Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:15]2[N:14]([CH3:16])[C:13]3[C:12](=[O:17])[N:11]([CH3:18])[CH2:10][CH2:9][C:8]=3[C:7]=2[C:6]([C:19]([O:21]C2C=CC([N+]([O-])=O)=CC=2)=O)=[CH:5][CH:4]=1.[NH2:31][C:32]1[C:37]([Cl:38])=[CH:36][N:35]=[CH:34][C:33]=1[Cl:39].[H-].[Na+].Cl>>[Cl:39][C:33]1[CH:34]=[N:35][CH:36]=[C:37]([Cl:38])[C:32]=1[NH:31][C:19]([C:6]1[C:7]2[C:8]3[CH2:9][CH2:10][N:11]([CH3:18])[C:12](=[O:17])[C:13]=3[N:14]([CH3:16])[C:15]=2[C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[O:21]
Reactant: Nc1c(Cl)cncc1Cl
Reactant: COc1ccc(C(=O)Oc2ccc([N+](=O)[O-])cc2)c2c3c(n(C)c12)C(=O)N(C)CC3
Agent: Cl
Agent: [H-]
Agent: [Na+]
Product: COc1ccc(C(=O)Nc2c(Cl)cncc2Cl)c2c3c(n(C)c12)C(=O)N(C)CC3
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of p-nitrophenyl ester (from step 6) (1 mmol) and 4-amino-3,5-dichloropyridine (1.2 mmol), NaH (1.2 mmol) was added at once and the reaction mixture was stirred for 18 h at room temperature it was then acidified with few drops of 6N HCl. Desired amide precipitated out that was filtered and dried (80-90%).
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[C:3]=1[C:10]([O:12][CH3:13])=[O:11].C([Li])CCC.C[Si](Cl)(C)C.Cl>O1CCCC1.CCCCCC>[CH3:8][C:4]1([CH3:9])[CH2:5][CH2:6][CH2:7][C:2](=[CH2:1])[CH:3]1[C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)C1=C(C)CCCC1(C)C
Agent: C[Si](C)(C)Cl
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C=C1CCCC(C)(C)C1C(=O)OC
Reaction time: 0.17 h

Procedure:
A solution of methyl 2,6,6-trimethyl-cyclohex-1-ene-carboxylate (80.0 g) in tetrahydrofuran (THF, 640 ml), contained in a 1.5 l flask equipped with a mechanical strirrer and a nitrogen inlet, was deprotonated by adding, between -10° and 0°, a solution of butyllithium in hexane (411 ml of a 1.5M solution). Once the addition was completed, the reaction was allowed to proceed at 15°-17° for 10 min. The temperature was reduced to -30° and trimethylsilyl chloride (143.35 g) was added to the reaction mixture over half an hour, while maintaining the temperature at 10° or below. The temperature was allowed to increase to 20° and the reaction mixture was poured on 5% HCl. After stirring for 10 min, the mixture was extracted with ether and the organic phase was washed with saturated aqueous solutions of NaHCO3 and NaCl, dried over Na2SO4, filtered and the solvents evaporated. After distillation on a column filled with inox helices and equipped with a total reflux top, two fractions of a crude product were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl[S:11]([N:14]=C=O)(=[O:13])=[O:12].O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([O:9][S:11](=[O:13])(=[O:12])[NH2:14])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: Oc1ccc(Cl)c(Cl)c1
Solvent: O
Solvent: Cc1ccccc1
Product: NS(=O)(=O)Oc1ccc(Cl)c(Cl)c1
Yield: 82.2 %

