Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]([C:12]#[N:13])=[C:10]2[C:5]([C:6](=[O:20])[C:7]([C:17]([OH:19])=[O:18])=[CH:8][N:9]2[CH:14]2[CH2:16][CH2:15]2)=[CH:4][C:3]=1[F:21].[C@@H:22]12[CH2:30][NH:29][CH2:28][C@@H:27]1[CH2:26][CH2:25][CH2:24][NH:23]2.N12CCN(CC1)CC2>CN(C)C=O.C(#N)C>[C:12]([C:11]1[C:2]([N:29]2[CH2:30][C@@H:22]3[C@@H:27]([CH2:26][CH2:25][CH2:24][NH:23]3)[CH2:28]2)=[C:3]([F:21])[CH:4]=[C:5]2[C:10]=1[N:9]([CH:14]1[CH2:16][CH2:15]1)[CH:8]=[C:7]([C:17]([OH:19])=[O:18])[C:6]2=[O:20])#[N:13]
Reactant: N#Cc1c(Cl)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Reactant: C1CN[C@@H]2CNC[C@@H]2C1
Agent: C1CN2CCN1CC2
Solvent: CN(C)C=O
Solvent: CC#N
Product: N#Cc1c(N2C[C@@H]3CCCN[C@@H]3C2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12

Procedure:
690 mg (2.25 mmol) of 7-chloro-8-cyano-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid are stirred with 312 mg (2.47 mmol) of (1S,6S)-2,8-diazabicyclo[4.3.0]nonane and 504 mg (4.50 mmol) of 1,4-diazabicyclo[2.2.2]-octane (DABCO) in a mixture of 6.6 ml of dimethylformamide and 6.6 ml of acetonitrile at room temperature overnight. All the volatile components are removed in vacuo, the residue is taken up in water and the resulting solution is brought to pH 7 with dilute hydrochloric acid. The precipitate formed is filtered off with suction, the filtrate is extracted with methylene chloride and the combined organic phases are dried with sodium sulfate and concentrated in vacuo.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][C:32]=1[CH3:33])[CH2:5][CH:6]([CH2:10][C:11](=[O:29])[N:12]1[CH2:17][CH2:16][CH:15]([N:18]2[CH2:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[NH:20][C:19]2=[O:28])[CH2:14][CH2:13]1)[C:7](O)=[O:8].[CH2:34]([N:36]1[CH2:41][CH2:40][N:39]([CH:42]2[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]2)[CH2:38][CH2:37]1)[CH3:35]>>[CH3:1][C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][C:32]=1[CH3:33])[CH2:5][CH:6]([CH2:10][C:11]([N:12]1[CH2:13][CH2:14][CH:15]([N:18]2[CH2:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[NH:20][C:19]2=[O:28])[CH2:16][CH2:17]1)=[O:29])[C:7]([N:45]1[CH2:44][CH2:43][CH:42]([N:39]2[CH2:38][CH2:37][N:36]([CH2:34][CH3:35])[CH2:41][CH2:40]2)[CH2:47][CH2:46]1)=[O:8]
Reactant: CCN1CCN(C2CCNCC2)CC1
Reactant: Cc1ccc(CC(CC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)C(=O)O)cc1C
Product: CCN1CCN(C2CCN(C(=O)C(CC(=O)N3CCC(N4Cc5ccccc5NC4=O)CC3)Cc3ccc(C)c(C)c3)CC2)CC1

Procedure:
Prepared analogously to Example 76e) from 2-(3,4-dimethyl-benzyl)-4-oxo-4-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-butanoic acid and 1-ethyl-4-piperidin-4-yl-piperazine
Reaction SMILES: [CH2:1]([N:8]([CH2:16][C:17]#[N:18])[C@@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C:10]1=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li].[CH2:20]([O:22][CH:23]=[CH2:24])[CH3:21].C(=O)([O-])[O-].[K+].[K+]>C1COCC1>[CH2:1]([N:8]([CH2:16][C:17]#[N:18])[C@@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@@:10]1([C:20]([O:22][CH2:23][CH3:24])=[CH2:21])[OH:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#CCN(Cc1ccccc1)[C@@H]1CCCCC1=O
Reactant: C=COCC
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Li]
Solvent: C1CCOC1
Product: C=C(OCC)[C@@]1(O)CCCC[C@H]1N(CC#N)Cc1ccccc1
Temperature: 25 °C

