Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]2[O:11][CH:12]=[CH:13][CH:14]=2)=[CH:4][C:3]=1[O:15][CH3:16].CON(C)[C:20](=[O:36])[CH:21]([O:34][CH3:35])[C:22]1[CH:27]=[CH:26][C:25]([C:28]2[O:29][C:30]([CH3:33])=[N:31][N:32]=2)=[CH:24][CH:23]=1>>[F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]2[O:11][C:12]([C:20](=[O:36])[CH:21]([O:34][CH3:35])[C:22]3[CH:23]=[CH:24][C:25]([C:28]4[O:29][C:30]([CH3:33])=[N:31][N:32]=4)=[CH:26][CH:27]=3)=[CH:13][CH:14]=2)=[CH:4][C:3]=1[O:15][CH3:16]
Reactant: COC(C(=O)N(C)OC)c1ccc(-c2nnc(C)o2)cc1
Reactant: COc1cc(-c2ccco2)cc(OC)c1F
Product: COc1cc(-c2ccc(C(=O)C(OC)c3ccc(-c4nnc(C)o4)cc3)o2)cc(OC)c1F

Procedure:
1-(5-(4-Fluoro-3,5-dimethoxyphenyl)furan-2-yl)-2-methoxy-2-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)ethanone was prepared from 2-(4-fluoro-3,5-dimethoxyphenyl)furan and N,2-dimethoxy-N-methyl-2-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)acetamide according to the procedure used in Example 30. Purification by chromatography (60% EtOAc-hexanes) gave the product as a pale yellow solid (0.036 g, 8% yield). MS: m/z 453.2 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[C:15]1([S:21](Cl)(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[H-].[Na+].[Cl-].[NH4+]>>[C:15]1([S:21]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=2[N+:12]([O-:14])=[O:13])(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Nc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Product: O=[N+]([O-])c1cc(C(F)(F)F)ccc1NS(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.6 %

Procedure:
To a solution of 4-amino-3-nitrobenzotrifluoride (3.09 g) in THF sodium hydride (660 mg) was added. The mixture was stirred for 30 minutes at room temperature. After stirring, benzenesulfonylchloride (3.18 g) was added thereto. The mixture was stirred for 2 hours at room temperature. In addition, sodium hydride (420 mg) was added thereto. The mixture was stirred for 1 hour. The reaction mixture was acidified by adding an aqueous solution of ammonium chloride and extracted with ethyl acetate. The organic layer was washed, dried over, filtered and concentrated to give the title compound (4.86 g) having the following physical data.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[C:17]([NH2:19])=[O:18])=[CH:4][CH:3]=1.[CH2:20]([C:22]1[CH:23]=[C:24]([N:28]=[C:29]=[O:30])[CH:25]=[CH:26][CH:27]=1)[CH3:21]>>[CH2:20]([C:22]1[CH:23]=[C:24]([NH:28][C:29](=[O:30])[NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[C:16]4[C:11](=[N:12][CH:13]=[CH:14][CH:15]=4)[NH:10][C:9]=3[C:17]([NH2:19])=[O:18])=[CH:6][CH:7]=2)[CH:25]=[CH:26][CH:27]=1)[CH3:21]
Reactant: CCc1cccc(N=C=O)c1
Reactant: NC(=O)c1[nH]c2ncccc2c1-c1ccc(N)cc1
Product: CCc1cccc(NC(=O)Nc2ccc(-c3c(C(N)=O)[nH]c4ncccc34)cc2)c1