Procedure:
A solution of 16.3 g (0.1 mole) of 3,4-dichlorophenol in 100 ml of toluene was heated at reflux utilizing a Dean-Stark trap to remove any water that may have been present. The solution was cooled in an ice bath, treated with 9.1 ml (14.8 g, 0.105 mole) of chlorosulfonyl isocyanate, and heated at reflux overnight. The solution was cooled in an ice bath, vigorously stirred, and treated dropwise with water until gas evolution ceased. The solid which precipitated was collected by filtration, washed with water and benzene, dried, and recrystallized from benzene to yield 19.9 g (82%) of a white solid, mp 121°-123° C.
Reaction SMILES: [C:1]([OH:4])(=O)[CH3:2].[C:5]([O:9][C:10]([C:12]1[C:20]2[CH2:19][CH:18]([CH2:21][NH2:22])[O:17][CH2:16][C:15]=2[S:14][C:13]=1[NH2:23])=[O:11])([CH3:8])([CH3:7])[CH3:6]>C(#N)C>[C:5]([O:9][C:10]([C:12]1[C:20]2[CH2:19][CH:18]([CH2:21][N:22]3[CH2:16][C:15]4[C:2](=[CH:21][CH:18]=[CH:19][CH:20]=4)[C:1]3=[O:4])[O:17][CH2:16][C:15]=2[S:14][C:13]=1[NH2:23])=[O:11])([CH3:8])([CH3:6])[CH3:7]
Reactant: CC(=O)O
Reactant: CC(C)(C)OC(=O)c1c(N)sc2c1CC(CN)OC2
Solvent: CC#N
Product: CC(C)(C)OC(=O)c1c(N)sc2c1CC(CN1Cc3ccccc3C1=O)OC2
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 62.4 %

Procedure:
Phthalic dicarboxaldehyde (52 mg, 0.36 mmol) was dissolved in a mixture of anhydrous acetonitrile (2 ml) and acetic acid (44 μl, 0.72 mmol). The above 2-amino-5-aminomethyl-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester (0.11 g, 0.36 mmol) was added and the reaction stirred for 20 minutes at room temperature. The volatiles were evaporated in vacuo and the residue dissolved in ethyl acetate (25 ml). The organic mixture was washed with saturated sodium bicarbonate (5 ml), 1% hydrochloric acid (5 ml), brine (5 ml), dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified by chromatography using a gradient from 15% ethyl acetateldichloromethane to 17% ethyl acetate/dichloromethane as eluent affording 45 mg (30%) of 2-amino-5-(1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester as a solid.
Reaction SMILES: [O:1]=[C:2]1[C:11]([C:12](O)=[O:13])=[CH:10][C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(Cl)(=O)C([Cl:24])=O.CN(C)C=O>ClCCl>[O:1]=[C:2]1[C:11]([C:12]([Cl:24])=[O:13])=[CH:10][C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cc2cccnc2n(-c2ccccc2)c1=O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1cc2cccnc2n(-c2ccccc2)c1=O
Temperature: 40 °C
Reaction time: 1 h

Procedure:
1.62 g (6.1 mmol) of 2-oxo-1-phenyl-1,2-dihydro-1,8-naphthyridine-3-carboxylic acid was dissolved in dichloromethane (60 mL), and 3.7 mL (44 mmol) of oxalyl chloride was added thereto. One droplet of N,N-dimethylformamide was added to the above mixture, and the resulting mixture was stirred for one hour at 40° C. The reaction mixture was concentrated under reduced pressure, and thus 2-oxo-1-phenyl-1,2-dihydro-1,8-naphthyridine-3-carboxylic acid chloride was obtained. The acid chloride thus obtained was dissolved in dichloromethane (60 mL), and 0.75 g (6.7 mmol) of 1,3-cyclohexanedione and 1.03 mL (7.3 mmol) of triethylamine were added to the above solution. The resulting mixture was stirred for 2 hours at room temperature. The reaction mixture was poured into an aqueous solution of sodium hydrogen carbonate, and the mixture was extracted with dichloromethane. The organic phase was dried and concentrated. The residue was washed with diisopropyl ether, and thus 2.16 g (yield: 99%) of the title compound was obtained as a light yellow solid.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[N:5]=1)([CH3:3])=[CH2:2].[Cl:11]N1C(=O)CCC1=O.C(Cl)(Cl)(Cl)Cl>CCCCCC>[Cl:11][CH2:2][C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[N:5]=1)=[CH2:3]
Reactant: O=C1CCC(=O)N1Cl
Reactant: C=C(C)c1cccc(C)n1
Solvent: CCCCCC
Solvent: ClC(Cl)(Cl)Cl
Product: C=C(CCl)c1cccc(C)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 33.9 %