Procedure:
To {benzyl[(1R)-2-oxocyclohexyl]amino}acetonitrile (298 mg, 1.230 mmol) in THF (9 ml) at −78° C. was added ethylvinyl ether lithium (7.38 ml, 3.69 mmol) in THF via a cannula dropwise over 25 min. The reaction mixture was stirred for an addition 40 min at −78° C. before wet THF (THF/Water 10/1, 10 ml) was added. The reaction was allowed to warm to room temperature. The mixture was cooled, aqueous potassium carbonate (saturated, 10 mL) was added and the mixture was extracted with ethyl acetate (3×20 mL). The combined organic fractions were washed with brine (saturated, 30 mL), dried, filtered and the solvent was evaporated under reduced pressure to give the title compound. The crude product was used directly without further purification in the next step.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([CH3:27])=[C:8]([C:10]2[N:15]=[C:14]3[N:16]([CH3:26])[C:17](=[O:25])[N:18]([CH2:19][C@H:20]4[CH2:22][C:21]4([F:24])[F:23])[C:13]3=[CH:12][CH:11]=2)[CH:9]=1)(=[O:3])[CH3:2].[F-].[Cs+].C[Si](C)(C)[C:32]([F:35])([F:34])[F:33]>CN(C=O)C.CO>[F:24][C:21]1([F:23])[CH2:22][CH:20]1[CH2:19][N:18]1[C:13]2[C:14](=[N:15][C:10]([C:8]3[CH:9]=[C:4]([C:1]([OH:3])([CH3:2])[C:32]([F:35])([F:34])[F:33])[CH:5]=[CH:6][C:7]=3[CH3:27])=[CH:11][CH:12]=2)[N:16]([CH3:26])[C:17]1=[O:25]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: CC(=O)c1ccc(C)c(-c2ccc3c(n2)n(C)c(=O)n3C[C@H]2CC2(F)F)c1
Agent: [Cs+]
Agent: [F-]
Solvent: CO
Solvent: CN(C)C=O
Product: Cc1ccc(C(C)(O)C(F)(F)F)cc1-c1ccc2c(n1)n(C)c(=O)n2CC1CC1(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a microwave vial, 5-(5-acetyl-2-methylphenyl)-1-{[(1R)-2,2-difluorocyclopropyl]methyl}-3-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (9-4) (25 mg, 0.067 mmol) and Cesium fluoride (21 mg, 0.135 mmol) were dissolved in DMF (0.35 mL). Trimethyl(trifluoromethyl)silane (54 uL, 0.34 mmol) was added dropwise and allowed to stir at room temperature for 30 minutes. The mixture was diluted with methanol and purified using reverse phase chromatography (10-100%, 0.1% TFA in H2O/Acetonitrile); the desired fractions were collected and concentrated to produce racemic 1-[(2,2-difluorocyclopropyl)methyl]-3-methyl-5-[2-methyl-5-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phenyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (10-1). HRMS (M+H)+: observed=442.1543, calculated=442.1548.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:4][OH:5].Cl[C:11]1[C:16]([CH3:17])=[CH:15][C:14]([N+:18]([O-:20])=[O:19])=[CH:13][N:12]=1.O>O1CCCC1>[CH3:17][C:16]1[C:11]([O:5][CH2:4][C:3]([O:7][CH2:8][CH3:9])=[O:6])=[N:12][CH:13]=[C:14]([N+:18]([O-:20])=[O:19])[CH:15]=1
Reactant: Cc1cc([N+](=O)[O-])cnc1Cl
Reactant: CCOC(=O)CO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)COc1ncc([N+](=O)[O-])cc1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (116 mg: 60%) was suspended in tetrahydrofuran (4 mL). While the suspension was cooled on ice, ethyl glycolate (273 μL) was added. The mixture was stirred at room temperature (20 to 30° C.) for 30 min. Subsequently, 2-chloro-3-methyl-5-nitropyridine (200 mg) was added to the mixture portionwise at room temperature (20 to 30° C.) and the mixture was stirred at room temperature (20 to 30° C.) for 3 hours. Water was then added to the reaction mixture and the mixture was extracted twice with chloroform. The organic layer was concentrated under reduced pressure to afford 310 mg of the crude desired product of Compound 19 as a brown amorphous.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][C:22](=O)[CH3:23])=[CH:17][CH:16]=3)=[N:11]2)=[CH:6][CH:5]=1.C([O-])(=O)C.[NH4+].C([BH3-])#[N:33].[Na+]>CO>[F:1][C:2]([F:26])([F:25])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][CH:22]([NH2:33])[CH3:23])=[CH:17][CH:16]=3)=[N:11]2)=[CH:6][CH:5]=1
Reactant: CC(=O)Cc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CC(N)Cc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Reaction time: 8 h
Yield: 102.2 %

