Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:6]=[C:7]([NH:11][C:12]2[N:17]=[CH:16][N:15]=[C:14]([N:18]3[CH2:34][CH2:33][C:21]4([CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]4)[CH2:20][CH2:19]3)[N:13]=2)[CH:8]=[CH:9][CH:10]=1)=[O:4].[C:35]([OH:41])([C:37]([F:40])([F:39])[F:38])=[O:36]>C(Cl)Cl>[CH2:25]1[C:21]2([CH2:20][CH2:19][N:18]([C:14]3[N:15]=[CH:16][N:17]=[C:12]([NH:11][C:7]4[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=4)[C:3]([NH:2][CH3:1])=[O:4])[N:13]=3)[CH2:34][CH2:33]2)[CH2:22][CH2:23][NH:24]1.[C:35]([OH:41])([C:37]([F:40])([F:39])[F:38])=[O:36]
Reactant: CNC(=O)c1cccc(Nc2ncnc(N3CCC4(CCN(C(=O)OC(C)(C)C)C4)CC3)n2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNC(=O)c1cccc(Nc2ncnc(N3CCC4(CCNC4)CC3)n2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a flask charged with tert-butyl 8-(4-(3-(methylcarbamoyl)phenylamino)-1,3,5-triazin-2-yl)-2,8-diazaspiro[4.5]decane-2-carboxylate (300 mg, 0.642 mmol) was added DCM (5 mL), and TFA (494 mL, 6.42 mmol) respectively. The resulting mixture was stirred overnight at RT. The reaction mixture was concentrated, and the resulting solid was triturated with ethyl acetate to obtain 3-(4-(2,8-diazaspiro[4.5]decan-8-yl)-1,3,5-triazin-2-ylamino)-N-methylbenzamide as a bis-TFA salt (233 mg, 99% yield) as white solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([Cl:12])=[N:4][N:3]=1.[CH3:13][O:14][C:15]1[CH:24]=[C:23]2[C:18]([CH:19]=[CH:20][C:21]([OH:25])=[CH:22]2)=[CH:17][CH:16]=1.[Cl-].[Al+3].[Cl-].[Cl-]>ClCCCl>[Cl:12][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([C:22]2[C:23]3[C:18](=[CH:17][CH:16]=[C:15]([O:14][CH3:13])[CH:24]=3)[CH:19]=[CH:20][C:21]=2[OH:25])=[N:3][N:4]=1
Reactant: Clc1nnc(Cl)c2ccccc12
Reactant: COc1ccc2ccc(O)cc2c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: COc1ccc2ccc(O)c(-c3nnc(Cl)c4ccccc34)c2c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 78.8 %

Procedure:
In a 1 L flask under nitrogen were mixed 1,4-dichlorophthalazine (11.4 g, 57.3 mmol) with 7-methoxy-naphthalen-2-ol (10.0 g, 57.5 mmol). To this was added 1,2-dichloroethane (450 ml). After stirring for 10 min, aluminum chloride (7.64 g, 57.4 mmol) was added. The resulting suspension was stirred for 20 hrs at 80° C. After cooling to room temperature, the black suspension was poured on ice-water (500 ml) and stirred for 1 hr. The two layers were separated. The aqueous layer was extracted with dichloromethane (3×200 ml). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The crude solid was triturated with dichloromethane (35 ml) for 1 hr and collected by filtration to give 15.2 g of the title compound as a grey solid. (Yield: 80%)
Reaction SMILES: [CH:1]1([CH:7]([CH3:10])[CH:8]=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[O:11]=O>>[CH:1]1([CH:7]([CH3:10])[C:8]([OH:11])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=O
Reactant: CC(C=O)C1CCCCC1
Product: CC(C(=O)O)C1CCCCC1
Yield: 35 %

