Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:17])[CH:9]=[CH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.[C:18]([O:26][CH2:27][CH3:28])(=[O:25])[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:17])[CH2:9][CH:10]([CH:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:18]([O:26][CH2:27][CH3:28])=[O:25])[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[CH:6][CH:7]=1
Reactant: O=C(C=Cc1ccccc1)c1ccc(Br)cc1
Reactant: CCOC(=O)CC(=O)OCC
Product: CCOC(=O)C(C(=O)OCC)C(CC(=O)c1ccc(Br)cc1)c1ccccc1

Procedure:
By a procedure similar to that of example 1.59.2, starting from 1-(4-bromophenyl)-3-phenylprop-2-en-1-one and diethyl malonate, diethyl 2-[3-(4-bromophenyl)-3-oxo-1-phenylpropyl]malonate was obtained as colourless solid.
Reaction SMILES: [C:1]1(=[O:8])[O:7][C:5](=[O:6])[CH2:4][CH2:3][CH2:2]1.[OH-:9].[Na+]>O.[N+]([O-])([O-])=O.[Ag+]>[C:1]([OH:7])(=[O:8])[CH2:2][CH2:3][CH2:4][C:5]([OH:9])=[O:6]
Reactant: [OH-]
Reactant: O=C1CCCC(=O)O1
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C(O)CCCC(=O)O
Reaction time: 1 h

Procedure:
An 11.76 g portion of 97% glutaric anhydride was dissolved in a mixture of 40 ml of 5N sodium hydroxide and 200 ml of water. A solution of 33.8 g of silver nitrate in 100 ml of water was added, the suspension was stirred for 1 hour in the dark, then the solid was collected, washed with water and dried, giving 33.5 g of glutaric acid, disilver salt.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][CH:6]([C:10](=O)[CH3:11])[C:7](=O)[CH3:8])[CH3:2].[CH3:14][NH:15][NH2:16]>C(O)(=O)C>[CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]1[C:10]([CH3:11])=[N:16][N:15]([CH3:14])[C:7]=1[CH3:8])[CH3:2]
Reactant: CCOC(=O)CC(C(C)=O)C(C)=O
Reactant: CNN
Solvent: CC(=O)O
Product: CCOC(=O)Cc1c(C)nn(C)c1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 73.2 %

Procedure:
Dissolve 3-acetyl-4-oxopentanoic acid ethyl ester (3.35 g, 19.5 mmol) in glacial acetic acid (20 mL) and add methylhydrazine (1.13 mL, 21.4 mmol) dropwise. Stir the resulting mixture at room temperature for 16 hr. Concentrate and partition the residue between ethyl acetate (100 mL) and saturated aqueous sodium bicarbonate solution (50 mL). Separate organic layer, dry (sodium sulfate), filter, concentrate and purify (silica gel chromatography, eluting with 7:3 hexanes:ethyl acetate) to give (1,3,5-trimethyl-1H-pyrazol-4-yl)-acetic acid ethyl ester (2.8 g, 73%) as an oil. 1H NMR (CDCl3) δ 4.08 (q, 2H), 3.67 (s, 3H), 3.29 (s, 2H), 2.18 (s, 6H), 1.21 (t, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[N:7][C:6]([N:9]2[CH:13]=[N:12][C:11]([CH3:14])=[N:10]2)=[C:5]2[NH:15][CH:16]=[C:17]([C:18](=[O:22])[C:19]([OH:21])=O)[C:4]=12.[N:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]1[N:38]=[CH:37][CH:36]=[C:35]2[C:30]=1[CH2:31][CH2:32][NH:33][CH2:34]2.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:8]=[N:7][C:6]([N:9]2[CH:13]=[N:12][C:11]([CH3:14])=[N:10]2)=[C:5]2[NH:15][CH:16]=[C:17]([C:18](=[O:22])[C:19]([N:33]3[CH2:32][CH2:31][C:30]4[C:35](=[CH:36][CH:37]=[N:38][C:29]=4[C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][N:23]=4)[CH2:34]3)=[O:21])[C:4]=12
Reactant: COc1cnc(-n2cnc(C)n2)c2[nH]cc(C(=O)C(=O)O)c12
Reactant: c1ccc(-c2nccc3c2CCNC3)nc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cnc(-n2cnc(C)n2)c2[nH]cc(C(=O)C(=O)N3CCc4c(ccnc4-c4ccccn4)C3)c12
Temperature: 25 °C
Reaction time: 15.75 h