Procedure:
1-(4-(1-(4-(Trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propan-2-one (CB57) (1.0 g, 2.8 mmol) and ammonium acetate (1.7 g, 22 mmol) were combined in dry methanol (22 mL) and stirred at room temperature while sodium cyanoborohydride (0.17 g, 2.7 mmol) was added in 3 equal portions over 30 minutes. The reaction was stirred overnight. The reaction was concentrated and partitioned between aqueous potassium carbonate and diethyl ether. The layers were separated, dried, filtered, and concentrated. Purification by reverse-phase flash column (C18) chromatography using 0-100% acetonitrile/water as eluent provided the title compound as a tan solid (1.0 g, 38%): mp 140-160° C.; 1H NMR (400 MHz, CDOD3) d 9.13 (s, 1H), 8.09 (d, J=8.0 Hz, 2H), 8.00 (d, J=9.0 Hz, 2H), 7.52 7.43 (m, 2H), 7.35 (d, J=8.0 Hz, 2H), 3.40-3.33 (m, 1H), 2.86 (t, J=6.7 Hz, 1H), 2.77 (dd, J=13.3, 7.3 Hz, 1H), 1.18 (d, J=6.2 Hz, 3H) (NH2 not observed); ESIMS m/z 363 ([M+H]+).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]2[C:11]3[C:12](Cl)=[N:13][CH:14]=[CH:15][C:16]=3[O:17][C:9]=2[C:8]([O:19][CH:20]([F:22])[F:21])=[CH:7][CH:6]=1)=[O:4].[OH-].[NH4+].[H][H]>CO.CN(C)C=O.O.[Pd]>[CH3:1][O:2][C:3]([C:5]1[C:10]2[C:11]3[CH:12]=[N:13][CH:14]=[CH:15][C:16]=3[O:17][C:9]=2[C:8]([O:19][CH:20]([F:22])[F:21])=[CH:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccc(OC(F)F)c2oc3ccnc(Cl)c3c12
Reactant: [H][H]
Agent: [Pd]
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC(F)F)c2oc3ccncc3c12