Procedure:
0.8 mg of solid white 3-{4-[3-(3-ethylphenyl)ureido]phenyl}-1H-pyrrolo[2,3-b]pyridine-2-carboxamide is prepared as described in Example 7 starting with 3-(4-aminophenyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide and 3-ethylphenyl isocyanate.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([NH:17][CH:18]2[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]2)[C:13](=[O:31])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:32](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([N:17]([CH3:32])[CH:18]2[CH2:19][CH2:20][N:21]([C:24]([O:26][C:27]([CH3:28])([CH3:30])[CH3:29])=[O:25])[CH2:22][CH2:23]2)[C:13](=[O:31])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)N1CCC(NN2CCN(C(=O)OCc3ccccc3)CC2=O)CC1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CN(C1CCN(C(=O)OC(C)(C)C)CC1)N1CCN(C(=O)OCc2ccccc2)CC1=O
Temperature: 50 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
A mixture of 4-benzyloxycarbonyl-1-[1-(tert-butoxycarbonyl)-4-piperidinylamino]-2-piperazinone (9.00 g), potassium carbonate (3.46 g) and methyl iodide (29.81 g) in DMF (100 ml) was stirred at 50° C. overnight. The reaction mixture was concentrated under reduced pressure, and the residue was combined with water (200 ml) and extracted with a mixture of ethyl acetate and tetrahydrofuran (1:1, 120 ml×3). The extract was washed with water and brine, dried and concentrated. The residue was crystallized from diisopropyl ether to obtain the title compound (8.55 g) as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[CH:17][C:3]=1[C:4]([C:6]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([OH:14])=[C:8]([O:15][CH3:16])[CH:7]=1)=O.[CH2:25]1[C:30](=[O:31])[O:29][CH2:28][C:26]1=O>S(=O)(=O)(O)O.C(O)(=O)C>[CH3:22][O:21][C:19]1[C:18]([O:23][CH3:24])=[CH:17][C:3]2[C:4]([C:6]3[CH:11]=[C:10]([O:12][CH3:13])[C:9]([OH:14])=[C:8]([O:15][CH3:16])[CH:7]=3)=[C:25]3[C:30](=[O:31])[O:29][CH2:28][C:26]3=[N:1][C:2]=2[CH:20]=1
Reactant: O=C1COC(=O)C1
Reactant: COc1cc(N)c(C(=O)c2cc(OC)c(O)c(OC)c2)cc1OC
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: COc1cc2nc3c(c(-c4cc(OC)c(O)c(OC)c4)c2cc1OC)C(=O)OC3
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 87.9 %

Procedure:
One drop of conc. sulfuric acid was added to a mixture of 2-amino-4,5,3',5'-tetramethoxy-4'-hydroxy-benzophenone (0.333 g), tetronic acid (tetrahydrofuran-2,4-dione)(0.11 g) and acetic acid (10 ml), and the mixture was stirred at 100° C. for 1.5 hours. The reaction mixture was concentrated under reduced pressure. The residual oil was poured into water, neutralized with an aqueous saturated sodium bicarbonate solution and extracted with chloroform. The chloroform layer was washed with water and dried over magnesium sulfate. Evaporation of the solvent gave 6,7-dimethoxy-9-(4-hydroxy-3,5-dimethoxyphenyl)furo[3,4-b]quinoline-1(3H)-one (0.349 g, 88%) which was then recrystallized from methanol. Pale yellow needles. mp. 247°-248° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:8][C:9]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[C:10]=1[CH:11]=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClC(Cl)C.C(Cl)Cl.O>[Cl:17][C:13]1[CH:14]=[CH:15][CH:16]=[C:9]([F:8])[C:10]=1[CH2:11][NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1c(F)cccc1Cl
Reactant: Nc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Solvent: ClCCl
Product: Fc1cccc(Cl)c1CNc1ccccc1
Temperature: 70 °C
Reaction time: 1 h
Yield: 103 %