Procedure:
To a suspension of 2-(4-methoxy-7-(3-methyl-1H-1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoacetic acid (0.062 g, 0.205 mmol), 5-(pyridin-2-yl)-1,2,3,4-tetrahydro-2,6-naphthyridine (0.062 g, 0.205 mmol), and TBTU (0.086 g, 0.267 mmol) in DMF (3 mL) was added Hunig's Base (0.2 mL, 1.145 mmol). The mixture was stirred at rt for 15.75 h and quenched with 5 mL of water and concentrated under reduced pressure. The residue was dissolved in DMF, filtered through a plug of glass wool, and was purified by prep HPLC. The fractions containing the expected product were combined and concentrated. The residue was dissolved in dichloromethane and washed with sat. aq. NaHCO3. The organic layer was dried with MgSO4, was filtered, and was concentrated under reduced pressure to give the expected product as a light pink solid. The compound was further purified using BIOTAGE® flash chromatography with a 0-6% MeOH in dichloromethane gradient. The expected product, 1-(4-methoxy-7-(3-methyl-1H-1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(5-(pyridin-2-yl)-3,4-dihydro-2,6-naphthyridin-2(1H)-yl)ethane-1,2-dione, 1.4 H2O (0.041 g, 0.077 mmol, 37.7% yield), was isolated as an off-white solid. LC/MS: m/z 495.19 (M+H)+, 0.922 min (method 4). 1H NMR (500 MHz, DMSO-d6) δ ppm 11.04 (br. s., 1H) 9.07-9.12 (m, 1H) 8.48-8.71 (m, 2H) 8.20-8.26 (m, 1H) 7.79-7.90 (m, 2H) 7.71-7.74 (m, 1H) 7.27-7.37 (m, 1H) 7.00-7.23 (m, 1H) 4.80-5.00 (m, 2H) 3.75-3.96 (m, 5H) 3.22-3.36 (m, 2H) 2.50-2.61 (m, 3H) 1.57 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:25])=[C:4]([N:8]2[C:13](=[O:14])[CH:12]=[CH:11][N:10](CC3C=CC(OC)=CC=3)[C:9]2=[O:24])[CH:5]=[CH:6][CH:7]=1.FC(F)(F)S(O)(=O)=O>C(O)(C(F)(F)F)=O>[Br:1][C:2]1[C:3]([CH3:25])=[C:4]([N:8]2[C:13](=[O:14])[CH:12]=[CH:11][NH:10][C:9]2=[O:24])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(Cn2ccc(=O)n(-c3cccc(Br)c3C)c2=O)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(Br)cccc1-n1c(=O)cc[nH]c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.6 %

