Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:20])=[C:4](/[CH:8]=[C:9](/[C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[F:19])\[C:10]#[N:11])[CH:5]=[CH:6][CH:7]=1.[CH3:21][C:22]([CH3:32])([CH3:31])[CH2:23]/[CH:24]=[N:25]/[CH2:26][Si](C)(C)C.C(O)(=O)C.O>CN(C)P(N(C)C)(N(C)C)=O>[Cl:1][C:2]1[C:3]([F:20])=[C:4]([CH:8]2[CH2:26][NH:25][CH:24]([CH2:23][C:22]([CH3:32])([CH3:31])[CH3:21])[C:9]2([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[F:19])[C:10]#[N:11])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)C/C=N/C[Si](C)(C)C
Reactant: N#C/C(=C\c1cccc(Cl)c1F)c1ccc(Cl)cc1F
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(C)CC1NCC(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 24.4 %

Procedure:
To a solution of (Z)-3-(3-chloro-2-fluoro-phenyl)-2-(4-chloro-2-fluoro-phenyl)-acrylonitrile (1.2 g, 3.87 mmol) in hexamethylphosphoramide (20 mL) was added [3,3-dimethyl-but-(E)-ylidene]-trimethylsilanylmethyl-amine (1.1 g, 5.9 mmol), acetic acid (60 mg, 1 mmol) and H2O (0.1 g, 5.6 mmol) sequentially. The reaction mixture was stirred at room temperature for 18 h. Water was added. The mixture was extracted with ethyl acetate. The organic layer was separated, and aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with water twice, dried over MgSO4, then concentrated. The residue was purified by chromatography (EtOAc:hexanes=1:4, 1;3) to give rac-(2S,3R,4S)-4-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-2-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile as a white foam (0.4 g, 24%).
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[NH:3][C:2]1=O.CN(C)C1C=CC=CC=1.P(Cl)(Cl)([Cl:24])=O>>[Cl:24][C:2]1[N:3]=[C:4]([OH:11])[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:1]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]c(=O)c2ccccc2[nH]1
Solvent: CN(C)c1ccccc1
Product: Oc1nc(Cl)nc2ccccc12

Procedure:
A mixture of 300 g of the product of Step A, 150 ml of N,N-dimethyl-aniline and 1 liter of phosphoryl chloride was refluxed for 51/2 hours and was cooled and poured with vigorous stirring onto crushed ice. The mixture was filtered and the product was washed with ice water until the wash water was neutral. The product was added with stirring to 2.25 liters of 2 N aqueous sodium hydroxide and the mixture was stirred for about 3 hours until complete dissolution occured. The mixture was filtered and the filtrate was neutralized by addition of glacial acetic acid. The mixture was filtered and the product was washed with water and dried to obtain 263 g of 2-chloro-4-hydroxy-quinazoline.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:17]([OH:19])=[O:18])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:20](=O)([O-])O.[K+].CN(C)C=O.CI>O>[CH3:20][O:18][C:17](=[O:19])[C@H:9]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7]
Reactant: O=C([O-])O
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 5 h
Yield: 97.4 %

Procedure:
To a mixture of N-tert-butoxycarbonylphenylalanine (13.3 g, 50.0 mmol), potassium hydrogencarbonate (10.0 g, 100 mmol) and N,N-dimethylformamide (80 mL) was added methyl iodide (5 mL, 80 mmol). The resulting mixture was stirred at room temperature for 5 h, and water (200 mL) was added. The mixture was extracted with ethyl acetate-benzene (1:1), and the organic layer was washed successively with water, 5% aqueous sodium sulfite solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated and the obtained residue was separated and purified by silica gel column chromatography (hexane-ethyl acetate, 90:10) to give 13.6 g (96%) of N-tert-butoxycarbonylphenylalanine methyl ester as a colorless oil.
Reaction SMILES: C([O:4][C:5]1[CH:33]=[CH:32][C:8]([CH2:9][N:10]2[CH2:14][CH:13]([CH2:15][CH2:16][CH2:17][CH3:18])[CH:12]([CH2:19][N:20]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:21]=[O:22])[C:11]2=[O:31])=[CH:7][CH:6]=1)C=C.N1CCOCC1.O>ClCCl.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>[CH2:24]([O:23][N:20]([CH2:19][CH:12]1[CH:13]([CH2:15][CH2:16][CH2:17][CH3:18])[CH2:14][N:10]([CH2:9][C:8]2[CH:32]=[CH:33][C:5]([OH:4])=[CH:6][CH:7]=2)[C:11]1=[O:31])[CH:21]=[O:22])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: C=CCOc1ccc(CN2CC(CCCC)C(CN(C=O)OCc3ccccc3)C2=O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Solvent: C1COCCN1
Product: CCCCC1CN(Cc2ccc(O)cc2)C(=O)C1CN(C=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.7 %

