Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][O:6][CH2:7][C:8]([OH:10])=O.[CH3:11][NH:12][C:13](=[O:31])[CH2:14][NH:15][C:16](=[O:30])[C:17]1[C:22]([I:23])=[C:21]([NH2:24])[C:20]([I:25])=[C:19]([C:26]([OH:28])=[O:27])[C:18]=1[I:29]>CC(N(C)C)=O>[CH3:11][NH:12][C:13](=[O:31])[CH2:14][NH:15][C:16](=[O:30])[C:17]1[C:22]([I:23])=[C:21]([NH:24][C:8](=[O:10])[CH2:7][O:6][CH3:5])[C:20]([I:25])=[C:19]([C:26]([OH:28])=[O:27])[C:18]=1[I:29]
Reactant: COCC(=O)O
Reactant: CNC(=O)CNC(=O)c1c(I)c(N)c(I)c(C(=O)O)c1I
Solvent: CC(=O)N(C)C
Solvent: O=S(Cl)Cl
Product: CNC(=O)CNC(=O)c1c(I)c(NC(=O)COC)c(I)c(C(=O)O)c1I
Temperature: 0 °C
Reaction time: 2 h

Procedure:
At maximally 10° C., 29.0 ml. of thionyl chloride is added dropwise under agitation to 28.2 ml. of methoxyacetic acid in 100 ml. of dimethylacetamide within 40 minutes. After, at 0° C., the reaction mixture has been agitated for another 2 hours, 63.0 g. (0.1 mole) of N-(3-carboxy-5-amino-2,4,6-triiodobenzoyl)-glycine methylamide (IVa), m.p. 252°-253° C. (decomposition), in 100 ml. of dimethylacetamide is added dropwise under agitation to the reaction mixture at maximally 8° C. during the course of one hour. Then, the solution is agitated overnight. After the addition of 5 ml. of water, the mixture is concentrated under vacuum, the residue is stirred with 700 ml. of water, the precipitate is vacuum-filtered, carefully washed with water, and, while still moist, reprecipitated from dilute ammonia with concentrated hydrochloric acid. After allowing the mixture to stand for some time, the acid is vacuum-filtered, washed well with water, stirred with fresh water, and, after another filtering step, dried under vacuum at 70° C.
Reaction SMILES: N[C:2]1[C:7]([Br:8])=[CH:6][C:5]([Cl:9])=[CH:4][N:3]=1.[OH2:10]>>[Br:8][C:7]1[C:2](=[O:10])[NH:3][CH:4]=[C:5]([Cl:9])[CH:6]=1
Reactant: Nc1ncc(Cl)cc1Br
Reactant: O
Product: O=c1[nH]cc(Cl)cc1Br
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a cooled (0° C.) solution of 2-amino-3-bromo-5-chloropyridine (100 g, 0.482 tool) in water (815 mL) and concentrated HC1 (130 mL) was added a solution of sodium nitrite (33.26 g, 0.482 tool) in water (272 mL). The resulting suspension was allowed to warm to room temperature and stir for 18 hours, at which point the solids were filtered, washed with carbon tetrachloride (2×50 mL), and dried in a vacuum oven (40° C.) to yield 75.1 g (74.8%) of gray-yellow so lid, m.p. 170°-173° C.: IR (mineral oil (Nujol (trademark ) ) 3111, 3041, 2947, 2850, 2722, 1814, 1696, 1663, 1643, 1585, 1527, 1462, 1377, 1302, 1234, 1171, 1153, 1123, 1106, 1040, 917, 896, 876, 839, 747, 726, 644, 635, 561, 539, 523, 410, 251, 235, 225, 220cm-1 ; 1H NMR (300 MHz, D6 -DMSO)δ 7.72 (d, 1H, J=2.2Hz) , 8.08 (d, 1H , J=2 . 2Hz ), 12.41 (br s, 1H); 13C NMR (DMSO) δ 110.88, 115.35, 134.08, 142.64, 157.56; exact mass calculated for C5H3NBrClO=206.9086. High resolution mass spec. 206.9093.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][C:9]1[CH:14]=[C:13]([CH:15]=O)[CH:12]=[C:11]([Cl:17])[C:10]=1[F:18])([CH3:4])([CH3:3])[CH3:2].[CH3:20][O:21][CH2:22][CH2:23][NH:24][CH3:25].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1>[C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][C:9]1[CH:14]=[C:13]([CH2:15][N:24]([CH2:23][CH2:22][O:21][CH3:20])[CH3:25])[CH:12]=[C:11]([Cl:17])[C:10]=1[F:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: CNCCOC
Reactant: CC(C)(C)OC(=O)NCc1cc(C=O)cc(Cl)c1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COCCN(C)Cc1cc(Cl)c(F)c(CNC(=O)OC(C)(C)C)c1