Procedure:
A mixture of aniline (3.95 mL, 43.3 mmol), 2-fluoro-6-chlorobenzaldehyde (7.46 g, 47.7 mmol) and glacial acetic acid (6.2 mL, 105.2 mmol) in dichloroethane (100 mL) was heated at 70° C. for 2 h. After cooling to rt, sodium triacetoxyborohydride (13.8 g, 65.1 mmol) was added and the mixture stirred at rt for 2.5 h, before further sodium triacetoxyborohydride (4.6 g, 21.7 mmol) was added and the mixture stirred at rt for 1 h. H2O (100 mL) was added cautiously and the mixture was stirred for 5 min; 10M aqueous NaOH (20 mL) and DCM (50 mL) were added, the phases were separated, and the aqueous phase was extracted with DCM (2×50 mL). The combined organic phases were washed with brine (50 mL) and concentrated in vacuo. Purification by gradient column chromatography eluting with 0-10% EtOAc in iso-hexane yielded the title compound (10.5 g, 44.6 mmol).
Reaction SMILES: [Br:1][CH:2]([CH2:12][O:13][CH3:14])[C:3]([NH:5][C:6]([CH3:11])([CH3:10])[C:7]#[C:8][CH3:9])=[O:4].Cl.NC(C)(C)C#C[CH2:20][O:21]C>>[Br:1][CH:2]([CH2:12][O:13][CH3:14])[C:3]([NH:5][C:6]([CH3:10])([CH3:11])[C:7]#[C:8][CH2:9][O:21][CH3:20])=[O:4]
Reactant: CC#CC(C)(C)NC(=O)C(Br)COC
Reactant: COCC#CC(C)(C)N
Agent: Cl
Product: COCC#CC(C)(C)NC(=O)C(Br)COC

Procedure:
2-Bromo-N-(1-methoxy-4-methylpent-2-yn-4-yl)-3-methoxypropionamide was prepared from 2-bromo-1-methoxypropionic acid in a similar manner to 2-bromo-N-(4-methylpent-2-yn-4-yl)-3-methoxypropionamide described in Example 3, Stage 1, Step 2 using 4-amino-1-methoxy-4-methylpent-2-yne hydrochloride in place of 4-amino-4-methylpent-2-yne hydrochloride.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C@@H:8]([OH:10])[CH3:9])[C:5]([F:11])=[CH:4][CH:3]=1.C(N(CC)CC)C.[H][H]>[Pd].C(Cl)Cl>[F:11][C:5]1[C:6]([C@@H:8]([OH:10])[CH3:9])=[N:7][CH:2]=[CH:3][CH:4]=1
Reactant: [H][H]
Reactant: C[C@H](O)c1nc(Br)ccc1F
Agent: [Pd]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H](O)c1ncccc1F
Yield: 64.8 %

Procedure:
(1S)-1-(6-Bromo-3-fluoro-pyridin-2-yl)ethanol (1.3 g, 5.9 mmol), triethylamine (1.6 mL, 11.5 mmol) and palladium on carbon (0.64 g, 0.34 mmol) were mixed in DCM (25 mL). The flask was evacuated/filled with hydrogen gas in 4 cycles and then left at 2.5 atm pressure hydrogen gas at room temperature for 24 h. The mixture was filtered and the solid washed with DCM. The filtrate was washed with water and Brine and dried over sodium sulphate and concentrated in vacuo. The crude product was purified by flash column chromatography (eluent DCM:methanol gradient) to yield 0.54 g (65% yield) of the title compound.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[NH:8][C:9]([NH:11][NH2:12])=[S:10].[Cl:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=1>>[CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[NH:8][C:9](=[S:10])[NH:11][N:12]=[CH:18][C:17]1[CH:20]=[CH:21][C:14]([Cl:13])=[CH:15][CH:16]=1
Reactant: NNC(=S)NC1CC2C=CC1C2
Reactant: O=Cc1ccc(Cl)cc1
Product: S=C(NN=Cc1ccc(Cl)cc1)NC1CC2C=CC1C2

Procedure:
The title compound was prepared from a mixture of N1-bicyclo[2.2.1]hept-5-en-2-ylhydrazine-1-carbothioamide (100 mg, 0.56 mmol) and 4-chlorobenzaldehyde (79 mg, 0.56 mmol) similar to Example 3 and isolated as a white solid (68 mg, 40%). 1H NMR (CDCl3): 9.15 (s, 1H), 7.73 (s, 1H), 7.56 (d, J=8.4 Hz, 2H), 7.44 (s, 1H), 7.39 (d, J=8.7 Hz, 2H), 6.24-6.14 (m, 2H), 4.30-4.25 (m, 1H), 3.06 (s, 1H), 2.97 (s, 1H), 1.95-1.87 (m, 1H), 1.68 (d, J=9.0 Hz, 1H), 1.51 (d, J=9.0 Hz, 1H), 1.45-1.39(m, 1H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[OH-].[K+].Br[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[Cl-].[NH4+]>CS(C)=O.C(OCC)(=O)C>[CH2:13]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1)[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCBr
Reactant: c1ccc2[nH]ccc2c1
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCCCCn1ccc2ccccc21
Reaction time: 0.5 h