Procedure:
A mixture of Methyl-1-chloro-6-difluoromethyloxybenzo[4,5]furo[3,2-c]pyridine-9-carboxylate (8.0 g), ammonium hydroxide (2.0 mL) and 10% Pd/C (4.0 g) in a mixture of methanol (100 mL) and dimethylformamide (5.0 mL) was hydrogenated in a Parr apparatus at 40-45 psi of hydrogen for 5-6 hrs. catalyst was removed by filtration and residue obtained was diluted with water. The solid product obtained was filtered and dried. Yield=6.5 g.
Reaction SMILES: C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O.[OH:12][CH2:13][C:14]1[CH:15]=[C:16]([C:20]2[NH:24][C:23](=[O:25])[O:22][N:21]=2)[CH:17]=[CH:18][CH:19]=1.ClCCl>O1CCCC1>[O:25]=[C:23]1[O:22][N:21]=[C:20]([C:16]2[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=2)[CH:13]=[O:12])[NH:24]1
Reactant: O=c1[nH]c(-c2cccc(CO)c2)no1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=Cc1cccc(-c2noc(=O)[nH]2)c1
Yield: 71.9 %

Procedure:
Add PCC (5.22 g, 24.2 mmol) to a solution of 3-(3-hydroxymethyl-phenyl)-4H-[1,2,4]oxadiazol-5-one (3.10 g, 16.1 mmol) in tetrahydrofuran:dichloromethane (125 mL:125 mL) and stir. After 4 hours concentrate under reduced pressure to give a residue. Purify the residue by flash chromatography eluting with ethyl acetate:hexanes:acetic acid (50%:50%:0.1%) to yield the title product as a white solid (2.20 g, 72%): 1H NMR (DMSO-d6) δ 7.83 (t, 1H), 8.10-8.17 (m, 2H), 8.35 (m, 1H), 10.09 (s, 1H), 13.15 (bs, 1H).
Reaction SMILES: [CH:1](=[O:5])[CH2:2][CH2:3][CH3:4]>C(C1OCC(C)(C)CO1)=O>[CH2:3]([C:2](=[CH:1][CH2:2][CH2:3][CH3:4])[CH:1]=[O:5])[CH3:4]
Reactant: CCCC=O
Agent: CC1(C)COC(C=O)OC1
Product: CCCC=C(C=O)CC
Yield: 50.8 %

Procedure:
A solution of 288 g of n-butyraldehyde in 288 g of 2-formyl-5,5-dimethyl-1,3-dioxane is reacted as described in Example 3, and 285.6 g (72.1% of theory) of 4-neopentylglycol acetal of 2-ethylfumardialdehyde of boiling point 82°-84° C./1 mbar are obtained by fractional distillation, in addition to 128 g of 2-ethylhexenal as light ends.
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:33])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]([F:32])([F:31])[F:30])=[CH:8]2)=[O:4].[NH2:34][CH2:35][CH2:36][C:37]([OH:39])=[O:38].C[O-].[Na+]>C([O-])(O)=O.[Na+]>[CH2:15]([N:11]1[C:12]2[C:7](=[C:6]([OH:33])[C:5]([C:3]([NH:34][CH2:35][CH2:36][C:37]([OH:39])=[O:38])=[O:4])=[N:14][CH:13]=2)[CH:8]=[C:9]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[C:29]([F:31])([F:32])[F:30])[C:10]1=[O:22])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: COC(=O)c1ncc2c(cc(-c3ccccc3C(F)(F)F)c(=O)n2Cc2ccccc2)c1O
Reactant: NCCC(=O)O
Agent: C[O-]
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C(O)CCNC(=O)c1ncc2c(cc(-c3ccccc3C(F)(F)F)c(=O)n2Cc2ccccc2)c1O
Temperature: 25 °C
Yield: 53 %