Procedure:
To a solution of (+/−)-(3RS,4SR)-N-[1-(4-allyloxybenzyl)-4-butyl-2-oxopyrrolidin-3-yl-methyl]-N-benzyloxyformamide (2.6 g, 5.77 mmol) in dichloromethane (60 mL) under argon was added morpholine (6 mL), water (1.2 mL) and then tetrakis(triphenylphosphine)palladium (0.33 g, 0.28 mmol). The reaction mixture was stirred at rt for 1 h, filtered through a Celite pad and concentrated. The residue was purified by flash column chromatography (silica gel, ethyl acetate/hexanes 4:1) to afford (+/−)-(3RS,4SR)-N-benzyloxy-N-[4-butyl-1-(4-hydroxybenzyl)-2-oxopyrrolidin-3-yl-methyl]formamide as a white solid (2.1 g, 88%). MS(ES) m/e 411 [M+H]+.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].C(N(CC)CC)C.[CH3:13][NH:14][CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1>C(OCC)C>[CH3:13][N:14]([CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1)[C:1](=[O:4])[CH:2]=[CH2:3]
Reactant: CNCCc1ccccn1
Reactant: C=CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: C=CC(=O)N(C)CCc1ccccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Acryloyl chloride (4.52 g, 0.05 mole) was added dropwise to a stirring solution of triethylamine (30 ml) and 2-(β-methylaminoethyl)pyridine (6.81 g, 0.05 mole) in ethyl ether (500 ml). After stirring overnight at room temperature, the white solid was removed by filtration and washed well with ethyl ether. The organic phases were combined, dried over sodium sulfate, filtered then concentrated to dryness to give an orange oil. The structure was confirmed by NMR.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:15]=[CH:14][C:13]([C:16]2[N:17]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:18]3[C:23]([CH:24]=2)=[CH:22][C:21]([CH2:25][N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[CH:20][CH:19]=3)=[C:12]2[C:8]=1[CH2:9][NH:10][C:11]2=[O:39])(=O)=O.[NH2:42][C:43]([C:45]1[CH:46]=[C:47](B(O)O)[CH:48]=[CH:49][CH:50]=1)=[O:44].C(=O)([O-])[O-].[K+].[K+].O>C(COC)OC>[C:43]([C:45]1[CH:50]=[C:49]([C:7]2[CH:15]=[CH:14][C:13]([C:16]3[N:17]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:18]4[C:23]([CH:24]=3)=[CH:22][C:21]([CH2:25][N:26]3[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]3)=[CH:20][CH:19]=4)=[C:12]3[C:8]=2[CH2:9][NH:10][C:11]3=[O:39])[CH:48]=[CH:47][CH:46]=1)(=[O:44])[NH2:42]
Reactant: NC(=O)c1cccc(B(O)O)c1
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(OS(=O)(=O)C(F)(F)F)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)n1c(-c2ccc(-c3cccc(C(N)=O)c3)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Yield: 47.4 %

Procedure:
In a similar manner to Step 1 of Example 152, 4-trifluoromethanesulfonyloxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (80.0 mg, 0.135 mmol) was dissolved in dimethoxyethane (5.6 mL), and the solution was added with (3-aminocarbonylphenyl)boronic acid (89 mg, 0.54 mmol), [bis(diphenylphosphino)ferrocene]dichloropalladium (17.6 mg, 0.0216 mmol), potassium carbonate (93.0 mg, 0.675 mmol) and water (0.049 mL), followed by purification by preparative thin-layer chromatography (chloroform/methanol=5/1) to obtain 4-(3-carbamoylphenyl)-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (36.1 mg, yield 47%).
Reaction SMILES: [C:1]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1C(=O)CCCC=C.[CH:20]([SH:24])([SH:23])[CH2:21][CH3:22].B(F)(F)F.[OH-].[Na+]>C(Cl)Cl>[C:14]1([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:15]=[CH:16][C:17]([C:20]2([CH2:21][CH2:22][CH2:6][CH:1]=[CH2:2])[S:24][CH2:5][CH2:4][CH2:3][S:23]2)=[CH:18][CH:19]=1
Reactant: C=CCCCC(=O)c1ccccc1-c1ccccc1
Reactant: CCC(S)S
Agent: FB(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: C=CCCCC1(c2ccc(-c3ccccc3)cc2)SCCCS1
Reaction time: 24 h