Procedure:
To a solution of 1H-indole in DMSO was added KOH at RT and was stirred for 30 minutes. Then to this mixture, 1-bromo-hexane was added and stirred for 3 hours. The reaction was treated with saturated ammonium chloride and ethyl acetate. The product was purified by column chromatography.
Reaction SMILES: [CH2:1]([S:5][C:6]1[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][CH:7]=1)[CH:2]([CH3:4])[CH3:3].[NH2:15][C@@H:16]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:17]([NH2:19])=[O:18]>>[C:17]([C@@H:16]([NH:15][C:12]([C:10]1[CH:9]=[CH:8][CH:7]=[C:6]([S:5][CH2:1][CH:2]([CH3:3])[CH3:4])[N:11]=1)=[O:14])[CH2:20][CH:21]([CH3:23])[CH3:22])(=[O:18])[NH2:19]
Reactant: CC(C)C[C@H](N)C(N)=O
Reactant: CC(C)CSc1cccc(C(=O)O)n1
Product: CC(C)CSc1cccc(C(=O)N[C@@H](CC(C)C)C(N)=O)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-(isobutylthio)picolinic acid (CAN 1247607-03-9) and (2S)-2-amino-4-methyl-pentanamide (CAN 687-51-4) as starting materials. MS (EI): m/e=324.2 [M+H]+.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([NH:11][C:12]2[C:13]([Cl:19])=[CH:14][CH:15]=[CH:16][C:17]=2[Cl:18])=[C:5]([CH2:7][C:8]([OH:10])=[O:9])[CH:6]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:32][C@H:33]([C:40]([OH:42])=[O:41])[CH2:34][C:35]1[N:39]=[CH:38][NH:37][CH:36]=1>O1CCCC1>[Cl:19][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]([Cl:18])[C:12]=1[NH:11][C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][C:5]=1[CH2:7][C:8]([O:10][NH:32][C@H:33]([C:40]([OH:42])=[O:41])[CH2:34][C:35]1[N:39]=[CH:38][NH:37][CH:36]=1)=[O:9]
Reactant: O=C(O)Cc1ccccc1Nc1c(Cl)cccc1Cl
Reactant: N[C@@H](Cc1c[nH]cn1)C(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=C(Cc1ccccc1Nc1c(Cl)cccc1Cl)ON[C@@H](Cc1c[nH]cn1)C(=O)O