Procedure:
A solution of 3-(3-bromo-2-methylphenyl)-1-(4-methoxybenzyl)pyrimidine-2,4(1H,3H)-dione (0.87 g, 2.17 mmol) in TFA (5.5 mL) was treated with trifluoromethanesulfonic acid (0.55 mL) and the mixture was stirred at room temperature overnight. The mixture was slowly poured onto ice and stirred while warming to room temperature. The precipitate was collected by filtration, washed with water and dried to provide 3-(3-bromo-2-methylphenyl)pyrimidine-2,4(1H,3H)-dione as a purple solid (0.62 g, 96% yield). Mass spectrum m/z 281, 283 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 11.36 (d, J=4.4 Hz, 1H), 7.67 (dd, J=6.5, 2.8 Hz, 1H), 7.60 (dd, J=7.7, 5.9 Hz, 1H), 7.27-7.21 (m, 2H), 5.72 (dd, J=7.7, 1.3 Hz, 1H), 2.07 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][NH2:16])=[CH:11][CH:10]=2)[CH:6]=[CH:5][N:4]=1.[N:19]1[CH:24]=[CH:23][N:22]=[CH:21][C:20]=1[C:25]1[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][CH:26]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[N:19]1[CH:24]=[CH:23][N:22]=[CH:21][C:20]=1[C:25]1[CH:26]=[CH:27][C:28]([C:29]([NH:16][CH2:15][C:12]2[CH:11]=[CH:10][C:9]([C:7]3[CH:6]=[CH:5][N:4]=[C:3]([C:2]([F:1])([F:17])[F:18])[CH:8]=3)=[CH:14][CH:13]=2)=[O:30])=[CH:32][CH:33]=1
Reactant: O=C(O)c1ccc(-c2cnccn2)cc1
Reactant: NCc1ccc(-c2ccnc(C(F)(F)F)c2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCc1ccc(-c2ccnc(C(F)(F)F)c2)cc1)c1ccc(-c2cnccn2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of (4-(2-(trifluoromethyl)pyridin-4-yl)phenyl)methanamine 28-3 (16 mg, 0.063 mmol), 4-(pyrazin-2-yl)benzoic acid 18-3 (13 mg, 0.065 mmol), and HATU (26 mg, 0.068 mmol) were added N,N-diisopropylethylamine (DIEA, 17 μL, 0.1 mmol) and DMF (0.5 mL). The solution was stirred overnight at room temperature and was subjected directly to reverse phase preparative HPLC to yield 4-(pyrazin-2-yl)-N-(4-(2-(trifluoromethyl)pyridin-4-yl)benzyl)benzamide 28 as a solid. MS m/z 435.0 (M+1).
Reaction SMILES: [H-].[Na+].[C:3]([O:13][C:14]([CH3:17])([CH3:16])C)(=[O:12])[CH2:4][C:5](OC(C)(C)C)=O.[CH2:18]([O:20][C:21]([C:23]1[C:32](=[O:33])[N:31]2[C:26]([C:27](C)=[C:28](Cl)[C:29]([F:34])=[CH:30]2)=[C:25]([CH:37]2[CH2:39][CH2:38]2)[CH:24]=1)=[O:22])[CH3:19].O>CN(C=O)C>[CH2:18]([O:20][C:21]([C:23]1[C:32](=[O:33])[N:31]2[C:26]([C:27]([CH3:28])=[C:5]([CH2:4][C:3]([O:13][CH:14]([C:16]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:17]3[CH:37]=[CH:25][CH:24]=[CH:23][CH:21]=3)=[O:12])[C:29]([F:34])=[CH:30]2)=[C:25]([CH:37]2[CH2:39][CH2:38]2)[CH:24]=1)=[O:22])[CH3:19]
Reactant: CCOC(=O)c1cc(C2CC2)c2c(C)c(Cl)c(F)cn2c1=O
Reactant: CC(C)(C)OC(=O)CC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(C2CC2)c2c(C)c(CC(=O)OC(c3ccccc3)c3ccccc3)c(F)cn2c1=O

Procedure:
To a suspension of NaH in DMF with ice bath cooling is added di-t-butyl malonate. After the addition, 8-chloro-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid ethyl ester from Example 253i above is added. The reaction is then heated to 50° to 60° C., and the mixture is poured into water and acidified. The product is extracted into methylene chloride and dried over MgSO4. The residue, after removal of the solvent, is dissolved in methylene chloride and trifluoroacetic acid at room temperature. The solvent is removed under vacuum, and the product is treated with diphenyldiazomethane in methylene chloride and methanol. When the reaction is finished, the solvents are removed under vacuum, and the product is purified by column chromatography to give the title compound.
Reaction SMILES: [OH-].[K+].[NH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[C:11]([C:15]1[O:19][C:18](S(C)(=O)=O)=[N:17][N:16]=1)([CH3:14])([CH3:13])[CH3:12]>CS(C)=O>[C:11]([C:15]1[O:19][C:18]([O:10][C:7]2[CH:8]=[CH:9][C:4]([NH2:3])=[CH:5][CH:6]=2)=[N:17][N:16]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: Nc1ccc(O)cc1
Reactant: CC(C)(C)c1nnc(S(C)(=O)=O)o1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CC(C)(C)c1nnc(Oc2ccc(N)cc2)o1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
7.3 g of pulverised KOH are added to 10.9 g of 4-aminophenol in 100 ml of dimethyl sulfoxide, and the mixture is stirred for 15 minutes. Then 20.4 g of 5-tert-butyl-2-methylsulfonyl-1,3,4-oxadiazole are added, the reaction mixture is stirred for 12 hours at room temperature and poured into ice water. The mixture is extracted with diethyl ether and the combined extracts are dried and concentrated by evaporation. Petroleum ether is added to the oily residue, whereupon the product crystallises. The product is then isolated by filtration and dried. Yield: 16.5 g (71% of theory). Melting point: 80°-81° C.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([NH:8][CH2:9][C@@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:15]([C:17]2[N:18]=[C:19]([CH3:29])[S:20][C:21]=2[C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)=[O:16])=[N:6][CH:7]=1.[Cl-].[Li+].[CH3:32][Sn](C)(C)C>CN(C)C=O>[F:28][C:25]1[CH:26]=[CH:27][C:22]([C:21]2[S:20][C:19]([CH3:29])=[N:18][C:17]=2[C:15]([N:11]2[CH2:12][CH2:13][CH2:14][C@H:10]2[CH2:9][NH:8][C:5]2[N:4]=[CH:3][C:2]([CH3:32])=[CH:7][N:6]=2)=[O:16])=[CH:23][CH:24]=1
Reactant: Cc1nc(C(=O)N2CCC[C@H]2CNc2ncc(Br)cn2)c(-c2ccc(F)cc2)s1
Reactant: C[Sn](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: Cc1cnc(NC[C@@H]2CCCN2C(=O)c2nc(C)sc2-c2ccc(F)cc2)nc1
Temperature: 100 °C