Procedure:
was prepared according to Scheme C2 (step C) from (3-chloro-2-fluoro-5-formyl-benzyl)-carbamic acid tert-butyl ester (200 mg, 0.59 mmol), N-methoxyethyl-methylamine (74 mg, 0.83 mmol), acetic acid (0.06 mL, 1.0 mmol) and sodium triacetoxyborohydride (368 mg, 1.7 mmol) in THF (8 mL). MS (LC-MS): 362.3 [M+H]+; tR (HPLC conditions c): 4.04 min.
Reaction SMILES: Cl.[CH3:2][O:3][NH:4][CH3:5].Cl.C(N=C=NCCCN(C)C)C.[F:18][C:19]1[CH:27]=[C:26]([N+]([O-])=O)[CH:25]=[CH:24][C:20]=1[C:21]([OH:23])=O>N1C=CC=CC=1>[F:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21]([N:4]([O:3][CH3:2])[CH3:5])=[O:23]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1F
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: c1ccncc1
Product: CON(C)C(=O)c1ccccc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5.79 g of N-methoxy-N-methylamine hydrochloride and 12.4 g of 1-ethyl-3-(3′-dimethylaminopropyl)-carbodiimide hydrochloride were added to a pyridine (80 ml) suspension of 10 g of 2-fluoro-4-nitrobenzoic acid, and the reaction liquid was stirred overnight at room temperature. Pyridine was evaporated away under reduced pressure, and water was added to it. The resulting deposit was taken out through filtration, washed with water, and dried to obtain the entitled compound as a pale yellow solid.
Reaction SMILES: [CH2:1]([N:4]1[CH:8]=[CH:7][N:6]=[C:5]1[C:9]1[S:10][CH:11]=[CH:12][C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[Cl:21])[CH:2]=[CH2:3].C([Li])CCC.CCCCCC.[I:33]I>C1COCC1>[CH2:1]([N:4]1[CH:8]=[CH:7][N:6]=[C:5]1[C:9]1[S:10][C:11]([I:33])=[CH:12][C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[Cl:21])[CH:2]=[CH2:3]
Reactant: II
Reactant: C=CCn1ccnc1-c1sccc1-c1ccc(Cl)cc1Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C=CCn1ccnc1-c1sc(I)cc1-c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.7 %

Procedure:
To a solution of 1-allyl-2-[3-(2,4-dichlorophenyl)-2-thienyl]-1H-imidazole (2.50 g, 7.46 mmol) in THF (80.0 mL) cooled to −78° C. was added dropwise 2.50 M of n-butyllithium in hexane (3.28 mL, 8.20 mmol) and the mixture was stirred for 30 min. To the solution was added dropwise a solution of iodine (2.84 g, 11.2 mmol) in THF (10.0 mL) and the resulting solution was stirred for 15 min at −78° C. The reaction mixture was quenched by addition of saturated sodium bisulfite solution (200 mL) and the resulting mixture was warmed to room temperature while stirring for 30 min. The mixture was extracted with EtOAc (3×250 mL) and the combined organic layers were washed with brine (200 mL). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO2, elution with 1-6% EtOAc in hexane) to give crude product which was further purified by column chromatography (SiO2, elution with 2% MeOH in DCM) to provide 2.57 g of product (71%). LC/MS (FA), ES+ 462. 1H NMR (400 MHz, d6-DMSO) δ: 7.30 (d, J=2.2 Hz, 1H), 7.09 (s, 1H), 6.97 (dd, J=2.2, 8:2 Hz, 1H), 6.75 (d, J=1.3 Hz, 1H), 6.71 (d, J=8.2 Hz, 1H), 6.60 (d, J=1.3 Hz, 1H), 5.10-5.21 (m, 1H), 4.60-4.65 (m, 1H), 4.35-4.41 (m, 1H), 3.80-3.85 (m, 2H).
Reaction SMILES: [CH3:1][NH2:2].[Br:3][C:4]1[CH:5]=[N:6][C:7](Cl)=[N:8][CH:9]=1>CO>[Br:3][C:4]1[CH:5]=[N:6][C:7]([NH:2][CH3:1])=[N:8][CH:9]=1
Reactant: CN
Reactant: Clc1ncc(Br)cn1
Solvent: CO
Product: CNc1ncc(Br)cn1
Yield: 100 %