Procedure:
A mixture of 1-benzyl-5-hydroxy-2-oxo-3-(2-trifluoromethyl-phenyl)-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (27 mg, 0.059 mmol), β-alanine (530 mg, 5.9 mmol) and NaOMe solution (9.6 mL, 4.8 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added until pH was about 3. The aqueous layer was extracted with additional EtOAc, and the organic layers were combined, dried over MgSO4 and concentrated. The crude product was purified by silica gel chromatography (5-60% EtOAc/hexanes+1% AcOH). The product isolated was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 3, and the resulting precipitate was isolated by filtration to give 16 mg of the title compound. MS: (+) m/z 512.27 (M+1).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][CH:7]=1.[F:9][C:10]1[CH:27]=[CH:26][C:13]([O:14][CH2:15][C@H:16]2[CH2:25][N:20]3[CH2:21][CH2:22][NH:23][CH2:24][C@@H:19]3[CH2:18][CH2:17]2)=[CH:12][CH:11]=1.Cl>>[F:9][C:10]1[CH:11]=[CH:12][C:13]([O:14][CH2:15][C@H:16]2[CH2:25][N:20]3[CH2:21][CH2:22][N:23]([C:5]4[N:4]=[N:3][C:2]([Cl:1])=[CH:7][CH:6]=4)[CH2:24][C@@H:19]3[CH2:18][CH2:17]2)=[CH:26][CH:27]=1
Reactant: Fc1ccc(OC[C@@H]2CC[C@H]3CNCCN3C2)cc1
Reactant: Clc1ccc(Cl)nn1
Agent: Cl
Product: Fc1ccc(OC[C@@H]2CC[C@H]3CN(c4ccc(Cl)nn4)CCN3C2)cc1

Procedure:
The title compound was prepared according to Preparation 3 with 3,6-dichloropyridazine and (7R,9aS)-7-(4-fluorophenoxy)methyl-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine. mp (—HCl) 265-270° C. 13C NMR (base, CDCl3): δ26.8, 29.0, 36.4, 45.1, 50.4, 54.4, 58.6, 60.3, 71.5, 115.2, 115.3, 115.4, 115.6, 115.9, 128.7, 146.7, 155.0, 155.6, 158.76, 158.82. HRMS calcd for C19H22ClFN4O: 376.1461; found: 376.1453.
Reaction SMILES: [CH:1]([Si:4]([CH:15]([CH3:17])[CH3:16])([CH:12]([CH3:14])[CH3:13])[O:5][C@H:6]([CH3:11])[CH2:7][C:8](O)=[O:9])([CH3:3])[CH3:2].C(Cl)(=O)C([Cl:21])=O>ClCCl>[CH:1]([Si:4]([CH:15]([CH3:17])[CH3:16])([CH:12]([CH3:14])[CH3:13])[O:5][C@H:6]([CH3:11])[CH2:7][C:8]([Cl:21])=[O:9])([CH3:3])[CH3:2]
Reactant: CC(C)[Si](O[C@H](C)CC(=O)O)(C(C)C)C(C)C
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CC(C)[Si](O[C@H](C)CC(=O)Cl)(C(C)C)C(C)C
Reaction time: 5 h

Procedure:
0.0475 mol (12.36 g ) of the product from stage 2 is dissolved in 200 ml of absolute dichloromethane and treated with stirring with 0.0523 mol (6.64 g) of oxalyl chloride. After 5 hours at room temperature, the mixture is concentrated under reduced pressure.
Reaction SMILES: [OH-].[Na+].[CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[S:13]([NH:16][CH:17]1[CH:22]2[CH:18]1[CH2:19][N:20]([C:23]1[N:28]=[CH:27][C:26]([C:29]([O:31]CC)=[O:30])=[CH:25][N:24]=1)[CH2:21]2)(=[O:15])=[O:14]>C1COCC1.CO>[CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[S:13]([NH:16][CH:17]1[CH:18]2[CH:22]1[CH2:21][N:20]([C:23]1[N:28]=[CH:27][C:26]([C:29]([OH:31])=[O:30])=[CH:25][N:24]=1)[CH2:19]2)(=[O:15])=[O:14]
Reactant: CCOC(=O)c1cnc(N2CC3C(C2)C3NS(=O)(=O)c2ccc3ccccc3c2)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cnc(N2CC3C(C2)C3NS(=O)(=O)c2ccc3ccccc3c2)nc1
Reaction time: 18 h
Yield: 93.2 %