Procedure:
A mixture of 4.7 g of 2-isopropenyl-6-methylpyridine, 4.7 g of N-chlorosuccinimide and 10 ml of carbon tetrachloride was stirred at 150° to 160° C. for 30 minutes. After the reaction mixture was cooled to room temperature, n-hexane was added thereto to remove the insoluble matter through filtration. After distilling off the solvent, the residue was purified by silica gel column chromatography (eluted with n-hexane-ethyl acetate 20:1). to obtain 2.0 g of the objective compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:48]2[CH:53]=[CH:52][C:51]([O:54][CH3:55])=[CH:50][CH:49]=2)([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[NH:10][C:11]2[CH2:12][O:13][CH2:14][C:15]([F:41])([F:40])[C@:16]([C:19]3[CH:24]=[C:23]([N:25]=C(C4C=CC=CC=4)C4C=CC=CC=4)[CH:22]=[CH:21][C:20]=3[F:39])([CH3:18])[N:17]=2)=[CH:5][CH:4]=1.Cl>O1CCOCC1>[NH2:25][C:23]1[CH:22]=[CH:21][C:20]([F:39])=[C:19]([C@:16]2([CH3:18])[C:15]([F:41])([F:40])[CH2:14][O:13][CH2:12][C:11]([NH:10][C:9]([C:48]3[CH:49]=[CH:50][C:51]([O:54][CH3:55])=[CH:52][CH:53]=3)([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=3)=[N:17]2)[CH:24]=1
Reactant: COc1ccc(C(NC2=N[C@](C)(c3cc(N=C(c4ccccc4)c4ccccc4)ccc3F)C(F)(F)COC2)(c2ccccc2)c2ccc(OC)cc2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: COc1ccc(C(NC2=N[C@](C)(c3cc(N)ccc3F)C(F)(F)COC2)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 23 °C
Reaction time: 3 h
Yield: 52.5 %

Procedure:
To a solution of (R)—N-(bis(4-methoxyphenyl)(phenyl)methyl)-5-(5-(diphenylmethyleneamino)-2-fluorophenyl)-6,6-difluoro-5-methyl-2,5,6,7-tetrahydro-1,4-oxazepin-3-amine (intermediate A9A) (3.55 g, 4.8 mmol) in dioxane (100 ml) at 23° C. was added 1 M hydrochloric acid (4.8 ml, 4.8 mmol) and the mixture was stirred at 23° C. for 3 h. The reaction mixture was concentrated in vacuum and the residue was purified by silica gel flash chromatography with n-heptane/ethyl acetate to give the [(R)-5-(5-amino-2-fluoro-phenyl)-6,6-difluoro-5-methyl-2,5,6,7-tetrahydro-[1,4]oxazepin-3-yl]-[bis-(4-methoxy-phenyl)-phenyl-methyl]-amine (1.45 g, 52%) as a white foam. MS (ISP): m/z=576.5 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9](=O)[CH2:10][C:11]([NH:13][C:14]2[CH:19]=[C:18]([N:20]3[CH:24]=[CH:23][CH:22]=[CH:21]3)[CH:17]=[CH:16][C:15]=2[N+:25]([O-])=O)=[O:12])[CH:6]=[CH:7][CH:8]=1)#[N:2].O.O.Cl[Sn]Cl>CCO>[O:12]=[C:11]1[CH2:10][C:9]([C:5]2[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=2)[C:1]#[N:2])=[N:25][C:15]2[CH:16]=[CH:17][C:18]([N:20]3[CH:24]=[CH:23][CH:22]=[CH:21]3)=[CH:19][C:14]=2[NH:13]1
Reactant: N#Cc1cccc(C(=O)CC(=O)Nc2cc(-n3cccc3)ccc2[N+](=O)[O-])c1
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: N#Cc1cccc(C2=Nc3ccc(-n4cccc4)cc3NC(=O)C2)c1