Procedure:
To the compound of Example 194 (0.36 g) in dimethylformamide was added lithium chloride (0.096 g), tetramethyl tin (0.126 ml) and dichlorobis(triphenylphosphine) palladium (0) (0.035 g) and the resulting mixture heated at 100° C. under argon for 18 h. The reaction was then evaporated, diluted with dichloromethane, filtered and the filtrate washed with water, dried and evaporated. Chromatography of the residue on silica gel, eluting with methanol-dichloromethane mixtures, afforded the title product (0.2 g) as a yellow amorphous solid. Mass Spectrum (API+): Found 412 (MH+). C21H22FN5OS requires 411.
Reaction SMILES: S(Cl)([Cl:3])=O.[OH:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH:16]([CH3:18])[CH3:17])[CH:14]=2)[N:9]=[CH:8][C:7]=1[C:19]([OH:21])=O>C1C=CC=CC=1>[OH:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH:16]([CH3:18])[CH3:17])[CH:14]=2)[N:9]=[CH:8][C:7]=1[C:19]([Cl:3])=[O:21]
Reactant: O=S(Cl)Cl
Reactant: CC(C)c1ccc2ncc(C(=O)O)c(O)c2c1
Solvent: c1ccccc1
Product: CC(C)c1ccc2ncc(C(=O)Cl)c(O)c2c1

Procedure:
3.8 ml of thionyl chloride were added to a suspension of 10 g of the raw product of Step C in 300 ml of anhydrous benzene and the mixture was refluxed for 21/2 hours and was then cooled. The mixture was vacuum filtered and the precipitate was empasted with a little anhydrous benzene to obtain 10.74 g of 4-hydroxy-6-isopropyl-quinoline-3-carboxylic acid chloride melting at 252° C.
Reaction SMILES: C([O:8][CH2:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20](=[O:30])[CH2:21][O:22]CC2C=CC=CC=2)=[CH:15][CH:14]=1)=[O:11])C1C=CC=CC=1>CO.[Pd]>[OH:8][CH2:9][C:10]([NH:12][C:13]1[CH:14]=[CH:15][C:16]([O:19][C:20](=[O:30])[CH2:21][OH:22])=[CH:17][CH:18]=1)=[O:11]
Reactant: O=C(COCc1ccccc1)Nc1ccc(OC(=O)COCc2ccccc2)cc1
Agent: [Pd]
Solvent: CO
Product: O=C(CO)Nc1ccc(OC(=O)CO)cc1
Reaction time: 10 h