Procedure:
Aqueous 1M NaOH (500 ml) was added to a solution of ethyl 2-{6-[(2-napthylsulphonyl)amino]-3-azabicyclo[3.1.0]hex-3-yl}pyrimidine-5-carboxylate (25.40 g, 58.00 mmol) in THF (500 ml) and MeOH (100 ml) at r.t. The reaction mixture was stirred for 18 h. The organic solvents were removed in vacuo and the resultant aqueous solution was acidified to pH˜5 with 1M aq. HCl. A heavy white precipitate was formed which was isolated by filtration, washed with H2O and dried by azeotroping with toluene, giving the product as a white solid (22.19 g, 93%). LCMS purity 100%, m/z 411 [M+H]+, 1H NMR (400 MHz, d6-DMSO) δ: 1.97 (2H, s), 2.05 (1H, s), 3.64-3.67 (2H, m), 3.82-3.89 (2H, m), 7.84-7.88 (2H, m), 8.01 (1H, m), 8.21 (1H, d), 8.31-8.36 (3H, m), 8.66 (1H, s), 8.83 (2H, s).
Reaction SMILES: [C:1]1([N:7]2[CH:11]=[CH:10][N:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F-].[Cs+].C1([As](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Br[C:34]1[CH:35]=[CH:36][C:37]2[N:41]=[CH:40][N:39]([C:42]3[CH:47]=[CH:46][C:45]([F:48])=[CH:44][CH:43]=3)[C:38]=2[CH:49]=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:48][C:45]1[CH:46]=[CH:47][C:42]([N:39]2[C:38]3[CH:49]=[C:34]([C:11]4[N:7]([C:1]5[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=5)[CH:8]=[N:9][CH:10]=4)[CH:35]=[CH:36][C:37]=3[N:41]=[CH:40]2)=[CH:43][CH:44]=1
Reactant: Fc1ccc(-n2cnc3ccc(Br)cc32)cc1
Reactant: c1ccc(-n2ccnc2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [Cs+]
Product: Fc1ccc(-n2cnc3ccc(-c4cncn4-c4ccccc4)cc32)cc1
Temperature: 140 °C
Reaction time: 48 h
Yield: 18.5 %

Procedure:
To a flame-dried reaction flask were added commercially available 1-phenyl-1H-imidazole (50.5 mg, 0.35 mmol), palladium(II)acetate (7.86 mg, 35.0 μmol), cesium fluoride (106 mg, 0.7 mmol), triphenylarsine (21.4 mg, 70.0 μmol) and 6-bromo-1-(4-fluoro-phenyl)-1H-benzo[d]imidazole (intermediate G) (204 mg, 0.7 mmol). The reaction flask was evacuated, and backfilled with argon, and this sequence was repeated twice. Afterwards DMF (1.75 ml) was added successively under a stream of argon by syringe at room temperature. The resulting mixture was allowed to stir at 140° C. under an argon atmosphere for 48 h. Afterwards the reaction mixture was cooled to room temperature, poured into water (20 ml), extracted with ethyl acetate (2×30 ml) and washed with brine (20 ml). The combined organic layers were dried (MgSO4) and evaporated. The crude product was purified by flash chromatography on silica gel [dichloromethane/MeOH (0-3%)] and crystallization from dichloromethane/hexane to yield the title compound as an off-white solid (23 mg, 19%), MS (ISP) m/z=355.1 [(M+H)+], mp 216° C.
Reaction SMILES: Cl[CH:2]([C:8](=O)[C:9]([F:12])([F:11])[F:10])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH3:14][O:15][C:16]1[CH:17]=[C:18]([NH:28][C:29]([NH2:31])=[S:30])[CH:19]=[CH:20][C:21]=1[N:22]1[CH:26]=[C:25]([CH3:27])[N:24]=[CH:23]1>>[CH2:6]([O:5][C:3]([C:2]1[S:30][C:29]([NH:28][C:18]2[CH:19]=[CH:20][C:21]([N:22]3[CH:26]=[C:25]([CH3:27])[N:24]=[CH:23]3)=[C:16]([O:15][CH3:14])[CH:17]=2)=[N:31][C:8]=1[C:9]([F:12])([F:11])[F:10])=[O:4])[CH3:7]
Reactant: CCOC(=O)C(Cl)C(=O)C(F)(F)F
Reactant: COc1cc(NC(N)=S)ccc1-n1cnc(C)c1
Product: CCOC(=O)c1sc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)nc1C(F)(F)F
Yield: 24.2 %