Procedure:
Alternatively, the title compound was also prepared from (3-(3-cyano-phenyl)-N-(2-nitro-5-pyrrol-1-yl-phenyl)-3-oxo-propionamide (Example M4) by reductive cyclization with SnCl2.2H2O in EtOH at 70° C. according to the general procedure J (method b). Obtained as an olive solid (161 mg).
Reaction SMILES: C(C(CC)CNCC1SC(C2C=C3C(=C(C(N)=O)C=2)NC=C3C2CCN(S(CC)(=O)=O)CC2)=CC=1)C.[CH:37]([C:39]1[S:43][C:42]([B:44]([OH:46])[OH:45])=[CH:41][CH:40]=1)=O.[CH3:47][C:48]([CH3:53])([CH3:52])[CH2:49][CH2:50][NH2:51].[BH3-]C#N.[Na+]>>[CH3:47][C:48]([CH3:53])([CH3:52])[CH2:49][CH2:50][NH:51][CH2:37][C:39]1[S:43][C:42]([B:44]([OH:46])[OH:45])=[CH:41][CH:40]=1
Reactant: CC(C)(C)CCN
Reactant: O=Cc1ccc(B(O)O)s1
Agent: CCC(CC)CNCc1ccc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)s1
Agent: [BH3-]C#N
Agent: [Na+]
Product: CC(C)(C)CCNCc1ccc(B(O)O)s1
Yield: 38.9 %

Procedure:
Following the general procedure of 5-(5-{[(2-ethylbutyl)amino]methyl}-2-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide, (5-formyl-2-thienyl)boronic acid (50 mg, 0.32 mmol), (3,3-dimethylbutyl)amine (32 mg, 0.32 mmol), and NaCNBH3 (40 mg, 0.64 mmol) were reacted to give 30 mg of crude (5-{[(3,3-dimethylbutyl)amino]methyl}-2-thienyl)boronic acid. The crude (5-{[(3,3-dimethylbutyl)amino]methyl}-2-thienyl)boronic acid was then reacted with 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (65 mg, 0.157 mmol), K2CO3 (130 mg, 0.942 mmol), and tetrakis(triphenylphosphine)palladium(0) (9 mg, 0.0079 mmol) to give 4.5 mg of the title compound (5%).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:13]([O-:15])=[O:14])=[C:6]([CH:8]2[O:12][CH2:11][CH2:10][O:9]2)[CH:7]=1.ClCCl.[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>>[O:9]1[CH2:10][CH2:11][O:12][CH:8]1[C:6]1[CH:7]=[C:2]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[CH:3]=[CH:4][C:5]=1[N+:13]([O-:15])=[O:14]
Reactant: O=[N+]([O-])c1ccc(Cl)cc1C1OCCO1
Reactant: C1COCCN1
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(N2CCOCC2)cc1C1OCCO1
Temperature: 25 °C
Yield: 97.1 %

Procedure:
2-(5-Chloro-2-nitrophenyl)-1,3-dioxolane (13.4 g, 58.4 mmol) was dissolved in morpholine (150 mL). The mixture was then heated to reflux for 16 hours. Cooling to room temperature, dichloromethane was added. The organic phase was washed with water, dried over anhydrous sodium sulfate, evaporated and purified by silica gel chromatography to afford the product 4-(3-(1,3-dioxolan-2-yl)-4-nitrophenyl)morpholine (15.9 g, yield 97.1%).
Reaction SMILES: [CH:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[C:6]([C:14]([O:16]CC)=[O:15])[C:5]1=[O:19])([CH3:3])[CH3:2].[OH-].[Na+].C(O)C>O>[CH:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[C:6]([C:14]([OH:16])=[O:15])[C:5]1=[O:19])([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1cc2ccccc2n(C(C)C)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)n1c(=O)c(C(=O)O)cc2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.3 %

Procedure:
A solution of 1.55 g of ethyl 1-isopropyl-2(1H)-quinolone-3-carboxylate and 0.28 g of sodium hydroxide in a solvent mixture of 10 ml of ethanol and 2 ml of water was stirred at room temperature overnight. The solvent was evaporated under reduced pressure, and after addition of dil. hydrochloric acid, the precipitated solid was collected by filtration, washed with water and dried to give 1.22 g of 1-isopropyl-2(1H)-quinolone-3-carboxylic acid. m.p. 168°-169° C. (ethyl acetate)
Reaction SMILES: [CH2:1]=O.[CH:3]([O:6][C:7](=[O:31])[CH:8]([NH2:30])[CH:9]([C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:20]=2)[NH:15][CH:14]=1)[CH2:10][O:11][CH3:12])([CH3:5])[CH3:4]>O.Cl>[CH:3]([O:6][C:7]([CH:8]1[CH:9]([CH2:10][O:11][CH3:12])[C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH:20]=3)[NH:15][C:14]=2[CH2:1][NH:30]1)=[O:31])([CH3:5])[CH3:4]
Reactant: COCC(c1c[nH]c2ccc(OCc3ccccc3)cc12)C(N)C(=O)OC(C)C
Reactant: C=O
Agent: Cl
Solvent: O
Product: COCC1c2c([nH]c3ccc(OCc4ccccc4)cc23)CNC1C(=O)OC(C)C
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 80.8 %