Procedure:
Benzyloxy-acetic acid 4-(2-benzyloxy-acetylamino)-phenyl ester 7 is dissolved in methanol (50 ml) in a pressure vessel, Palladium on carbon (5%, 4 grams) added and the mixture stirred under an atmosphere of hydrogen (4 Kg) for 10 hours. The catalyst is removed by filtration, methanol distilled under vacuum. The crude 8 can be purified by column chromatography on silica gel using benzene: ethyl acetate (8:2) as eluant to get the desired product.
Reaction SMILES: B.[CH2:2]=[C:3]1[CH2:9][O:8][CH2:7][CH2:6][N:5]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:4]1.[OH-:17].[Na+].OO>C1COCC1.CCCCCC>[OH:17][CH2:2][CH:3]1[CH2:9][O:8][CH2:7][CH2:6][N:5]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:4]1
Reactant: [OH-]
Reactant: C=C1COCCN(C(=O)OC(C)(C)C)C1
Agent: B
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)N1CCOCC(CO)C1
Temperature: 25 °C

Procedure:
1M borane in THF (450 mL, 0.45 mol, 0.9 eq) was added under stirring and cooling on an ice bath to a stirred in a stream of argon solution of tert-butyl 6-methylene-1,4-oxazepane-4-carboxylate (Preparation 79, 107 g, 0.5 mol, 1 eq) in THF (300 mL). The reaction mixture was heated to 25° C. and stirred at this temperature for 3 h. Then the reaction mixture was cooled to 0-10° C. and treated at this temperature sequentially with 3N sodium hydroxide (170 mL) and 30% hydrogen peroxide (66 mL). The obtained homogenous mixture was stirred overnight, then treated with hexane (45 mL), and dried over potassium carbonate. The organic layer was decanted from the precipitate, which was washed with DCM. The organic layers were evaporated in vacuo, and the residue was purified rapidly (due to instability of the product on silica gel) by chromatography (carbon tetrachloride/chloroform/isopropanol 100:0:0→0:100:0→0:90:10) on silica gel (1.2 kg; 63-100 μm) to give title compound as a colorless oil in (85 g, 0.368 mol, 72%).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([OH:13])=O)=[CH:8][CH:9]=2)[N:4]=[CH:3][CH:2]=1.S(Cl)([Cl:16])=O>C1COCC1>[N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([Cl:16])=[O:13])=[CH:8][CH:9]=2)[N:4]=[CH:3][CH:2]=1
Reactant: O=C(O)c1ccc2nccnc2c1
Reactant: O=S(Cl)Cl
Solvent: C1CCOC1
Product: O=C(Cl)c1ccc2nccnc2c1

Procedure:
In a 1 l 3 neck flask was placed Quinoxaline-6-carboxylic acid (20.2 g) in 500 ml of THF. To this solution was slowly added thionylchloride (42 ml, Seq.). The reaction mechanically stirred was warmed up to reflux and followed by HPLC quenching the sample with NH4OH. After 3 h at reflux no more starting material was present, the solvent was removed under reduced pressure and SOCl2 was chased with toluene 3 times. The solid was suspended in 100 ml EtOAc and filtered to obtain 23.47 g of a beige solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:31]([N:32]2[CH2:36][CH2:35][C:34]([F:38])([F:37])[CH2:33]2)=[CH:30][C:8]2[N:9]([CH3:29])[C:10]([NH:12][C:13]3[C:18]([Cl:19])=[CH:17][CH:16]=[C:15]([CH2:20][NH:21][C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])[C:14]=3[Cl:28])=[N:11][C:7]=2[CH:6]=1)=[O:4].[OH-].[Na+]>CCO>[Cl:28][C:14]1[C:15]([CH2:20][NH:21][C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:16][CH:17]=[C:18]([Cl:19])[C:13]=1[NH:12][C:10]1[N:9]([CH3:29])[C:8]2[CH:30]=[C:31]([N:32]3[CH2:36][CH2:35][C:34]([F:37])([F:38])[CH2:33]3)[C:5]([C:3]([OH:4])=[O:2])=[CH:6][C:7]=2[N:11]=1
Reactant: COC(=O)c1cc2nc(Nc3c(Cl)ccc(CNC(=O)C(C)(C)C)c3Cl)n(C)c2cc1N1CCC(F)(F)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cn1c(Nc2c(Cl)ccc(CNC(=O)C(C)(C)C)c2Cl)nc2cc(C(=O)O)c(N3CCC(F)(F)C3)cc21
Temperature: 50 °C
Reaction time: 2 h