Procedure:
To a diclofenac solution (3 g, 10.13 mmoles) in tetrahydrofuran (50 ml) cooled at 0° C., 1,1′-carbonyldiimidazol (1.69 g, 10.13 mmoles) is added under stirring. After 10 minutes the solution is treated with (L) histidine (1.57 g, 10.13 mmoles) and left under stirring at room temperature for 4 hours. The reaction mixture is concentrated under vacuum, treated with methylene chloride and then washed in sequence with HCl 1% and then with water. The organic phase is anhydrified with sodium sulphate and evaporated under vacuum. The obtained residue is purified by chromatography on silica gel column, eluting with ethyl acetate. [2-[(2,6-dichlorophenyl)amino] benzeneacetyloxy] (L)-histidine is obtained.
Reaction SMILES: N#N.C([O:5][C:6]([C:8]1[N:9]=[C:10]([CH2:13][C:14]2[O:15][C:16]([C:19](=[O:21])[CH3:20])=[CH:17][CH:18]=2)[S:11][CH:12]=1)=[O:7])C.[OH-].[Na+]>C1COCC1.Cl>[C:19]([C:16]1[O:15][C:14]([CH2:13][C:10]2[S:11][CH:12]=[C:8]([C:6]([OH:7])=[O:5])[N:9]=2)=[CH:18][CH:17]=1)(=[O:21])[CH3:20]
Reactant: CCOC(=O)c1csc(Cc2ccc(C(C)=O)o2)n1
Agent: Cl
Agent: N#N
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)c1ccc(Cc2nc(C(=O)O)cs2)o1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 2-(5-acetyl-furan-2-ylmethyl)-thiazole-4-carboxylic acid ethyl ester (1.71 g, 6.13 mmol) in THF (26 mL) was treated at rt with 1N NaOH (13 mL, 13.00 mmol) and the reaction mixture was stirred for 16 h at rt. The reaction mixture was poured in 1N HCl and extracted twice with EA. The combined org. extracts were dried over MgSO4, filtered, and the solvent was removed under reduced pressure to give the title compound as a deep brown foam. LC-MS-conditions 02: tR=0.71 min, [M+H]+=252.29.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[CH2:5][C:6]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][CH2:7]1.[CH:19]1([CH:24]([C:28]2[CH:33]=[CH:32][C:31]([CH2:34][N:35]3[CH2:43][C:42]4[C:37](=[CH:38][CH:39]=[CH:40][C:41]=4[F:44])[C:36]3=[O:45])=[CH:30][CH:29]=2)[C:25](O)=[O:26])[CH2:23][CH2:22][CH2:21][CH2:20]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[CH:19]1([CH:24]([C:28]2[CH:33]=[CH:32][C:31]([CH2:34][N:35]3[CH2:43][C:42]4[C:37](=[CH:38][CH:39]=[CH:40][C:41]=4[F:44])[C:36]3=[O:45])=[CH:30][CH:29]=2)[C:25]([NH:1][C:2]2[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=2)[CH2:5][C:6]2([C:9]([O:11][C:12]([CH3:15])([CH3:13])[CH3:14])=[O:10])[CH2:8][CH2:7]2)=[O:26])[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: O=C(O)C(c1ccc(CN2Cc3c(F)cccc3C2=O)cc1)C1CCCC1
Reactant: CC(C)(C)OC(=O)C1(Cc2cccc(N)c2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)C1(Cc2cccc(NC(=O)C(c3ccc(CN4Cc5c(F)cccc5C4=O)cc3)C3CCCC3)c2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
77.5 mg (0.31 mmol) of tert-butyl 1-(3-aminobenzyl)cyclopropanecarboxylate were added to a solution of 96 mg (0.26 mmol) of cyclopentyl{4-[(4-fluoro-1-oxo-1,3-dihydro-2H-isoindol-2-yl)methyl]phenyl}acetic acid in 1 ml of DMF. At 0° C., 136 μl (0.78 mmol) of DIEA and then, a little at a time, 119.2 mg (0.31 mmol) of HATU were added to the resulting mixture. The reaction mixture was then slowly warmed to RT and stirred at RT for 1 h. The reaction mixture was added to water and extracted three times with ethyl acetate. The combined organic phases were dried over magnesium sulfate and concentrated under reduced pressure. This gave 146 mg (93% of theory) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][C:7]2[N:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([CH:16]3[CH2:18][CH2:17]3)=[O:15])[CH:8]=2)=[CH:4][C:3]=1[CH3:21].[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]=[C:30]=[O:31])=[CH:25][C:24]=1[C:32]([F:35])([F:34])[F:33]>O1CCCC1.ClCCl>[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30]([NH:1][C:2]2[CH:20]=[CH:19][C:5]([O:6][C:7]3[N:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([CH:16]4[CH2:17][CH2:18]4)=[O:15])[CH:8]=3)=[CH:4][C:3]=2[CH3:21])=[O:31])=[CH:25][C:24]=1[C:32]([F:33])([F:34])[F:35]
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: Cc1cc(Oc2cc(NC(=O)C3CC3)ncn2)ccc1N
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1cc(Oc2cc(NC(=O)C3CC3)ncn2)ccc1NC(=O)Nc1ccc(Cl)c(C(F)(F)F)c1
Yield: 93.7 %