Procedure:
1-Biphenylyl-hex-5-en-1-one (1.5 g) was dissolved in DCM (30 ml). Propanedithiol (1.5 g) and boron trifluoride dietherate (1 ml) were added and the mixture stirred for 24 h. 5% NaOH (50 ml) was added and the mixture separated. The organic phase was washed with water, dried and evaporated to give an oil. Column chromatography (petrol/ethyl acetate) gave the title compound as a thick oil. δC (CDCl3, 62.9 MHz): 23.2, 25.3, 27.7, 33.6, 44.6, 58.9, 115.0, 127.1, 127.1, 127.4, 128.8, 129.4, 138.1, 139.6, 140.5 and 141.0. δH (CDCl3, 250 MHz): 1.40 (2H, m), 2.00 (6H, m), 2.70 (4H, m), 4.92 (2H, m), 5.68 (1H, m), 7.34 (1H, m), 7.44 (2H, m), 7.62 (4H, m) and 7.96 (2H, d, J 8.2).
Reaction SMILES: [CH3:1][CH2:2][OH:3].[K].Cl[C:6]1[C:7]([C:16]([F:19])([F:18])[F:17])=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[C:10]([NH2:12])[CH:11]=1>O>[CH2:2]([O:3][C:6]1[C:7]([C:16]([F:17])([F:19])[F:18])=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[C:10]([NH2:12])[CH:11]=1)[CH3:1]
Reactant: CCO
Reactant: Nc1cc(Cl)c(C(F)(F)F)cc1[N+](=O)[O-]
Agent: [K]
Solvent: O
Product: CCOc1cc(N)c([N+](=O)[O-])cc1C(F)(F)F
Yield: 96 %

Procedure:
To EtOH (500 mL) was added potassium metal (ca. 21 g, ca. 537 mmol) and the vigorous reaction had to be cooled with an ice bath. Stirring was continued until all potassium metal was dissolved. Solid commercially available 5-chloro-2-nitro-4-trifluoromethyl-phenylamine [CAS-No. 35375-74-7] (57.74 g, 240 mmol) was added in one portion and the resulting dark red mixture was stirred at 55-60° C. for 4 days. The warm reaction mixture was slowly poured into H2O (ca. 2000 mL), adjusted pH with conc. HC1 to pH 2, the yellow precipitate was filtered off, washed with H2O and dried in air at 60° C. to give a yellow solid (57.81 g, 96%), which was used without further purification. MS (ISN) 249 [M−H].
Reaction SMILES: [C:1]([C:4]1[CH:27]=[CH:26][C:7]([CH2:8][S:9][C:10]2[S:14][C:13]([S:15][CH2:16][CH2:17][CH2:18][S:19][CH2:20][C:21]([O:23]CC)=[O:22])=[N:12][N:11]=2)=[C:6]([CH2:28][CH2:29][CH3:30])[C:5]=1[OH:31])(=[O:3])[CH3:2].[OH-].[Na+].C(OCC)(=O)C.Cl>CO>[C:1]([C:4]1[CH:27]=[CH:26][C:7]([CH2:8][S:9][C:10]2[S:14][C:13]([S:15][CH2:16][CH2:17][CH2:18][S:19][CH2:20][C:21]([OH:23])=[O:22])=[N:12][N:11]=2)=[C:6]([CH2:28][CH2:29][CH3:30])[C:5]=1[OH:31])(=[O:3])[CH3:2]
Reactant: CCCc1c(CSc2nnc(SCCCSCC(=O)OCC)s2)ccc(C(C)=O)c1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCCc1c(CSc2nnc(SCCCSCC(=O)O)s2)ccc(C(C)=O)c1O
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 105.9 %

