](=[CH:41][CH:42]=1)[CH2:39][C@:29]1([C:37]3[C:32](=[N:33][CH:34]=[CH:35][CH:36]=3)[NH:31][C:30]1=[O:38])[CH2:28]2.C(N(CC)CC)C>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[F:1][C:2]1[CH:3]=[C:4]([C@@:9]2([CH3:23])[N:18]([CH2:19][C:20]#[C:21][C:25]3[CH:26]=[C:27]4[C:40](=[CH:41][CH:42]=3)[CH2:39][C@:29]3([C:37]5[C:32](=[N:33][CH:34]=[CH:35][CH:36]=5)[NH:31][C:30]3=[O:38])[CH2:28]4)[C:17](=[O:22])[C:12]3([CH2:13][CH2:14][CH2:15][CH2:16]3)[NH:11][CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: O=C1Nc2ncccc2[C@]12Cc1ccc(Br)cc1C2
Reactant: C#CCN1C(=O)C2(CCCC2)NC[C@@]1(C)c1cc(F)cc(F)c1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[C@@]1(c2cc(F)cc(F)c2)CNC2(CCCC2)C(=O)N1CC#Cc1ccc2c(c1)C[C@@]1(C2)C(=O)Nc2ncccc21
Temperature: 80 °C

Procedure:
A suspension of (8R)-8-(3,5-difluorophenyl)-8-methyl-9-prop-2-yn-1-yl-6,9-diazaspiro[4.5]decan-10-one from Step A (25 mg, 0.079 mmol), (R)-5-bromo-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one (25 mg, 0.079 mmol described in intermediate 12 tetrakis(triphenylphosphine)palladium(0) (4.5 mg, 0.0039 mmol), copper(I)iodide (3.0 mg, 0.016 mmol), and triethylamine (0.022 mL, 0.16 mmol) in degassed DMF (0.5 ml) was heated at 80° C. for 16 hour. The mixture was filtered and purified directly by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H—90:10:0.1 to 5:95:0.1. The desired fractions were concentrated in vacuo to yield the title compound. MS: m/z=553 (M+1). HRMS: m/z=553.2400; calculated m/z=553.2410 for C33H31F2N4O2.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[S:7][CH:8]=[CH:9][N:10]=1)CCC.Br[C:20]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:21]=1[NH2:22]>>[F:27][C:25]1[CH:26]=[CH:20][C:21]([NH2:22])=[C:23]([C:6]2[S:7][CH:8]=[CH:9][N:10]=2)[CH:24]=1
Reactant: Nc1ccc(F)cc1Br
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Product: Nc1ccc(F)cc1-c1nccs1
Yield: 7.7 %

Procedure:
2-Tributylstannanyl-thiazole (600 mg, 1.6 mmol) was reacted with 2-bromo-4-fluoroaniline (220 mg, 1.2 mmol) according to general procedure [B] for the preparation of substituted anilines described above, which gave the title compound (18 mg, 8%). [M+1] 195.
Reaction SMILES: [Fe].[Fe:2](Cl)Cl.[Fe].[CH3:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH3:14]>O.COCCOCCOC>[Fe:2].[CH3:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH3:14].[C:6]
Reactant: Cl[Fe]Cl
Agent: [Fe]
Solvent: COCCOCCOC
Solvent: O
Product: [C]