Procedure:
Into a 500 ml round bottom flask was charged 300 g of 2-cyclohexylpropanal and was fed a stream of oxygen at a rate of 100 ml per minute at 60° C. for 80 hours through a sintered liquid filter for liquid chromatography. The reaction mixture was analyzed by means of gas chromatography and confirmed that 2-cyclohexylpropionic acid was obtained in an yield of 65% and 35% of the 2-cyclohexylpropanal remained unreacted in the reaction mixture.
Reaction SMILES: [C:1](O)(=O)[CH2:2][C:3]([OH:5])=[O:4].C(=O)/[CH:9]=[CH:10]/[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.N1CCCCC1.Cl>N1C=CC=CC=1>[CH:1](=[CH:2][C:3]([OH:5])=[O:4])[CH:9]=[CH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(O)CC(=O)O
Reactant: O=C/C=C/c1ccccc1
Agent: Cl
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: O=C(O)C=CC=Cc1ccccc1
Temperature: 115 °C
Reaction time: 26 h

Procedure:
Cinnamylidene acetic acid was synthesized according to the method described in U.S. Pat. No. 3,257,664, the disclosure of which is incorporated herein by reference. In general, 104 gms of malonic acid (Aldrich), 126 ml of trans-cinnamaldehyde and 90 ml of pyridine were mixed and exposed to slight heating for complete solubilization of the reaction mixture. Piperidine (0.25 ml) was then added, and the mixture was allowed to stand at room temperature for approximately 26 hours. The reaction mixture was then refluxed at 115° C. for 18 hours. When the reaction was completed, the reaction mixture was allowed to cool to room temperature. In turn, the solution was poured into cold dilute (5 w/v %) hydrochloric acid. The resulting yellowish solid cake was washed repeatedly with deionized water, and the wet product was crystallized from ethyl alcohol to give cinnamylidene acetic acid (65.22 gms). The purity of cinnamylidene acetic acid was determined by 1HNMR and UV spectroscopy. 1HNMR (CDCl3-TMS): δ=6.1 ppm (d, 2H), δ=6.9 ppm (t, 2H), δ=7.5 ppm (m, 5H). The —COOH proton could not be detected in the NMR spectrum, but the product of the esterification reaction between cinnamylidene acetic chloride and polyethylene glycol established its existence. UV (in dichloromethane): λmax=313 nm, ε=37,390 L3mol−1cm−1, λmin=250 nm, ε=1985 L3mol−1cm−1.
Reaction SMILES: [C:1]([NH:3][C:4](=[N:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[NH:16][CH:15]=[N:14][C:13]=1[CH3:17])SC)#[N:2].[NH2:18][CH2:19][CH2:20][NH:21][CH3:22]>>[C:1]([NH:3][C:4]([NH:18][CH2:19][CH2:20][NH:21][CH3:22])=[N:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[NH:16][CH:15]=[N:14][C:13]=1[CH3:17])#[N:2]
Reactant: CSC(=NCCSCc1[nH]cnc1C)NC#N
Reactant: CNCCN
Product: CNCCNC(=NCCSCc1[nH]cnc1C)NC#N
Reaction time: 15 h

Procedure:
N-Cyano-N'-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]-S-methylisothiourea (5.4 g) and (2-aminoethyl)methylamine (25 ml) were mixed together and left for 15 hours at 20° C. Evaporation to dryness and azeotroping with acetonitrile to remove excess diamine gave a solid residue which was recrystallised from isopropanol to give the title compound (4.8 g), m.p. 146°-148° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:11][C@@H:12]2[CH2:17][O:16][C@@H:15]([CH2:18][OH:19])[CH2:14][CH2:13]2)=[C:4]2[S:10][CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1.[C:20](OCC)(OCC)(OCC)[CH3:21]>C(O)(=O)C.CO>[CH3:20][C:21]1[N:11]([C@@H:12]2[CH2:17][O:16][C@@H:15]([CH2:18][OH:19])[CH2:14][CH2:13]2)[C:3]2=[C:4]3[S:10][CH:9]=[CH:8][C:5]3=[N:6][CH:7]=[C:2]2[N:1]=1
Reactant: CCOC(C)(OCC)OCC
Reactant: Nc1cnc2ccsc2c1N[C@H]1CC[C@H](CO)OC1
Solvent: CO
Solvent: CC(=O)O
Product: Cc1nc2cnc3ccsc3c2n1[C@H]1CC[C@H](CO)OC1
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 42.2 %