Procedure:
In 2 ml of 90% methanol was suspended 0.14 g of ethyl [[3-[[5-[(4-acetyl-3-hydroxy-2-propylbenzyl)thio]-1,3,4-thiadiazol-2-yl]thio]propyl]thio]acetate obtained in Example 25. Further 1 ml of a 1N aqueous sodium hydroxide solution was added to the suspension followed by stirring at room temperature for 45 minutes. An aqueous sodium hydroxide solution and ethyl acetate were added to the reaction mixture to fractionate. The aqueous phase was made acidic with 1N hydrochloric acid and extracted with ethyl acetate. After the extract was washed with water and then dried over anhydrous magnesium sulfate, the solvent was distilled off. The residue was applied to silica gel column chromatography. Elution with a solvent mixture of hexane-ethyl acetate (1:2) gave 0.14 g of oily [[3-[[5-[(4-acetyl-3-hydroxy-2-propylbenzyl)thio]-1,3,4-thiadiazol -2-yl]thio]propyl]thio]acetic acid.
Reaction SMILES: [OH-].[K+].[F:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2.[NH:13]1[CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]1.Cl.O>CO.O>[F:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[C:16]1[CH2:17][CH2:18][NH:13][CH2:14][CH:15]=1
Reactant: O=C1CCNCC1
Reactant: Fc1ccc2[nH]ccc2c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Fc1ccc2[nH]cc(C3=CCNCC3)c2c1
Yield: 67.2 %

Procedure:
To a solution of 74 gm potassium hydroxide in 673 mL methanol were added 10.0 gm (74 mMol) 5-fluoroindole and 23.3 gm (151 mMol) 4-piperidone.HCl.H2O. The reaction mixture was stirred at reflux for 18 hours. The reaction mixture was diluted with 1.3 L of water and the resulting precipitate recovered by filtration and dried under reduced pressure to give 10.75 gm (67.2%) of 5-fluoro-3-[1,2,5,6-tetrahydro-4-pyridyl]-1H-indole as a yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][NH:7][CH:8]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].[CH3:15][O:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Cl)=[CH:19][CH:18]=1>CN(C=O)C.C(Cl)Cl>[CH3:15][O:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][N:6]2[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:8]=[N:7]2)=[CH:19][CH:18]=1
Reactant: O=[N+]([O-])c1cn[nH]c1
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc(Cn2cc([N+](=O)[O-])cn2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 4-nitro-1H-pyrazole (500 mg, 4.42 mmol; Bionet Research, Cornwall, UK) in DMF (5 mL) was treated with potassium carbonate (400 μL, 6.63 mmol) and 4-methoxybenzyl chloride (600 μL, 4.42 mmol). The reaction was stirred at room temperature for 2 h, then diluted with DCM (200 mL) and washed with water (4×40 mL). The organic layer was then dried (MgSO4), filtered and concentrated in vacuo to give the crude product, which was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[CH3:11]C1C2C(=CC=CC=2)NC=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[CH:6]=[CH:5]2
Reactant: Cc1c[nH]c2ccccc12
Reactant: Clc1ccc2[nH]ccc2c1
Product: Cn1ccc2cc(Cl)ccc21
Yield: 91 %

Procedure:
According to the procedure of Preparation 13 (a), except substituting 5-chloroindole for the 3-methylindole, the title compound (2.0 g, 91%) was obtained as an amber oil: MS (ES) m/e 166.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([NH:9][C:10](=[O:26])[C:11]2[C:16]([O:17][C:18]3[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=3[Cl:25])=[CH:15][CH:14]=[N:13][CH:12]=2)=[C:4]([N:27]([CH:29]2[CH2:31][CH2:30]2)[CH3:28])[CH:3]=1.[CH3:32]CCCCCC.C(OCC)(=O)C>>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([N:9]([CH3:32])[C:10](=[O:26])[C:11]2[C:16]([O:17][C:18]3[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=3[Cl:25])=[CH:15][CH:14]=[N:13][CH:12]=2)=[C:4]([N:27]([CH:29]2[CH2:31][CH2:30]2)[CH3:28])[CH:3]=1
Reactant: CN(c1cc(Cl)c(F)cc1NC(=O)c1cnccc1Oc1cc(Cl)ccc1Cl)C1CC1
Reactant: CCCCCCC
Solvent: CCOC(C)=O
Product: CN(C(=O)c1cnccc1Oc1cc(Cl)ccc1Cl)c1cc(F)c(Cl)cc1N(C)C1CC1