Procedure:
The title compound was prepared in analogy to example 1 step e) from 76 mg (0.33 mmol) ethyl 2-chloro-3-keto-4,4,4-trifluorobutyrate and 79 mg (0.3 mmol) [3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-thiourea. The reaction was refluxed for 5 days. The crude product was purified on silica gel with methylene chloride/methanol 9/1. The crude product was stirred with methylene chloride/diethyl ether. The precipitate was filtered off and dried to yield 31 mg (24%) of 2-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamino]-4-trifluoromethyl-thiazole-5-carboxylic acid ethyl ester as a light yellow solid. MS ISP (m/e): 427.1 (100) (M+H)+. 1H NMR (DMSO-D6, 250 MHz): δ (ppm)=11.27 (s, 1H), 7.71 (s, 1H), 7.60 (s, 1H), 7.37 (d, 1H), 7.18 (d, 1H), 7.08 (d, 1H), 4.29 (q, 1H), 3.81 (s, 3H), 2.15 (s, 3H), 1.28 (t, 3H).
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][C:14]([CH3:17])([CH3:16])[C:13](=[O:18])[C:12]=2[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[C:26](OC(=O)C)(=[O:28])[CH3:27].C(N(CC)CC)C>ClCCl.CN(C1C=CN=CC=1)C>[C:26]([NH:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[O:15][C:14]([CH3:16])([CH3:17])[C:13](=[O:18])[C:12]=2[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=2)=[CH:9][CH:10]=1)(=[O:3])=[O:4])(=[O:28])[CH3:27]
Reactant: CC(=O)OC(C)=O
Reactant: CC1(C)OC(c2ccc(S(N)(=O)=O)cc2)=C(c2cccc(F)c2)C1=O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NS(=O)(=O)c1ccc(C2=C(c3cccc(F)c3)C(=O)C(C)(C)O2)cc1

Procedure:
360 mg of 5-{4-(aminosulfonyl)phenyl}-2,2-dimethyl-4-(3-fluorophenyl)-3(2H)-furanone (Example 129) in 30 ml in dichloromethane was reacted with 0.8 ml acetic anhydride in the presence of 0.5 ml triethylamine and 50 mg of 4-(N,N-dimethylamino)pyridine at room temperature for 12 hours. The reaction mixture was concentrated in vacuo, which was followed by extraction with 30 ml water and dichloromethane (30 ml×3). The organic layer was concentrated under reduced pressure and then was purified by column chromatography (hexane/ethylacetate 2:1) to afford 397 mg of 5-[4-{(acetylamino)sulfonyl}phenyl]-2,2-dimethyl-4-(3-fluoro-phenyl)-3(2H)-furanone as a solid. mp: 178-179° C. NMR: δ1.57 (s, 6H), 2.08 (s, 3H), 7.05 (m, 3H), 7.34 (m, 1H), 7.82 (d, J=8.4 Hz, 2H), 8.05 (d, J=8.4 Hz, 2H), 8.20 (br s, 1H). IR (cm−1): 3238, 3198, 1431, 1261, 1159.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6]([C:8]1[S:9][C:10]([S:25][CH3:26])=[C:11]([C:23]#[N:24])[C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=1)=[O:7])C.Cl>C(O)C>[C:19]([C:16]1[CH:15]=[CH:14][C:13]([C:12]2[C:11]([C:23]#[N:24])=[C:10]([S:25][CH3:26])[S:9][C:8]=2[C:6]([OH:7])=[O:5])=[CH:18][CH:17]=1)([CH3:22])([CH3:20])[CH3:21]
Reactant: CCOC(=O)c1sc(SC)c(C#N)c1-c1ccc(C(C)(C)C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CSc1sc(C(=O)O)c(-c2ccc(C(C)(C)C)cc2)c1C#N
Reaction time: 24 h