Procedure:
To a solution of {(2R,5S)-5-[(6-aminothieno[3,2-b]pyridin-7-yl)amino]tetrahydro-2H-pyran-2-yl}methanol (131 mg, 0.469 mmol) in acetic acid (1.3 mL) was added triethyl orthoacetate (275 μL, 1.50 mmol). The mixture was stirred at 120° C. for 30 min. After cooling to room temperature, the mixture was diluted with methanol and purified with prep-LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) to give the desired product as white solid (60 mg, 42%). LCMS calculated for C15H18N3O2S (M+H)+: m/z=304.1. Found: 304.1.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH:7]=[C:6]([CH3:8])[CH2:5][CH2:4][CH:3]1[C:9](=O)[CH3:10].N1C=CC=CC=1.Cl.[CH3:20][O:21][NH2:22]>CO>[CH3:20][O:21][N:22]=[C:9]([CH:3]1[CH2:4][CH2:5][C:6]([CH3:8])=[CH:7][C:2]1([CH3:12])[CH3:1])[CH3:10]
Reactant: CC(=O)C1CCC(C)=CC1(C)C
Reactant: CON
Agent: Cl
Solvent: CO
Solvent: c1ccncc1
Product: CON=C(C)C1CCC(C)=CC1(C)C
Temperature: 24 °C
Reaction time: 16 h
Yield: 92.4 %

Procedure:
To a stirred solution of 1-(2,2,4-trimethyl-cyclohex-3-enyl)-ethanone (162 g; 0.97 mol), prepared as described in example P4, in methanol (500 ml) was added pyridine (160 ml; 1.95 mol) followed by a portionwise addition of methoxyamine hydrochloride (142 g; 1.70 mol). The reaction mixture was stirred at 24° C. for 16 hours under nitrogen atmosphere. Methanol was removed under reduced pressure, the residue poured in water (600 ml) and 1N hydrochloric acid was added (100 ml). The solution was extracted with dichloromethane (3×300 ml). Combined organic layers were washed with brine (500 ml) and dried over sodium sulfate. The solvent was removed in vacuo to afford 175 g (92% of theory) of 1-(2,2,4-trimethyl-cyclohex-3-enyl)-ethanone O-methyl-oxime as a clear red oil.
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][CH:5]=1.[Cl:12][C:13]1[CH:18]=[C:17]([C:19]([C:21]([F:24])([F:23])[F:22])=[CH2:20])[CH:16]=[C:15]([Cl:25])[CH:14]=1>C1(C)C=CC=CC=1>[Cl:12][C:13]1[CH:18]=[C:17]([C:19]2([C:21]([F:24])([F:22])[F:23])[O:1][N:2]=[C:3]([C:4]3[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][CH:5]=3)[CH2:20]2)[CH:16]=[C:15]([Cl:25])[CH:14]=1
Reactant: C=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Reactant: Cc1ccc(C(Cl)=NO)cc1
Solvent: Cc1ccccc1
Product: Cc1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1

Procedure:
A solution of 4-methylbenzaldehyde oxime (2 g) and N-chlorosuccinimide (2.17 g) in dimethylformamide (20 mL) was stirred for one hour at 55° C. After the reaction solution was diluted with t-butylmethylether, the solution was washed with water and saturated brine. The organic layer was dried over-anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain N-hydroxy-4-methylbenzene carboximidoyl chloride (2 g). A solution of resultant N-hydroxy-4-methylbenzene carboximidoyl chloride and 1,3-dichloro-5-[1-(trifluoromethyl)-vinyl]benzene (5.3 g) in toluene (50 mL) was heated to reflux for 8 hours. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography to obtain [5-(3,5-dichlorophenyl) 3-(4-methylphenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole (5.0 g).
Reaction SMILES: [CH:1](O)=[O:2].C(OC(=O)C)(=O)C.Cl.[NH2:12][CH2:13][C:14]1[N:19]=[C:18]([N:20]2[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]2)[C:17]([C:33]([O:35][CH3:36])=[O:34])=[CH:16][CH:15]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH:1]([NH:12][CH2:13][C:14]1[N:19]=[C:18]([N:20]2[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]2)[C:17]([C:33]([O:35][CH3:36])=[O:34])=[CH:16][CH:15]=1)=[O:2]
Reactant: COC(=O)c1ccc(CN)nc1N1CCN(C(=O)OC(C)(C)C)CC1
Reactant: O=CO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)OC(C)=O
Product: COC(=O)c1ccc(CNC=O)nc1N1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 48 h
Yield: 99.6 %