Procedure:
A solution is prepared from 3.8 g of 2-amino-3-(5-benzyloxyindol-3-yl)-4-methoxybutyric acid isopropyl ester (10 mmol) in 80 ml of xylene and added dropwise to a suspension of 360 mg of paraformaldehyde in 60 ml of xylene heated for 45 minutes to 100° C. The mixture is then refluxed for 2 hours on a water trap. After concentration, the residue is chromatographed over silica gel with methylene chloride:acetone=1:1 as the eluent, yielding 2.5 g of 6-benzyloxy-4-methoxymethyl-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid isopropyl ester (65% yield as an oil); or a suspension of 2.56 g of paraformaldehyde in 8 ml of water and 0.8 ml of concentrated hydrochloric acid is refluxed at 80° C. for 1 hour. One-tenth of the thus-obtained clear solution is added dropwise, after cooling to room temperature, to a solution of 3.8 g (10 mmol) of 2-amino-3-(5-benzyloxyindol-3 -yl)-4-methoxybutyric acid isopropyl ester in 500 ml of water and 10 ml of concentrated hydrochloric acid (pH=3). After 1/2 hour of agitation, an estimate of the amount of amino compound still remaining is made by thin-layer chromatography, and a corresponding quantity of formaldehyde solution is added. Thereupon, the mixture is stirred for another hour and then extracted twice by shaking with 50 ml of toluene, respectively. The organic phase is discarded. The aqueous phase is adjusted, after adding 100 ml of toluene, to a pH of 5.3 with 27% strength sodium hydroxide solution. After extraction by shaking, the mixture is additionally extracted by shaking twice with 50 ml of toluene; these 3 organic phases are combined, dried over sodium sulfate, filtered, and concentrated, thus obtaining 3.3 g (85%) of 6-benzyloxy-4-methoxymethyl-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid isopropyl ester as an oil.
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH2:12][CH2:13][N:14]=[N+]=[N-])[CH:10]=2)[NH:5][CH:4]=1)#[N:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[C:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH2:12][CH2:13][NH2:14])[CH:10]=2)[NH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1c[nH]c2ccc(CCN=[N+]=[N-])cc12
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: N#Cc1c[nH]c2ccc(CCN)cc12
Reaction time: 8 h
Yield: 98.3 %

Procedure:
A solution of 1.01 g (4.78 mmol) 3-cyano-5-(2-azidoethyl)indole (reference example 3) and 1.38 g (5.26 mmol) triphenylphosphine in 20 mL THF is stirred overnight to give a white precipitate. Another 20 mL THF and 1 mL distilled water is added. After stirring overnight the resulting solution is concentrated, and the residue chromatographed (10:1 CH2Cl2:7N NH3 in MeOH) to provide 0.870 g of the product as a white solid in 98% yield. 1H NMR (CD3OD): δ 2.87-2.97 (4H, m), 7.17 (1H, d, J=8 Hz), 7.45 (1H, d, J=8 Hz), 7.50 (1H, s), 7.90 (1H, s). MS (EI) m/z 185 M+, 169 (M−NH3)+, 155 (M−CH2NH2)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8]1)=[O:6].[F:17][C:18]1[C:26]([F:27])=[C:25]([F:28])[CH:24]=[CH:23][C:19]=1[C:20](Cl)=[O:21]>>[F:17][C:18]1[C:26]([F:27])=[C:25]([F:28])[CH:24]=[CH:23][C:19]=1[C:20]([NH:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:8][CH2:9][N:10]([CH3:13])[CH2:11][CH2:12]1)=[O:6])=[O:21]
Reactant: CN1CCC(C(=O)c2cccc(N)c2)CC1
Reactant: O=C(Cl)c1ccc(F)c(F)c1F
Product: CN1CCC(C(=O)c2cccc(NC(=O)c3ccc(F)c(F)c3F)c2)CC1