Procedure:
40% Aqueous methylamine solution (35 ml) and methanol (20 ml) were added to 5-bromo-2-chloropyrimidine (3 g, 15.5 mmol) and the resulting mixture was heated to reflux for 3 days. The mixture was cooled, then the solvent was evaporated under reduced pressure, the residue was partitioned with methylene chloride and 1 M sodium hydroxide, the organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (3.0 g, 100%) as a white solid.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[N:6][CH:5]=[N:4]1.[F:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2([CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[CH2:17][O:16]2)=[CH:11][CH:10]=1>CC(N(C)C)=O>[F:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]([OH:16])([CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[CH2:17][N:3]2[CH:7]=[N:6][CH:5]=[N:4]2)=[CH:13][CH:14]=1
Reactant: C[Si](C)(C)CC1(c2ccc(F)cc2)CO1
Reactant: c1nc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: C[Si](C)(C)CC(O)(Cn1cncn1)c1ccc(F)cc1
Temperature: 0 °C
Yield: 55.2 %

Procedure:
0.237 g (6.18 mmole) of a 60% w/v dispersion of sodium hydride in mineral oil was added to 10 ml of dimethylacetamide. The mixture was then cooled in an ice-water bath, after which 0.854 g (12.37 mmole) of 1,2,4-triazole was added, whilst stirring. The reaction mixture was stirred for 30 minutes, and then 1.4 g (6.24 mmole) of 2-(4-fluorophenyl)-2-trimethylsilylmethyloxirane (prepared as described in Example 66) were added. The mixture was stirred for a further 2 hours at 80° C., after which it was cooled, and the mixture was poured into 50 ml of ice water and extracted with 100 ml of ethyl acetate. The organic extract was washed twice, each time with 50 ml of a saturated aqueous solution of sodium chloride, and then dried over anhydrous sodium sulfate. The solvent was then removed by distillation under reduced pressure, to obtain crude crystals These crystals were recrystallized from diisopropyl ether, to give 1.01 g (yield 55%) of the title compound, as crystals, melting at 118°-119° C.
Reaction SMILES: [OH:1][C:2]1[C:6](=[O:7])[O:5][CH:4]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:3]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[C:21](=O)([O-])[O-].[K+].[K+].CI.Cl>CN(C)C=O>[CH3:21][O:1][C:2]1[C:6](=[O:7])[O:5][CH:4]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:3]=1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)CCC1OC(=O)C(O)=C1c1ccccc1
Agent: Cl
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CCOC(=O)CCC1OC(=O)C(OC)=C1c1ccccc1

Procedure:
To a mixture of ethyl 3-(4-hydroxy-5-oxo-3-phenyl-2,5-dihydro-2-furyl)propionate (86 g) and potassium carbonate (51.62 g) in N,N-dimethylformamide (855 ml) was added dropwise methyl iodide (23.25 ml) at ambient temperature with stirring and the mixture was stirred for 2.5 hours at the same temperature. The solvent was evaporated in vacuo to give a residue which was poured into diluted hydrochloric acid and extracted with ethyl acetate. The extract was washed with water and brine successively and dried. Evaporation of the solvent gave ethyl 3-(4-methoxy-5-oxo-3-phenyl-2,5-dihydro-2-furyl)propionate which was recrystallized from diisopropyl ether (73.07 g).
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.Br[CH2:9][CH2:10][CH2:11][Cl:12].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:12][CH2:11][CH2:10][CH2:9][S:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1
Reactant: Sc1ccncc1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: ClCCCSc1ccncc1
Yield: 86.9 %