Procedure:
Formic acid (2.2 mL, 58 mmol) and acetic anhydride (5.2 mL, 58 mmol) were stirred at room temperature for 1 hour. The mixture was added dropwise to a solution of tert-butyl 4-[6-(aminomethyl)-3-(methoxycarbonyl)pyridin-2-yl]piperazine-1-carboxylate hydrochloride (4.9 g, 13 mmol) in methylene chloride (90 mL) at 0° C. and stirred for 48 hours. Evaporation gave the crude material which was treated with sodium bicarbonate and extracted with methylene chloride to give the desired compound (4.9 g, 100%). LCMS calculated for C18H27N4O5 (M+H)+: m/z=379.2. found: 378.9.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH2:12])(=[O:11])=[O:10].[Cl:13][C:14]1[CH:19]=[CH:18][C:17](/[CH:20]=[CH:21]/[S:22](Cl)(=[O:24])=[O:23])=[C:16]([O:26][CH3:27])[CH:15]=1>>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([S:9]([NH2:12])(=[O:11])=[O:10])=[C:2]([NH:1][S:22](/[CH:21]=[CH:20]/[C:17]2[CH:18]=[CH:19][C:14]([Cl:13])=[CH:15][C:16]=2[O:26][CH3:27])(=[O:23])=[O:24])[CH:7]=1
Reactant: Nc1cc(Cl)ccc1S(N)(=O)=O
Reactant: COc1cc(Cl)ccc1/C=C/S(=O)(=O)Cl
Product: COc1cc(Cl)ccc1/C=C/S(=O)(=O)Nc1cc(Cl)ccc1S(N)(=O)=O
Yield: 100 %

Procedure:
The title compound was synthesized as described for Example 226 a) in 100% yield, starting from 2-amino-4-chlorobenzenesulfonamide and (E)-2-(4-chloro-2-methoxyphenyl)ethenesulfonyl chloride.
Reaction SMILES: [N:1]([CH:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=2[N:6]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:5]1=[O:21])=[N+]=[N-].[H][H]>[Pd].C(O)C>[NH2:1][CH:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=2[N:6]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:5]1=[O:21]
Reactant: [H][H]
Reactant: CCOC(=O)CN1C(=O)C(N=[N+]=[N-])CCc2ccccc21
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CN1C(=O)C(N)CCc2ccccc21

Procedure:
The reaction mixture of 3-azido-1-ethoxycarbonylmethyl-2,3,4,5-tetrahydro-1H[1]-benzazepin-2-one (13.98 kg) and 5% palladium on carbon (1.3 kg) in anhydrous ethanol (57 liters) was hydrogenated under 3 atmospheres pressure of hydrogen for 5 hours. The pressure reactor was vented at hourly intervals to remove the accumulated nitrogen. The catalyst was removed by filtration and washed with ethyl alcohol. The solution was evaporated to dryness to give 3-amino-1-ethoxycarbonylmethyl-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](S(C)=O)[C:5]([C:11]#[N:12])=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])[N:3]=1.[OH:21][CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:3]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])[C:5]([C:11]#[N:12])=[C:6]([O:21][CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)[N:7]=1
Reactant: COc1ccccc1-c1nc(N)nc(S(C)=O)c1C#N
Reactant: OCCc1ccccn1
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: COc1ccccc1-c1nc(N)nc(OCCc2ccccn2)c1C#N