Procedure:
A mixture of 2-{2,6-dichloro-3-[(2,2-dimethyl-propionylamino)-methyl]-phenylamino}-6-[3,3-difluoro-pyrrolidinyl]-1-methyl-1H-benzimidazole-5-carboxylic acid methyl ester (2.37 g, 4.17 mmol), 2 N NaOH-solution (9.8 ml) and EtOH (20 ml) is stirred for 1 h at rt and for 2 h at 50° C. and concentrated. Water is added and it is filtered. The filtrate is acidified with 4N HCl (pH 5) and the precipitate is filtered, washed with water and dried.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[Cl:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][C:19]=1[Cl:20])[C:14](Cl)=[O:15].CCN(CC)CC>CC#N>[Cl:10][C:11]1[CH:12]=[C:13]([C:14]([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH2:3][CH2:2]2)=[O:15])[CH:17]=[CH:18][C:19]=1[Cl:20]
Reactant: c1ccc2c(c1)CCN2
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C(c1ccc(Cl)c(Cl)c1)N1CCc2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of indoline (2.0 mL, 17.8 mmol) in MeCN (45.0 mL) was added 3,4-dichlorobenzoyl chloride (4.11 g, 19.6 mmol) followed by Et3N (7.5 mL, 53.5 mmol) at 0° C. The reaction mixture was stirred at room temperature for 1 h and then concentrated in vacuo. The residue was triturated with water and dried under high vacuum to give the title compound (5.2 g, 100%) as a light brown solid. 1H NMR (DMSO-d6) δ 7.89 (d, J=1.1 Hz, 1H), 7.77 (d, J=8.1 Hz, 1H), 7.60 (d, J=8.1 Hz, 1H), 7.29 (d, J=7.3 Hz, 1H), 7.19 (m, 1H), 7.06 (t, J=7.2 Hz, 1H), 4.00 (t, J=8.3 Hz, 2H), 3.09 (t, J=8.3 Hz, 2H); MS(ESI+) m/z 292.1 (M+H)+.
Reaction SMILES: [C:1]1([P:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH2:21][C:22](=[O:29])[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25]>C1COCC1.O>[O:29]=[C:22]([CH:21]=[P:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CCOC(=O)CC(=O)CCl
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
triphenylphosphine (30.0 g, 114.3 mmol) is added, at ambient temperature, to a solution of commercial ethyl 4-chloro-3-oxobutanoate (18.81 g, 114.3 mmol) in 200 mL of anhydrous THF. The reaction medium is taken to reflux for 18 h before being concentrated under vacuum. The oil obtained is taken up in distilled water then washed with ether. The aqueous phase is then basified by a saturated aqueous solution of NaHCO3 (up to pH 8). After extraction with AcOEt, the organic phases are combined, dried over MgSO4, filtered then concentrated under vacuum. Purification is carried out by recrystallization from ether in order to produce, after filtration and drying, compound 5′-2 (14.96 g, 38.0 mmol, 34%) in the form of a slightly yellow solid.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:17]([N+:18]([O-:20])=[O:19])=[C:16]([O:21][CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[N:15]=[CH:14][N:13]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Br[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=1.C(N(CC)CC)C>CN(C=O)C>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:17]([N+:18]([O-:20])=[O:19])=[C:16]([O:21][CH:22]3[CH2:27][CH2:26][N:25]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=4)[CH2:24][CH2:23]3)[N:15]=[CH:14][N:13]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: Brc1ccccn1
Reactant: CS(=O)(=O)c1ccc(Nc2ncnc(OC3CCNCC3)c2[N+](=O)[O-])cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)c1ccc(Nc2ncnc(OC3CCN(c4ccccn4)CC3)c2[N+](=O)[O-])cc1
Temperature: 165 °C