Procedure:
Catalysts containing 3% iron were prepared generally in accordance with the method described in Example 50. A particulate carbon support (10 g) having a Langmuir surface area of approximately 1500 m2/g described in Example 50 was added to a 1 liter flask containing deionized water (400 ml) to form a slurry. Iron chloride (FeCl3.H2O) (1.497 g) (available from Aldrich Chemical Co., Milwaukee, Wis.) was introduced to 60 ml of a 50/50 (v/v) mixture of diglyme (diethylene glycol dimethyl ether) (also available from Aldrich Chemical Co., Milwaukee, Wis.) and deionized water in a 100 ml beaker. The iron-diglyme mixture was added to the carbon slurry incrementally over the course of approximately 30 minutes (i.e., at a rate of approximately 2 ml/minute) to produce an iron-diglyme-carbon mixture. The pH of the carbon slurry was maintained at from about 4.0 and about 4.4 during addition of the iron-diglyme mixture to the carbon slurry by co-addition of sodium hydroxide solution (Aldrich Chemical Co., Milwaukee, Wis.). The iron-diglyme-carbon mixture was stirred using a mechanical stirring rod operating at 50% of output (Model IKA-Werke RW16 Basic) for approximately 30 minutes; the pH of the mixture was monitored using the pH meter and maintained at approximately 4.4 by dropwise addition of 0.1 wt. % sodium hydroxide. The mixture was then heated under a nitrogen blanket to approximately 70° C. at a rate of approximately 2° C. per minute while maintaining the pH at approximately 4.4 by dropwise addition of 0.1 wt. % sodium hydroxide. Upon reaching approximately 70° C., the pH of the mixture was raised by addition of a 0.1 wt. % sodium hydroxide solution according to the following pH profile: 10 minutes at pH of approximately 5.0, 20 minutes at pH of approximately 5.5, followed by continued stirring at pH of 6.0 until the pH became relatively constant. The resulting mixture was filtered and washed with a plentiful amount of deionized water and the wet cake was dried for approximately 16 hours in a vacuum oven at 120° C. to provide a catalyst precursor. Iron-containing catalyst precursor (5 g) was charged into the Hastelloy C tube reactor and heat treated as described above regarding preparation of the cobalt-containing catalysts. A catalyst containing 3% iron was also prepared using this method using polyglyme in place of diglyme. (Entries 1 and 2 in Table 31)
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[CH3:9][N:10]1[C:14]([C:15](Cl)=[O:16])=[CH:13][C:12]([CH3:18])=[N:11]1>N1C=CC=CC=1.ClCCCl>[I:1][C:2]1[CH:3]=[C:4]([NH:5][C:15]([C:14]2[N:10]([CH3:9])[N:11]=[C:12]([CH3:18])[CH:13]=2)=[O:16])[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1cccc(I)c1
Reactant: Cc1cc(C(=O)Cl)n(C)n1
Solvent: ClCCCl
Solvent: c1ccncc1
Product: Cc1cc(C(=O)Nc2cccc(I)c2)n(C)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-iodoaniline (131 mg, 0.60 mmol) in 1.5 ml pyridine at room temperature was added over 2 minutes a solution of 1,3-dimethylpyrazole-5-carbonyl chloride (79 mg, 0.50 mmol) in 0.3 ml 1,2-dichloroethane. The reaction was stirred at room temperature for 30 minutes, quenched into a NaHCO3 solution, and extracted into EtOAc. The EtOAc solution was washed with NaHCO3 solution, brine, dried with anhydrous Na2SO4 and rotary evaporated. The resultant gummy solid was recrystallized from hexane/EtOAc to give the title compound as solid white needles (135 mg, 80%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[CH:11]1([C:16](Cl)=[O:17])[CH2:15][CH2:14][CH2:13][CH2:12]1>O1CCOCC1>[CH:11]1([C:16]([NH:1][C:2]2[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=2)=[O:17])[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: O=C(Cl)C1CCCC1
Solvent: C1COCCO1
Product: O=C(O)c1ccc(NC(=O)C2CCCC2)cc1

Procedure:
In a 1 liter 2-neck roundbottom flask, 40 grams of 4-aminobenzoic acid was dissolved in about 400 mL of dioxane. Then, 19.35 g of cyclopentanecarbonyl chloride was added dropwise to the solution. The reaction intermediate, 4-(cyclopentanecarbonyl-amino)-benzoic acid, formed as a white solid in the step and was collected by filtration. After washing the product with about 200 mL dioxane and then with about 1 liter of boiling water, the reaction intermediate was dried in an oven at 110° C. The yield at this step was about 27.7 g (81%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:21])[N:5]([C:12]1([CH3:20])[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19])[C:6]2=[O:11].[Cl:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26](Cl)=[O:27].CO>C1COCC1>[Cl:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26]([NH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:21])[N:5]([C:12]1([CH3:20])[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19])[C:6]2=[O:11])=[O:27]
Reactant: CC1(N2C(=O)c3cccc(N)c3C2=O)CCC(=O)NC1=O
Reactant: O=C(Cl)c1cccc(Cl)c1
Solvent: CO
Solvent: C1CCOC1
Product: CC1(N2C(=O)c3cccc(NC(=O)c4cccc(Cl)c4)c3C2=O)CCC(=O)NC1=O
Reaction time: 0.25 h
Yield: 73.8 %