Procedure:
Beginning with 4-[3-aminobenzoyl]-1-methylpiperidine (25 mg, 0.115 mmol) and 2,3,4-trifluorobenzoyl chloride (29 μL, 0.229 mmol) and mixing for 24 h, 46.4 mg (>100%) of the title compound were recovered.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH3:31])[C:6]=1[C:7]1[CH:17]=[C:16]([NH:18][C:19](=[O:30])[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=2)[CH:15]=[CH:14][C:8]=1[O:9][CH2:10][C:11](O)=[O:12].C(N(CC)C(C)C)(C)C.[CH3:41][O:42][CH2:43][CH2:44][NH2:45]>ClCCl.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH3:31])[C:6]=1[C:7]1[CH:17]=[C:16]([NH:18][C:19](=[O:30])[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:27])([F:28])[F:29])[CH:21]=2)[CH:15]=[CH:14][C:8]=1[O:9][CH2:10][C:11]([NH:45][CH2:44][CH2:43][O:42][CH3:41])=[O:12]
Reactant: COCCN
Reactant: Cn1ncc(Cl)c1-c1cc(NC(=O)c2cccc(C(F)(F)F)c2)ccc1OCC(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COCCNC(=O)COc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1-c1c(Cl)cnn1C
Yield: 85.8 %

Procedure:
To a solution of 2-(2-(4-chloro-1-methyl-1H-pyrazol-5-yl)-4-(3-(trifluoromethyl)benzamido)phenoxy)acetic acid (0.060 g, 0.13 mmol) and N,N-diisopropylethylamine (0.034 g, 0.26 mmol) in dichloromethane (1.3 mL) was added BTU (0.075 g, 0.20 mmol) followed by 2-methoxyethylamine (0.015 g, 0.2 mmol). After 1.5 hours the reaction was diluted with ethyl acetate, washed with water, 1 M HCl (×3) and brine, dried over magnesium sulfate and concentrated. The residue was purified by flash chromatography (1:1-1:0 EtOAc/hexane) to give a white solid (57.0 mg, 84%). LCMS m/z (%)=511 (M+H, 35Cl, 100), 513 (M+H, 37Cl, 30). 1H NMR (400 MHz, CDCl3) δ 3.35 (s, 3H) 3.39-3.52 (m, 4H) 3.78 (s, 3H) 4.52 (s, 2H) 6.60 (br. s., 1H) 7.02 (d, J=9.09 Hz, 1H) 7.55 (s, 1H) 7.63-7.67 (m, 2H) 7.74 (dd, J=8.97, 2.91 Hz, 1H) 7.84 (d, J=6.82 Hz, 1H) 7.92 (s, 1H) 8.08 (d, J=6.57 Hz, 1H) 8.14 (s, 1H).
Reaction SMILES: C(OC([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([N:17]3[CH2:22][CH2:21][S:20](=[O:24])(=[O:23])[CH2:19][CH2:18]3)[CH:14]=2)[CH2:9]1)=O)(C)(C)C.[ClH:25]>>[ClH:25].[O:24]=[S:20]1(=[O:23])[CH2:19][CH2:18][N:17]([C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][CH:12]=2)[CH2:9][NH:8][CH2:16]3)[CH2:22][CH2:21]1
Reactant: CC(C)(C)OC(=O)N1Cc2ccc(N3CCS(=O)(=O)CC3)cc2C1
Agent: Cl
Product: O=S1(=O)CCN(c2ccc3c(c2)CNC3)CC1