Procedure:
From 2-amino-4-methanesulfinyl-6-(2-methoxy-phenyl)-pyrimidine-5-carbonitrile, 2-(2-hydroxyethyl)pyridine and DBU in DME. ES-MS m/e (%): 348 (M+H+, 100).
Reaction SMILES: [CH3:1][C:2]([CH3:24])=[CH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:9][CH:8]=1)=[O:5].[Cl-].[Al+3].[Cl-].[Cl-].O>C(Cl)Cl>[CH3:24][C:2]1([CH3:1])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH:13]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:11]=2)[NH:6][C:4](=[O:5])[CH2:3]1
Reactant: CCCCCC(C(=O)OCC)c1ccc(NC(=O)C=C(C)C)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: CCCCCC(C(=O)OCC)c1ccc2c(c1)C(C)(C)CC(=O)N2

Procedure:
1 g of (RS)-ethyl 2-[4-(3,3-dimethylacrylamido)-phenyl]-heptanoate was dissolved in 10 ml of methylene chloride and treated with 1.2 g of aluminium chloride. The mixture was heated to reflux for 6 hours. The mixture was poured onto 25 ml of iced water and then was extracted with two portions of 25 ml of methylene chloride. The combined extracts were washed with two portion of 25 ml of saturated aqueous sodium bicarbonate solution and one portion of 25 ml of saturated aqueous sodium chloride solution. The organic phase was dried over MgSO4 and concentrated in vacuo. The product was purified by flash chromatography (SiO2, 20% ethyl acetate/hexanes). 1H NMR (CDCl3): 8.92 (br. s, 1H), 7.21 (d, J=1.9 Hz, 1H), 7.13 (dd, J=8.1, 1.9 Hz, 1H), 6.78 (d, J=8.1 Hz, 1H), 4.20-4.00 (m, 2H), 3.48 (t, J=7.7 Hz, 1H), 2.48 (s, 2H), 2.10-1.90 (m, 1H), 1.80-1.65 (m, 1H), 1.35-1.15 (m, 6H), 1.33 (s, 3H), 1.32 (s, 3H), 1.22 (t, J=7.1 Hz, 3H), 0.86 (t, J=6.6 Hz, 3H).
Reaction SMILES: [CH2:1]([O:4][C:5]1[C:13]([Br:14])=[CH:12][C:8]([C:9]([OH:11])=O)=[C:7]([Cl:15])[CH:6]=1)[CH:2]=[CH2:3].Cl.[CH3:17][NH:18][O:19][CH3:20].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>C(Cl)Cl>[CH2:1]([O:4][C:5]1[C:13]([Br:14])=[CH:12][C:8]([C:9]([N:18]([O:19][CH3:20])[CH3:17])=[O:11])=[C:7]([Cl:15])[CH:6]=1)[CH:2]=[CH2:3]
Reactant: CNOC
Reactant: C=CCOc1cc(Cl)c(C(=O)O)cc1Br
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: C=CCOc1cc(Cl)c(C(=O)N(C)OC)cc1Br
Temperature: 25 °C
Reaction time: 15 h
Yield: 95.6 %