Procedure:
To a suspension of 4-amino-2-(3-methyl-2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione (0.10 g, 0.35 mmol) in THF (15 ml) was added 3-chlorobenzoyl chloride (0.12 g, 0.70 mmol) The mixture was heated to reflux for 18 h. The reaction mixture was allowed to cool and to the solution was added methanol (2 ml). The reaction mixture was stirred for an additional 15 minutes followed by solvent evaporation in vacuo. The resulting solid was slurried in diethyl ether (20 ml) and filtered to give 0.11 g (73%) of product as an off-white solid: mp 283–285° C.; 1H NMR (DMSO-d6) 11.06 (s, 1H), 10.43 (s, 1H), 8.48 (d, J=8.3 Hz, 1H), 7.98–7.61 (m, 6H), 2.80–2.51 (m, 3H), 2.11–2.01(m, 1H), 1.92 (s, 3H), 1.61 (t, J=6.4 Hz, 2H), 1.29 (bs, 6H), 0.87 (t, J=6.3 Hz, 3H); 13C NMR (DMSO-d6) 171.72, 171.64, 168.53, 167.11, 163.55, 135.81, 135.75, 135.35, 133.59, 132.07, 131.03, 130.73, 127.03, 126.37, 125.58, 118.43, 118.06, 58.80, 28.90, 28.37, 20.84; Anal. Calcd. For C21H16ClN3O5: C, 59.23; H, 3.79; N, 9.87 Found: C, 59.00; H, 3.80; N, 9.70.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[C:12]([CH3:15])[CH2:13]O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.P(Br)(Br)[Br:23]>CCCCC>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[C:12]([CH3:15])[CH2:13][Br:23])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=Cc1ccc(C(C)(C)C)cc1)CO
Reactant: BrP(Br)Br
Solvent: c1ccncc1
Solvent: CCCCC
Product: CC(=Cc1ccc(C(C)(C)C)cc1)CBr
Temperature: 25 °C
Reaction time: 3 h

Procedure:
73.2 g of 3-(p-tert.butyl-phenyl)-2-methyl-allyl alcohol nd 8.6 ml of pyridine in 700 ml of n-pentane are cooled down to -5° C. At this temperature there are added dropwise while stirring over a period of 2 hours 15.2 ml of phosphorus tribromide in 700 ml of n-pentane and the mixture is stirred at room temperature for 3 hours. The mixture is poured on to 500 g of ice and stirred up for 30 minutes. The pentane phase is separated and the aqueous phase is back-extracted with n-pentane. The combined n-pentane phases are washed neutral with saturated sodium bicarbonate solution and water, dried over sodium sulphate and evaporated. The 3-(p-tert.butyl-phenyl)-2-methyl-allyl bromide, distilled in a high vacuum, boils at 123° C./0.01 Torr.
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:8][C@H:7]([N:9]2[C:13]3[N:14]=[CH:15][N:16]=[C:17]([NH2:18])[C:12]=3[C:11]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH:20]=3)=[CH:10]2)[CH2:6]1)=[O:4].[Br:33]N1C(=O)CCC1=O>CN(C)C=O>[CH3:1][O:2][C:3]([C@H:5]1[CH2:6][C@H:7]([N:9]2[C:13]3[N:14]=[CH:15][N:16]=[C:17]([NH2:18])[C:12]=3[C:11]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH2:26][C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:20]=3)=[C:10]2[Br:33])[CH2:8]1)=[O:4]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)[C@H]1C[C@H](n2cc(-c3cccc(OCc4ccccc4)c3)c3c(N)ncnc32)C1
Solvent: CN(C)C=O
Product: COC(=O)[C@H]1C[C@H](n2c(Br)c(-c3cccc(OCc4ccccc4)c3)c3c(N)ncnc32)C1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To 11 g (25.67 mmol) trans-3-[4-amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutanecarboxylic acid methyl ester (see Example 4) in 275 ml dry N,N-dimethylformamide, 5.18 g (28.24 mmol) N-bromosuccinimide are added in small portions. The solution is stirred at RT in the dark and under Argon for 17 h. Thereafter the solvent is evaporated, and the residue purified by chromatography on silicagel (solvent: hexane-ethyl acetate 3:1). Further purification is done by crystallization from acetonitrile. Analytical HPLC: tR=3.61 min (shorty); ES-MS: m/eo=506.9 and 508.9; mp: 124-125° C.; NMR (DMSO-d6): 8.18/s (1H), 7.25-7.5/several m's (6H), 7.09/“d” (1H); 7.04/s (1H); 6.98/“d” (1H); 5.38/m (1H); 5.13/s (2H); 3.69/s (3H); 3.50/m (2H); 3.29/m (1H); 2.62/m (2H).