Procedure:
The title compound was prepared in analogy to Example 12, from N-[4-chloro-2-(cyclopropyl-methyl-amino)-5-fluoro-phenyl]-4-(2,5-dichloro-phenoxy)-nicotinamide and using a gradient of n-heptane:ethyl acetate (100:0 to 0:100) for the chromatographic purification. Colorless solid (79%). MS (ESI): m/z=496.058 [M+H]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[S:8][CH:9]=[C:10]([C:12]3[C:13](=[O:24])[NH:14][C:15]4[C:20]([CH:21]=3)=[CH:19][CH:18]=[C:17]([CH:22]=O)[CH:16]=4)[N:11]=2)=[CH:3][CH:2]=1.[NH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1>>[N:1]1[CH:6]=[CH:5][C:4]([C:7]2[S:8][CH:9]=[C:10]([C:12]3[C:13](=[O:24])[NH:14][C:15]4[C:20]([CH:21]=3)=[CH:19][CH:18]=[C:17]([CH2:22][N:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)[CH:16]=4)[N:11]=2)=[CH:3][CH:2]=1
Reactant: O=Cc1ccc2cc(-c3csc(-c4ccncc4)n3)c(=O)[nH]c2c1
Reactant: C1CCNC1
Product: O=c1[nH]c2cc(CN3CCCC3)ccc2cc1-c1csc(-c2ccncc2)n1

Procedure:
This compound was prepared according to the method described in example 8768 employing 3-(2-pyridin-4-yl-thiazol-4-yl)-1H-quinolin-2-one-7-carbaldehyde and pyrrolidine to give a yellow solid. MS m/z: 389.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].[C:13](Cl)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:13]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:20]
Reactant: Clc1ccc(Cl)cc1
Reactant: O=C(Cl)c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Product: O=C(c1ccccc1)c1cc(Cl)ccc1Cl
Temperature: 170 °C
Yield: 64 %

Procedure:
A mixture of 5.4 g of 1,4-dichlorobenzene, 4.2 g of aluminum chloride and 0.5 ml of benzoyl chloride was stirred at 170° C. Additional benzoyl chloride, up to a total of 4 g, was slowly added to the mixture over 2.5 hours, and the resulting mixture was stirred for another hour at 170° C. The molar ratio of reactants was 1.1/1.3/ (AClCl3 :Dichlorobenzene:Benzoyl Chloride). After work-up of the crude mixture as in Examples 7 through 10, 2,5-dichlorobenzophenone was obtained in 64% yield, as determined by gas chromatography using 3-chlorobenzophenone as the internal standard.
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][NH2:4].[C:7]([O:11][C:12]([NH:14][C@@H:15]([CH3:28])[C:16]([NH:18][N:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[C:24](OC)=[O:25])=[O:17])=[O:13])([CH3:10])([CH3:9])[CH3:8].C[Al](C)C.C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.O>[O:17]=[C:16]([NH:18][N:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[C:24](=[O:25])[NH:4][CH2:3][C:2]([F:6])([F:5])[F:1])[C@@H:15]([NH:14][C:12](=[O:13])[O:11][C:7]([CH3:10])([CH3:9])[CH3:8])[CH3:28]
Reactant: NCC(F)(F)F
Reactant: COC(=O)c1cccn1NC(=O)[C@H](C)NC(=O)OC(C)(C)C
Agent: C[Al](C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)Nn1cccc1C(=O)NCC(F)(F)F
Temperature: 80 °C
Reaction time: 8 h

Procedure:
2,2,2-Trifluoroethanamine (680 microl, 8.66 mmols) was added to a solution of (S)-methyl 1-(2-(tert-butoxycarbonylamino)propanamido)-1H-pyrrole-2-carboxylate (900 mg, 2.89 mmols) in toluene (36 ml). A 2M solution of trimethyl aluminium in toluene (7 ml, 14.00 mmols) was added and it was stirred at 80° C. overnight. Water (50 ml) and a 0.5M solution of sodium tartrate (25 ml) were added. It was extracted with ethylacetate. The combined organic layers were washed with water and brine. It was dried, filtered and concentrated in vacuum. The title compound was obtained (1.021 g, 93%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:16])=O>>[Cl:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([Cl:16])=[O:5]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1Cl
Product: O=C(Cl)c1ccc([N+](=O)[O-])cc1Cl