Procedure:
To a suspension of 4-(allyloxy)-5-bromo-2-chlorobenzoic acid 21 (5.0 g, 17.2 mmol) in CH2Cl2 (50 mL) were added N,O-dimethylhydroxylamine HCl (2.1 g, 20.6 mmol), EDCI (4.9 g, 25.8 mmol), HOBT (4.7 g, 34.4 mmol) and NMM (9.5 mL, 86.0 mmol). The reaction mixture was stirred at rt for 15 hours and evaporated in vacuo to remove volatiles. The mixture was extracted with EtOAc/H2O (100 mL/100 mL). The organic layer was dried over MgSO4, filtered and concentrated in vacuo. The residue was triturated with hexane (100 mL) and stirred at r.t. for 30 min. The solid was precipitated, filtered, washed with hexane (50 mL) and dried under high vacuum to obtain the desired product (5.5 g, 95%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][C:3]=1[C:12]([F:15])([F:14])[F:13].F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.CN(C)C=O.[NH2:54][C:55]1[CH:64]=[CH:63][CH:62]=[C:61]2[C:56]=1[CH:57]=[CH:58][N:59]([C@H:66]([CH3:70])[C:67]([NH2:69])=[O:68])[C:60]2=[O:65]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:54][C:55]2[CH:64]=[CH:63][CH:62]=[C:61]3[C:56]=2[CH:57]=[CH:58][N:59]([C@H:66]([CH3:70])[C:67]([NH2:69])=[O:68])[C:60]3=[O:65])=[O:11])=[CH:4][C:3]=1[C:12]([F:15])([F:14])[F:13]
Reactant: O=C(O)Cc1ccc(Cl)c(C(F)(F)F)c1
Reactant: C[C@H](C(N)=O)n1ccc2c(N)cccc2c1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@H](C(N)=O)n1ccc2c(NC(=O)Cc3ccc(Cl)c(C(F)(F)F)c3)cccc2c1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A round bottom flask was charged with 2-(4-chloro-3-(trifluoromethyl)phenyl)acetic acid (0.13 g, 0.00056 mol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (0.3 g, 0.0009 mol), N,N-diisopropylethylamine (0.2 mL, 0.0009 mol), N,N-dimethylformamide (3 mL, 0.04 mol) and (R)-2-(5-amino-1-oxoisoquinolin-2(1H)-yl)propanamide (0.1 g, 0.0004 mol). The reaction was stirred at room temperature for 16 h. The solvent was removed under reduced pressure and the residue purified by flash chromatography (12 g, 0-10% MeOH/DCM) to get the product as white solid. MS m/z=451.8(M+H). 1H NMR (400 MHz; DMSO-d6) δ 10.10 (s, 1H), 8.07(d, J=8.42 Hz, 1H), 7.89 (s, 1H), 7.82 (d, J=8.47 Hz, 1H) 7.73-7.68 (m, 2H), 7.63 (s, 1H), 7.46 (d, J=7.57 Hz, 2H), 7.23 (bs, 1H), 6.68 (d, J=8.02 Hz, 1H), 5.50-5.45 (q, J=7.24 Hz, 1H), 3.92 (s, 2H), 1.54 (d, J=7.66 Hz, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:13]=[CH:12][C:11]([CH3:14])=[C:10]2[C:5]=1[CH:6]([C:19]1[CH:20]=[CH:21][CH:22]=[C:23]3[C:28]=1[O:27][C:26]([CH3:29])=[CH:25][C:24]3=[O:30])[C:7]([C:16](O)=[O:17])=[C:8]([CH3:15])[NH:9]2)[CH3:2].C(OCC)(=O)C.C(N1C=CN=C1)([N:39]1C=CN=C1)=O.N>CN(C=O)C>[CH2:1]([O:3][C:4]1[N:13]=[CH:12][C:11]([CH3:14])=[C:10]2[C:5]=1[CH:6]([C:19]1[CH:20]=[CH:21][CH:22]=[C:23]3[C:28]=1[O:27][C:26]([CH3:29])=[CH:25][C:24]3=[O:30])[C:7]([C:16]([NH2:39])=[O:17])=[C:8]([CH3:15])[NH:9]2)[CH3:2]
Reactant: CCOc1ncc(C)c2c1C(c1cccc3c(=O)cc(C)oc13)C(C(=O)O)=C(C)N2
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: N
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOc1ncc(C)c2c1C(c1cccc3c(=O)cc(C)oc13)C(C(N)=O)=C(C)N2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
335.0 mg (0.824 mmol) of the compound from Example 41A are introduced into 10 ml of ethyl acetate, and 167.1 mg (0.537 mmol) of 1,1′-carbonyldiimidazole are added. The suspension is then stirred at room temperature overnight. Since a clear solution is not produced, 2 ml of DMF are added and the mixture is stirred at room temperature for a further two hours. Complete conversion is then established by TLC check. The volatile components are removed in a rotary evaporator, and the residue is taken up in 4 ml of DMF. Then 2.293 ml of ammonia (28% by weight solution in water, 16.5 mmol) and 10.1 mg of 4-N,N-dimethylaminopyridine are added. The reaction mixture is heated at 100° C. in a closed vessel for thirty minutes. After cooling, the solvent is removed under reduced pressure, and the residue is purified by preparative HPLC (eluent: acetonitrile/water with 0.1% formic acid, gradient 20:80→95:5). The product fractions are concentrated and the residue is taken up in a little dichloromethane, and diisopropyl ether is added until the solution is cloudy. The precipitated solid is isolated and dried in vacuo. 207 mg (59% of theory) of the title compound are obtained.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)=[CH:4][C:3]=1[C:17](=[O:25])[NH:18][C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1.[CH3:26][NH:27][CH2:28][C:29]1[N:30]([CH3:34])[CH:31]=[N:32][CH:33]=1>>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12](=[O:14])[N:27]([CH3:26])[CH2:28][C:29]3[N:30]([CH3:34])[CH:31]=[N:32][CH:33]=3)=[CH:10][CH:9]=2)=[CH:4][C:3]=1[C:17]([NH:18][C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1)=[O:25]
Reactant: CNCc1cncn1C
Reactant: Nc1ncc(-c2ccc(C(=O)O)cc2)cc1C(=O)Nc1ccncc1
Product: CN(Cc1cncn1C)C(=O)c1ccc(-c2cnc(N)c(C(=O)Nc3ccncc3)c2)cc1