Procedure:
A mixture of 4-mercaptopyridine (5.0 g), 1-bromo-3-chloropropane (14.2 g), and anhydrous potassium carbonate in 250 mL acetone is refluxed under nitrogen for 1 hour. The mixture is cooled, filtered and concentrated. The residue is taken up into diethyl ether and washed with brine, dried over magnesium sulfate and evaporated in vacuo. The crude product is purified by column chromatography (silica; hexane: ethyl acetate, 50:50) to give the title compound (7.34 g) as a colorless oil which is used directly in further transformations.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[O:3][C:4]1[CH:23]=[CH:22][C:7]([O:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)=[CH:6][CH:5]=1.[H-].[Na+].Br[C:29]1[N:30]([CH2:37][C@:38]2([CH3:41])[CH2:40][O:39]2)[CH:31]=[C:32]([N+:34]([O-:36])=[O:35])[N:33]=1>CN(C)C=O>[CH3:40][C@@:38]1([CH2:41][O:21][C:18]2[CH:19]=[CH:20][C:15]([N:12]3[CH2:11][CH2:10][CH:9]([O:8][C:7]4[CH:22]=[CH:23][C:4]([O:3][C:2]([F:1])([F:24])[F:25])=[CH:5][CH:6]=4)[CH2:14][CH2:13]3)=[CH:16][CH:17]=2)[O:39][C:29]2=[N:33][C:32]([N+:34]([O-:36])=[O:35])=[CH:31][N:30]2[CH2:37]1
Reactant: Oc1ccc(N2CCC(Oc3ccc(OC(F)(F)F)cc3)CC2)cc1
Reactant: C[C@@]1(Cn2cc([N+](=O)[O-])nc2Br)CO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@]1(COc2ccc(N3CCC(Oc4ccc(OC(F)(F)F)cc4)CC3)cc2)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 72.5 °C
Reaction time: 0.33 h
Yield: 32.7 %

Procedure:
4-[4-(4-Trifluoromethoxyphenoxy)piperidin-1-yl]phenol (693 mg) was dissolved in N,N-dimethylformamide (3 ml), then under ice-cooling condition, sodium hydride (86 mg) was added, the reaction mixture was stirred at 70-75° C. for 20 minutes. The reaction mixture was ice-cooled, a solution prepared by dissolving (R)-2-bromo-4-nitro-1-(2-methyl-2-oxiranylmethyl)imidazole (720 mg) prepared in example 6 in N,N-dimethylformamide (3 ml) was added and stirred at 70-75° C. for 20 minutes. The reaction mixture was turned back to a room temperature, ice-water (25 ml) was added, and extracted 3 times with dichloromethane (50 ml). The organic layers were combined, after being washed with water 3 times, the organic layer was dried over anhydrous magnesium sulfate. After being filterated under a reduced pressure, the filtrate was concentrated, and the obtained residue was purified by use of a silica gel column chromatography (eluent: dichloromethane/ethyl acetate=3/1). Recrystallized from ethyl acetate/diisopropyl ether, there was obtained (R)-2-methyl-6-nitro-2-{4-[4-(4-trifluoromethoxyphenoxy)piperidin-1-yl]phenoxymethyl}-2,3-dihydroimidazo[2,1-b]oxazole (343 mg, yield: 33%) as pale yellow powder product.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][CH:8]=1)C.O.[NH2:18][NH2:19]>C(O)C>[NH:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:7]([CH2:6][CH2:5][C:4]([NH:18][NH2:19])=[O:3])=[CH:8]1
Reactant: NN
Reactant: CCOC(=O)CCc1c[nH]c2ccccc12
Solvent: CCO
Solvent: O
Product: NNC(=O)CCc1c[nH]c2ccccc12
Yield: 98 %