Procedure:
As described for Reference Example 26, 25 g of 2-chloro-4-nitrobenzoic acid is reacted with thionyl chloride (124 ml) to give the product (27.0 g) as a brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:15]3[C:14]([CH3:16])=[N:13][NH:12][C:11]=3[C:10](=[O:17])[N:9]2[C:18]2[CH:23]=[C:22]([CH3:24])[C:21](=[O:25])[N:20]([CH3:26])[CH:19]=2)=[CH:4][CH:3]=1.[CH3:27][NH:28][C:29](N1C=CN=C1)=[O:30].C(N(CC)CC)C>C(Cl)Cl.C(Cl)Cl.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:15]3[C:11](=[N:12][N:13]([C:29]([NH:28][CH3:27])=[O:30])[C:14]=3[CH3:16])[C:10](=[O:17])[N:9]2[C:18]2[CH:23]=[C:22]([CH3:24])[C:21](=[O:25])[N:20]([CH3:26])[CH:19]=2)=[CH:4][CH:3]=1.[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:15]3[C:14]([CH3:16])=[N:13][N:12]([C:29]([NH:28][CH3:27])=[O:30])[C:11]=3[C:10](=[O:17])[N:9]2[C:18]2[CH:23]=[C:22]([CH3:24])[C:21](=[O:25])[N:20]([CH3:26])[CH:19]=2)=[CH:4][CH:3]=1
Reactant: CNC(=O)n1ccnc1
Reactant: Cc1n[nH]c2c1C(c1ccc(Cl)cc1)N(c1cc(C)c(=O)n(C)c1)C2=O
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CNC(=O)n1nc(C)c2c1C(=O)N(c1cc(C)c(=O)n(C)c1)C2c1ccc(Cl)cc1
Product: CNC(=O)n1nc2c(c1C)C(c1ccc(Cl)cc1)N(c1cc(C)c(=O)n(C)c1)C2=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 4-(4-chlorophenyl)-5-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-3-methyl-4,5-dihydropyrrolo[3,4-c]pyrazol-6(1H)-one (Example 27) (150 mg, 0.407 mmol), N-methyl-1H-imidazole-1-carboxamide [Duspara, Petar A.; Islam, Md. Sadequl; Lough, Alan J.; Batey, Robert A. Journal of Organic Chemistry (2012), 77(22), 10362-10368] (50.9 mg, 0.407 mmol) and triethylamine (0.057 mL, 0.407 mmol) in CH2Cl2 (4 mL) was stirred for 16 h at rt. N-methyl-1H-imidazole-1-carboxamide (50 mg) was added. The reaction mixture was stirred for 3 days at rt, diluted with CH2Cl2/water and extracted twice with CH2Cl2. The combined organic extracts were washed with brine, dried (Na2SO4) and concentrated. The residue was purified by chromatography (1% ammonia/5% MeOH/DCM), subsequent preparative achiral SFC (column: Reprosil 70 NH2, 250×30 mm, 5 μm, Dr Maisch; eluent: MeOH/scCO2; gradient: 1 min 21% MeOH, 21-26% MeOH in 6 min, 26-50% MeOH, in 1 min, 1.5 min 50% MeOH; flow: 100 mL/min) and trituration of the resulting products in diethyl ether to afford 57 mg of 4-(4-chlorophenyl)-5-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-N,3-dimethyl-6-oxo-5,6-dihydropyrrolo[3,4-c]pyrazole-2(4H)-carboxamide (Example 144) and 26 mg of the title compound. tR: 0.84 min (LC-MS 2); ESI-MS: 426.1 [M+H]+ (LC-MS 2); Rf=0.24 (NH3 1%/CH2Cl2/MeOH 5%); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.92 (s, 3H) 1.98 (s, 3H) 2.83 (d, J=4.30 Hz, 3H) 3.35 (s, 3H) 6.17 (s, 1H) 7.26-7.45 (m, 5H) 7.74 (br. s., 1H) 8.53 (d, J=4.30 Hz, 1H).