Procedure:
Reaction of 4-[6-amino-5-(pyridin-4-ylcarbamoyl)-pyridin-3-yl]-benzoic acid with methyl-(3-methyl-3H-imidazol-4-ylmethyl)-amine gives “A95”; method 1: HPLC/MS: 1.07 min, [M+H]=442;
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][C:10](Cl)=[O:11].[Br:13][C:14]1[CH:15]=[C:16]2[CH:22]=[CH:21][NH:20][C:17]2=[N:18][CH:19]=1.[Al+3].[Cl-].[Cl-].[Cl-]>C(Cl)Cl>[Br:13][C:14]1[CH:15]=[C:16]2[C:22]([C:10](=[O:11])[CH2:9][C:3]3[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=3[F:1])=[CH:21][NH:20][C:17]2=[N:18][CH:19]=1
Reactant: O=C(Cl)Cc1cccc(F)c1F
Reactant: Brc1cnc2[nH]ccc2c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(Cc1cccc(F)c1F)c1c[nH]c2ncc(Br)cc12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 98.4 %

Procedure:
2,3-Difluorophenylacetyl chloride(58.1 mmol) in CH2Cl2 (150 ml)was added to a suspension of 5-bromo-1H-pyrrolo[2,3-b]pyridine (8.0 g, 40.6 mmol) and AlCl3 (46 g, 345 mmol) in CH2Cl2 (100 ml) at 0° C. After the addition, the cooling bath was removed and the reaction mixture was stirred at room temperature for 1.5 hrs. The reaction was cooled with ice-bath and methanol (100 ml) was added to the reaction mixture while maintaining the temperature below 30° C. The reaction mixture was evaporated and the residue was suspended in water. The solid was collected by vacuum filtration, washed with water and hexane to give the title compound (14.03 g) in 98% yield.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[OH-].[K+].Cl[CH2:12][C:13]1[CH:27]=[CH:26][C:16]([C:17]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:18])=[CH:15][CH:14]=1.Cl>O.CO>[OH:8][C:5]1[CH:6]=[CH:7][C:2]([S:1][CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:17]([NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:18])=[CH:26][CH:27]=2)=[CH:3][CH:4]=1
Reactant: O=C(Nc1ccccc1)c1ccc(CCl)cc1
Reactant: Oc1ccc(S)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(Nc1ccccc1)c1ccc(CSc2ccc(O)cc2)cc1
Temperature: 10 °C
Reaction time: 3 h
Yield: 84.4 %

Procedure:
In a 200 ml four-necked flask equipped with a stirrer and a thermometer, 1.34 g (10.6 mmol) of 4-mercaptophenol, 0.7 g (10.6 mmol) of potassium hydroxide and 50 ml of methanol were added at room temperature. After confirming that potassium hydroxide has been dissolved, the inner temperature was cooled to 10° C. and 2.6 g (10.6 mmol) of 4-chloromethyl-N-phenylbenzamide was added, followed by stirring at room temperature for 3 hours. After the completion of the reaction, the reaction solution was acidified with hydrochloric acid and 50 ml of water was added, and then the deposited crystal was collected by filtration to obtain 3.0 g of 4-(4-hydroxyphenylthiomethyl)-N-phenylbenzamide. The yield was 84%. The melting point was 220–222° C.