Procedure:
A solution of 3-(1H-Indol-3-yl)-propionic acid ethyl ester (4.30 g, 1 eq) and hydrazine hydrate (˜9.6 ml, 10 eq) in ethanol (70 ml) is heated at 60° C. overnight. The reaction mixture is concentrated under reduced pressure and diluted with methylene chloride. The new organic solution is washed with water, dried over MgSO4, filtered and evaporated to dryness, to afford the title compound as white solid (3.9 g, 98% yield), which is used as such for the next step.
Reaction SMILES: C1([NH:7][C:8]([C:10]2[C:11](=[O:29])[N:12]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:13]3[C:18]([C:19]=2O)=[CH:17][C:16]([F:21])=[CH:15][CH:14]=3)=O)CCCCC1.P(Cl)(Cl)([Cl:32])=O>>[CH2:22]([N:12]1[C:13]2[C:18](=[CH:17][C:16]([F:21])=[CH:15][CH:14]=2)[C:19]([Cl:32])=[C:10]([C:8]#[N:7])[C:11]1=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(NC1CCCCC1)c1c(O)c2cc(F)ccc2n(Cc2ccccc2)c1=O
Reactant: O=P(Cl)(Cl)Cl
Product: N#Cc1c(Cl)c2cc(F)ccc2n(Cc2ccccc2)c1=O
Yield: 47 %

Procedure:
A solution of Compound 42 (3.5 g, 8.86 mmol) in 30 mL neat phosphorus oxychloride was heated at 90° C. for 5 h. The solvent was evaporated under reduced pressure. The residue was suspended in ice water and neutralized by solid sodium bicarbonate. The solids formed were filtered, washed by water, and purified by flash chromatography eluting with 1% methanol in dichloromethane to yield 1.29 g (47%) of yellow solids. M.P. 228° C. 1H NMR (DMSO-d6): δ 5.29 (s, 2H), 7.27 (m, 4H), 7.32 (m, 2H), 7.58 (dd, J=4.3, 9.3 Hz, 1H), 7.71 (td, J=2.4, 8.0 Hz, 1H), 7.91 (dd, J=2.9, 8.9 Hz, 1H). EIMS m/z 335 (M+23).
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:11][N:10]([C:12]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:13]=3[C:14]#[N:15])[CH2:9][CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([CH:28]([NH2:30])[CH3:29])=[CH:24][C:23]=1[S:31]([CH3:34])(=[O:33])=[O:32]>C(#N)C.C(N(CC)C(C)C)(C)C>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([CH:28]([NH:30][C:2]2[C:3]3[CH2:11][N:10]([C:12]4[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:13]=4[C:14]#[N:15])[CH2:9][CH2:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH3:29])=[CH:24][C:23]=1[S:31]([CH3:34])(=[O:32])=[O:33]
Reactant: CC(N)c1ccc(Cl)c(S(C)(=O)=O)c1
Reactant: Cc1ccc(N2CCc3ncnc(Cl)c3C2)c(C#N)c1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(N2CCc3ncnc(NC(C)c4ccc(Cl)c(S(C)(=O)=O)c4)c3C2)c(C#N)c1

Procedure:
A reaction mixture of 2-(4-chloro-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-5-methylbenzonitrile (250 mg, 0.88 mmol) and 1-(4-chloro-3-(methylsulfonyl)phenyl)ethanamine (300 mg, 1.28 mmol) in acetonitrile (2 mL) and N,N-diisopropylethylamine (700 μL) was subjected to microwave irradiation at 185° C. for 3.5 h. The reaction mixture was concentrated and the residue was purified by preparative HPLC (100×20.2 mm, C18 column; 30-60% acetonitrile-water [10 mM Et2NH]) to afford a light yellow solid.
Reaction SMILES: Br[CH2:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[C:5]([O:11][CH3:12])[CH:4]=1.CO.[NH3:15].N.CO>C(Cl)Cl>[NH2:15][CH2:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[C:5]([O:11][CH3:12])[CH:4]=1
Reactant: N
Reactant: COc1cc(CBr)ccc1C#N
Solvent: CO
Solvent: ClCCl
Product: COc1cc(CN)ccc1C#N
Reaction time: 2 h