Procedure:
Dissolve N-[6-(4-amino-3-methyl-phenoxy)pyrimidin-4-yl]cyclopropanecarboxamide (1.8 g, 6.3 mmol) in tetrahydrofuran (50 mL) and dichloromethane (50 mL), add slowly 4-chloro-3-(trifluoromethyl)phenyl isocynate (1.4 g, 6.3 mmol), stir the reaction at room temperature for 15 hrs. Collect the white solid formed by filtration (2.0 g), recover from the mother liquor to give another 1.0 g (total 3.0 g, 93.7% yield). MS: (M+1): 506.2.
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[CH2:13][C:12]3([CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]3)[O:11][N:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O.O.[OH-].[Na+]>C(Cl)Cl>[C:1]1([C:7]#[C:8][C:9]2[CH2:13][C:12]3([CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[O:11][N:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC(C#Cc1ccccc1)=NO2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C(#Cc1ccccc1)C1=NOC2(CCNCC2)C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of Compound 1b (200 mg, 0.59 mmol) in CH2Cl2 (12 mL) stirred at 0° C. was added trifluoroacetic acid (452 μl, 5.87 mmol) and the reaction mixture was stirred at 25° C. for 24 h, until the complete conversion of the reactant was observed by LC-MS. Water was added followed by 3N aq. NaOH to give a alkaline pH. Separation of the organic layer and extraction of the aqueous layer with CH2Cl2, washing with brine and drying over Na2SO4 the combined organic layers, afforded the title compound as beige solid, used in the next step without further purification.
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[CH:14][C:15]([CH2:17][C:18]([OH:20])=[O:19])=[CH:16][C:3]1=2.C([O-])([O-])=O.[K+].[K+].Br[CH2:28][C:29]([O:31][CH3:32])=[O:30].O>CN(C)C=O>[CH3:32][O:31][C:29](=[O:30])[CH2:28][O:19][C:18](=[O:20])[CH2:17][C:15]1[CH:14]=[CH:13][C:4]2[O:5][CH2:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[C:2](=[O:1])[C:3]=2[CH:16]=1
Reactant: COC(=O)CBr
Reactant: O=C(O)Cc1ccc2c(c1)C(=O)c1ccccc1CO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)COC(=O)Cc1ccc2c(c1)C(=O)c1ccccc1CO2
Temperature: 50 °C
Reaction time: 8 h
Yield: 86.7 %

Procedure:
A mixture of 15 g (0.052 m) of 6,11-dihydro-11-oxodibenz[b,e]oxepin-2-acetic acid in 100 ml of dimethylformamide and 3.87 g (0.028 m) of K2CO3 was warmed to an internal temperature of 50° C. in an atmosphere of nitrogen for 1.5 hours. To this mixture, 9.41 g (0.062 m) of methyl bromoacetate was added dropwise and the mixture was held at 50° C. overnight. The reaction mixture was poured into water and extracted with ether. The ether extract was washed with 5% NaHCO3 and water, dried over Na2SO4, filtered and evaporated to give 16.5 g (94%) of an oil of methyl(6,11-dihydro-11-oxodibenz[b,e]oxepin-2-yl)acetoxyacetate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[C:15]3[C:11]([CH2:12][C:13](=[O:17])[NH:14]3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH2:18]([O:20][C:21]([C:23]1[C:27]([CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[C:26]([CH:33]=O)[NH:25][C:24]=1[CH3:35])=[O:22])[CH3:19].C(CCC1C(C(OCC)=O)=C(C)NC=1)(O)=O>>[CH2:18]([O:20][C:21]([C:23]1[C:27]([CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[C:26]([CH:33]=[C:12]2[C:11]3[C:15](=[CH:16][C:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)=[CH:9][CH:10]=3)[NH:14][C:13]2=[O:17])[NH:25][C:24]=1[CH3:35])=[O:22])[CH3:19]
Reactant: CCOC(=O)c1c(C)[nH]c(C=O)c1CCC(=O)O
Reactant: O=C1Cc2ccc(-c3ccc(F)cc3)cc2N1
Agent: CCOC(=O)c1c(CCC(=O)O)c[nH]c1C
Product: CCOC(=O)c1c(C)[nH]c(C=C2C(=O)Nc3cc(-c4ccc(F)cc4)ccc32)c1CCC(=O)O