Procedure:
Prepared in analogy to Example A3(e) from 5-(1,1-dioxo-1lambda*6*-thiomorpholin-4-yl)-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester and hydrochloric acid. Brown solid. MS (m/e): 253.1 ([M+H]+, 100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([CH:14]([CH3:16])[CH3:15])[C:12]#[N:13])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH2:27][CH2:28][N:29]2[CH2:34][CH2:33][CH2:32][CH:31]([CH2:35]Cl)[CH2:30]2)[CH:22]=[C:23]([O:25][CH3:26])[CH:24]=1.[Na+].[Cl-]>C1COCC1>[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH2:27][CH2:28][N:29]2[CH2:34][CH2:33][CH2:32][CH:31]([CH2:35][C:11]([C:5]3[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=3)([CH:14]([CH3:16])[CH3:15])[C:12]#[N:13])[CH2:30]2)[CH:22]=[C:23]([O:25][CH3:26])[CH:24]=1
Reactant: COc1cc(OC)cc(C(C#N)C(C)C)c1
Reactant: COc1cc(CCN2CCCC(CCl)C2)cc(OC)c1
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(CCN2CCCC(CC(C#N)(c3cc(OC)cc(OC)c3)C(C)C)C2)cc(OC)c1
Temperature: -50 °C
Reaction time: 0.33 h

Procedure:
The reaction mixture is stirred at -50° C. for 20 minutes, a solution of 2.75 g (0.0125 mol) of the nitrile prepared under (a) in 10 cc of THF is then added dropwise, the mixture is stirred again at -50° C. for 30 minutes and a solution of 3 g of the compound prepared under (b) in 10 cc of THF is then added. The reaction mixture is stirred for 1 hour at -50° C. and then left to stand overnight at ambient temperature. It is poured into 0.5 liter of a water/ice mixture, saturated with NaCl and extracted with diethyl ether. The organic phase is dried and evaporated. The oil obtained is chromatographed on a silica 60 column, elution being carried out with a 70/30 CH2Cl2 /acetone mixture.
Reaction SMILES: [OH-].[Na+].Cl[CH2:4][CH2:5][C:6]([OH:8])=[O:7].[C:9]([NH:12][C:13]1[CH:14]=[C:15]([OH:26])[CH:16]=[CH:17][C:18]=1[O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)(=[O:11])[CH3:10]>O>[C:9]([NH:12][C:13]1[CH:14]=[C:15]([CH:16]=[CH:17][C:18]=1[O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[O:26][CH2:4][CH2:5][C:6]([OH:8])=[O:7])(=[O:11])[CH3:10]
Reactant: O=C(O)CCCl
Reactant: CC(=O)Nc1cc(O)ccc1Oc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)Nc1cc(OCCC(=O)O)ccc1Oc1ccccc1
Yield: 31.7 %

Procedure:
8.0 g of sodium hydroxide was dissolved in 240 ml of water. In this solution was dissolved 24.3 g of 3-acetylamino-4-phenoxyphenol. Thereto was added 10.9 g of 3-chloropropionic acid. The mixture was refluxed for 30 minutes. The reaction mixture was water-cooled. The resulting crystal was removed by filtration. The filtrate was adjusted to pH 9 with 4N hydrochloric acid and washed with two 50-ml portions of ethyl acetate. The aqueous layer was separated, adjusted to pH 4 with 4N hydrochloric acid, and extracted with 200 ml of ethyl acetate. The extract (the organic layer) was washed with water and a saturated aqueous sodium chloride solution in this order, and dried with anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The resulting crystal was mixed with diethyl ether. The resulting crystal was collected by filtration to obtain 10.0 g (yield: 31.7%) of 3-(3-acetylamino-4-phenoxyphenoxy)propionic acid having a melting point of 138°-140° C.
Reaction SMILES: [NH2:1][C:2]1[N:16]=[CH:15][C:14](Br)=[CH:13][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1)=[O:5].[F:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][C:24]=1[C:25]([O:27][CH3:28])=[O:26]>>[CH3:28][O:27][C:25](=[O:26])[C:24]1[CH:23]=[CH:22][C:21]([C:14]2[CH:15]=[N:16][C:2]([NH2:1])=[C:3]([C:4](=[O:5])[NH:6][C:7]3[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=3)[CH:13]=2)=[CH:20][C:19]=1[F:18]
Reactant: Nc1ncc(Br)cc1C(=O)Nc1ccncc1
Reactant: COC(=O)c1ccc(B(O)O)cc1F
Product: COC(=O)c1ccc(-c2cnc(N)c(C(=O)Nc3ccncc3)c2)cc1F

Procedure:
Reaction of 2-amino-5-bromo-N-pyridin-4-yl-nicotinamide with 3-fluoro-4-methoxycarbonyl-phenylboronic acid gives “A80”; method 1: HPLC/MS: 1.48 min, [M+H]=367;