Procedure:
Add NaOH 1M (1 ml) to a suspension of 3-(4-tert-butyl-phenyl)-4-cyano-5-methylsulfanyl-thiophene-2-carboxylic acid ethyl ester (general preparation 28, general preparation 29, general example E-1) (0.128 mmol) in ethanol (1 ml) and stir 24 h. Add 6 N HCl until pH approx. 1 and white solid precipitates. Filter the solid to provide the title compound: MS (ES+, m/e): 332 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH3:15])[CH2:10][CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH:16][C:17]1[N:22]=[CH:21][N:20]=[C:19]([N:23]([CH3:39])[C:24]([NH:26][C:27]2[C:32]([Cl:33])=[C:31]([O:34][CH3:35])[CH:30]=[C:29]([O:36][CH3:37])[C:28]=2[Cl:38])=[O:25])[CH:18]=1.C(N(CC)CC)C.[Cl:47]/[CH:48]=[CH:49]\[C:50](O)=[O:51].C(Cl)Cl.C(P1(=O)OP(=O)(CCC)OP(=O)(CCC)O1)CC>>[Cl:47]/[CH:48]=[CH:49]\[C:50]([NH:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:9][CH2:10][N:11]([CH2:14][CH3:15])[CH2:12][CH2:13]2)[CH:5]=[CH:4][C:3]=1[NH:16][C:17]1[CH:18]=[C:19]([N:23]([CH3:39])[C:24]([NH:26][C:27]2[C:32]([Cl:33])=[C:31]([O:34][CH3:35])[CH:30]=[C:29]([O:36][CH3:37])[C:28]=2[Cl:38])=[O:25])[N:20]=[CH:21][N:22]=1)=[O:51]
Reactant: CCN1CCN(c2ccc(Nc3cc(N(C)C(=O)Nc4c(Cl)c(OC)cc(OC)c4Cl)ncn3)c(N)c2)CC1
Reactant: O=C(O)/C=C\Cl
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCN1CCN(c2ccc(Nc3cc(N(C)C(=O)Nc4c(Cl)c(OC)cc(OC)c4Cl)ncn3)c(NC(=O)/C=C\Cl)c2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.4 %

Procedure:
The title compound was synthesized following the approach outlined in Procedure 2C (Example 108), modifying step (g) to the following procedure: To a solution of 1-(6-((2-amino-4-(4-ethylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)-3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-methylurea (11 g, 0.019 mmol), triethylamine (9.67 g, 0.096 mmol), and (Z)-3-chloroacrylic acid (2.43 g, 0.023 mmol) in DCM (0.4 ml, 6.21 mmol) was added a solution of 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (21.9 g, 0.034 mmol) at 0° C., and the resulting mixture was stirred at room temperature for 30 min. The mixture was concentrated and the residue was purified by silica gel column to obtain the title compound (7.5 mg, yield: 59%). 1H NMR (400 MHz, CDCl3) δ 1.29 (t, J=8.0 Hz, 3H) 2.90 (br. s., 4H) 3.27 (s, 3H) 3.45 (t, J=4.64 Hz, 4H) 3.91 (s, 6H) 5.90 (s, 1H) 6.32 (d, J=8.41 Hz, 1H) 6.52 (s, 1H) 6.59 (d, J=8.41 Hz, 1H) 6.73 (dd, J=8.78, 2.76 Hz, 1H) 7.09 (br. s., 1H) 7.24 (s, 2H) 7.83 (br. s., 1H) 8.36 (s, 1H) 8.69 (br. s., 1H) 12.52 (s, 1H); MS (ESI): 663.1 [M+H]+.