Procedure:
6-(4-Fluorophenyl)-1,3-dihydroindol-2-one (60 mg, 0.26 mmol) was condensed with 4-(2-carboxyethyl)-5-formyl-2-methyl-1H-pyrrole-3-carboxylic acid ethyl ester (65 mg), prepared by formylation of 4-(2-carboxyethyl)-3-ethoxycarbonyl-2-methylpyrrole (Bulter, A. R., and George, S. D. (1993) Tetrahedron 49: 7017-7026), to give the title compound.
Reaction SMILES: [CH:1](=O)[CH3:2].[C:4]1([CH3:11])[C:5]([CH3:10])=[CH:6][CH:7]=[CH:8][CH:9]=1>>[CH3:11][C:4]1[CH:9]=[C:8]([CH:4]([C:5]2[CH:6]=[CH:7][C:8]([CH3:9])=[C:1]([CH3:2])[CH:10]=2)[CH3:11])[CH:7]=[CH:6][C:5]=1[CH3:10]
Reactant: Cc1ccccc1C
Reactant: CC=O
Product: Cc1ccc(C(C)c2ccc(C)c(C)c2)cc1C

Procedure:
A process for preparing 3,4,3',4'-benzophenonetetracarboxylic dianhydride which comprises condensing an impure ortho-xylene mixture with acetaldehyde in contact with an acid catalyst to obtain an impure 1,1-bis(3,4-dimethylphenyl)ethane mixture, oxidizing the 1,1-bis(3,4-dimethylphenyl)ethane mixture with nitric acid to obtain a mixture of carboxylic acids, from which by crystallization and dehydration substantially pure 3,4,3',4'-benzophenonetetracarboxylic dianhydride is recovered.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:16]=[CH:15][C:14]2[C:13](=[O:17])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6](=[O:18])[C:5]=2[CH:4]=1.[CH2:19]([OH:22])[CH2:20][OH:21]>>[OH:21][CH2:20][CH2:19][O:22][CH2:2][C:3]1[CH:16]=[CH:15][C:14]2[C:13](=[O:17])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6](=[O:18])[C:5]=2[CH:4]=1
Reactant: OCCO
Reactant: O=C1c2ccccc2C(=O)c2cc(CCl)ccc21
Product: O=C1c2ccccc2C(=O)c2cc(COCCO)ccc21
Yield: 80.92 %

Procedure:
10 g (0.039 mol) of 2-chloromethylanthraquinone (prepared in accordance with the instructions of G. Izoret, Ann. Chim. 7, 151 (1962)) in 200 ml of ethylene glycol are refluxed for 3 hours, with stirring and with exclusion of moisture. The product which has crystallised out on cooling is washed with water and recrystallised from ethanol. 8.9 g (80.92% of theory) of 2-(2-hydroxyethoxymethyl)-anthraquinone are obtained. 8 g (0.03 mol) of 2-(2-hydroxyethoxymethyl)-anthraquinone are dissolved in 180 ml of tetrahydrofuran, 4.34 ml (0.05 mol) of triethylamine are added and the mixture is cooled to 5° C. 3 ml (0.03 mol) of methacryloyl chloride in 10 ml of tetrahydrofuran are then added dropwise, with stirring and under an inert gas, such that the temperature does not exceed 5° C. When the dropwise addition has ended, stirring is continued at room temperature for 5 hours. The solvent is then stripped off on a rotary evaporator and the solid product is washed several times with 1% citric acid and water and dried in vacuo. 7.76 g of (2-anthraquinonyl)-7-oxa-4-oxa-3-oxo-2-methyloct-1-ene are obtained, and 7.48 g (71.17% of theory) after recrystallisation from ethanol.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[C:5]([OH:7])=[O:6].[C:14](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[C:5]([O:7][CH3:14])=[O:6]
Reactant: O=C(O)c1cc(Br)cc([N+](=O)[O-])c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1cc(Br)cc([N+](=O)[O-])c1

Procedure:
Prepared according to Procedure S using 3-bromo-5-nitrobenzoic acid (5.0 g, 20.32 mmol), potassium carbonate (5.62 g, 40.6 mmol), DMF (55 mL), and methyl iodide (2.54 mL, 40.6 mmol) to afford methyl 3-bromo-5-nitrobenzoate as an orange amorphous solid. Mass Spectrum (ESI) m/e=261.1 (M+1).