Procedure:
Compound A2 (0.13 mmol, 50 mg), and 2-bromo-pyridine (0.53 mmol, 53 μL) were dissolved in DMF (1 mL) and triethylamine (0.46 mmol, 63 μL). The reaction was heated in a microwave at 165° C. for 40 minutes. The mixture was quenched with water and extracted with ethyl acetate. Removal of organic solvent in vacuo and purification by prep-TLC provided Compound A9 as a yellow solid (12 mg, 20%). 1H NMR (400 MHz, CDCl3) δ (ppm): 10.10 (s, 1H), 8.35 (s, 1H), 8.13 (m, 1H), 7.89 (d, 2H), 7.81 (d, 2H), 7.42 (m, 1H), 6.64 (d, 1H), 6.55 (m, 1H), 5.58 (heptet, 1H), 3.78 (m, 2H), 3.60 (m, 2H), 3.00 (s, 3H), 2.02 (m, 2H), 1.91 (m, 2H). LCMS (ESI), m/z 471.4 (M+H+, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8](=O)[CH2:9][C:10]#[N:11])[CH:5]=[CH:6][CH:7]=1.O.[NH2:14][NH2:15]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([NH2:11])[NH:14][N:15]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: N#CCC(=O)c1cccc(Cl)c1
Reactant: NN
Solvent: O
Solvent: CCO
Product: Nc1cc(-c2cccc(Cl)c2)n[nH]1
Temperature: 80 °C
Reaction time: 15 h
Yield: 71.2 %

Procedure:
To a stirring solution of 3-(3-chlorophenyl)-3-oxo-propionitrile (2 g, 11.1 mmol) in absolute ethanol (20 mL) was added hydrazine hydrate (3.24 mL, 67 mmol). The reaction mixture was stirred at 80° C. for 15 h, cooled to room temperature, concentrated in vacuo, and absorbed on silica gel. Purification on silica gel with 0-10% MeOH in CH2Cl2 as eluent provided 1.53 g (70%) of 5-(3-chloro-phenyl)-2H-pyrazol-3-ylamine as a green solid. 1H NMR (d6-DMSO) δ: 11.6 and 11.9 (2 broad s, 1H, NH+tautomer), 7.69 (s, 1H), 7.60 (d, 1H), 7.38 (t, 1H), 7.29 (d, 1H), 5.77 (broad s, 1H), 4.98 (broad s, 2H, NH2).
Reaction SMILES: [OH:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][CH:7]([C:18]([O:20]C(C)(C)C)=[O:19])[CH2:8][C@@H:9]([C:11]([O:13]C(C)(C)C)=[O:12])[NH2:10])=[CH:4][CH:3]=1>FC(F)(F)C(O)=O.C1(C)C=CC=CC=1>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C@@H:7]([C:18]([OH:20])=[O:19])[CH2:8][C@@H:9]([C:11]([OH:13])=[O:12])[NH2:10])=[CH:25][CH:26]=1
Reactant: CC(C)(C)OC(=O)C(Cc1ccc(O)cc1)C[C@H](N)C(=O)OC(C)(C)C
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: N[C@@H](C[C@@H](Cc1ccc(O)cc1)C(=O)O)C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Di-tert-butyl 4-(4-hydroxybenzyl)-L-glutamate (27 mg, 58 μmol) was dissolved in trifluoroacetic acid (1 ml) and stirred at room temperature for 2 h. The mixture was then taken up in toluene and concentrated under reduced pressure. The residue was purified by preparative HPLC (RP-18; solvents: acetonitrile (+0.1% trifluoroacetic acid), water (+0.1% trifluoroacetic acid); gradient: 30%->40% acetonitrile (20 min)).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH2:14][C:13]3([CH2:18][CH2:17][N:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:15]3)[O:12][N:11]=2)[CH:5]=[CH:6][CH:7]=1.ClC1C=C(C#CC2C[C:36]3(CCNC3)[O:35]N=2)C=CC=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH2:14][C:13]3([CH:18]([O:35][CH3:36])[CH2:17][N:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:15]3)[O:12][N:11]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)N1CCC2(CC(C#Cc3cccc(Cl)c3)=NO2)C1
Reactant: Clc1cccc(C#CC2=NOC3(CCNC3)C2)c1
Product: CCOC(=O)N1CC(OC)C2(CC(C#Cc3cccc(Cl)c3)=NO2)C1

Procedure:
The title compound was synthesized following the method herein described for the compound of Example 112 but replacing Compound 126a for Compound 27d. After the usual work-up procedure the crude was purified by means of automated flash chromatography (SP01®TM-Biotage; gradient Petroleum Ether-EtOAc from 8:2 to 1:1) giving the title compound. Yield: 52.6%.