Procedure:
2.5 g of the bromide (b) were introduced into 10 ml of MeOH, and NH3 was passed in during dropwise addition of 38 ml of conc. ammonia/MeOH 1:1. After 2 h, the solvent was stripped off, the product was taken up in DCM and washed with water, and the organic phase was dried over Na2SO4. The product was precipitated as hydrochloride with ethereal HCl. 1H-NMR (DMSO-d6, δ in ppm): 8.6 (broad signal, NH3+), 7.79 (1H), 7.55 (1H), 7.20 (1H), 4.10 (s, 2H), 3.93 (s, 3H)
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([NH2:8])[N:5]2[N:9]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)[N:11]=[C:4]2[CH:3]=1.[C:18]1([OH:24])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN1CCCC1=O>[O:24]([C:2]1[CH:7]=[C:6]([NH2:8])[N:5]2[N:9]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)[N:11]=[C:4]2[CH:3]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Nc1cc(Br)cc2nc(-c3ccccn3)nn12
Reactant: Oc1ccccc1
Solvent: CN1CCCC1=O
Product: Nc1cc(Oc2ccccc2)cc2nc(-c3ccccn3)nn12

Procedure:
A mixture of 1 eq. 7-bromo-2-pyridin-2-yl-[1,2,4]triazolo[1,5-a]pyridin-5-ylamine, 5 eq. phenol and a catalytic amount of CS2CO3 in 200 μl N-methyl-pyrrolidon was heated for 2 h to 160°. The mixture was, after filtration, purified with reversed phase column chromatography eluting with an acetonitrile/water gradient yielding the title compound, MS m/e (%): 303 M+H+ (100%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[C@H:7]([NH2:22])[CH2:8][CH2:9][CH2:10][N:11]1[C:19](=[O:20])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]1=[O:21])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]2[CH:43]=[CH:42][C:41]([S:44](Cl)(=[O:46])=[O:45])=[CH:40][CH:39]=2)=[CH:34][CH:33]=1>ClCCl>[C:1]([O:5][C:6](=[O:23])[C@H:7]([NH:22][S:44]([C:41]1[CH:40]=[CH:39][C:38]([C:35]2[CH:36]=[CH:37][C:32]([Cl:31])=[CH:33][CH:34]=2)=[CH:43][CH:42]=1)(=[O:45])=[O:46])[CH2:8][CH2:9][CH2:10][N:11]1[C:12](=[O:21])[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:19]1=[O:20])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)[C@H](N)CCCN1C(=O)c2ccccc2C1=O
Reactant: O=S(=O)(Cl)c1ccc(-c2ccc(Cl)cc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)[C@@H](CCCN1C(=O)c2ccccc2C1=O)NS(=O)(=O)c1ccc(-c2ccc(Cl)cc2)cc1
Reaction time: 0.5 h
Yield: 52.9 %

Procedure:
A solution of the title H compound, (2R)-amino-5-(1,3-dioxo-1,3-dihydroisoindol-2-yl)pentanoic acid t-butyl ester (1.02 g, 3.19 mmol) and triethylamine (1.34 mL, 9.61 mmol) in 20 mL of dichloromethane is treated with the title 1 compound, 4′-chlorobiphenyl-4-sulfonyl chloride (0.92 g, 3.19 mmol) at 0° C. After stirring at this temperature for 30 min, then at RT for 16 h, the solution is washed with 35 mL of 2M aqueous HCl and the organic solution is washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. Chomatography on silica gel (eluant; ethyl acetate) affords 0.96 g (53%) of (2R)-(4′-chlorobiphenyl-4-sulfonylamino)-5-(1,3-dioxo-1,3-dihydroisoindol-2-yl)pentanoic acid t-butyl ester as a waxy, white solid: NMR(CDCl3) 1.21 (s, 9H), 1.60-1.68 (br m, 1H), 1.75-1.84 (br m, 3H), 3.68-3.74 (m, 2H), 3.82-3.92 (m, 1H), 5.24 (d, 1H, J=9.2), 7.44 (d, 2H, J=8.6), 7.49 (d, 2H, J=8.6), 7.65 (d, 2H, J=8.5), 7.70-7.74 (m, 2H), 7.83-7.86 (m, 2H), 7.92 (d, 2H, J=8.5); IR 1774, 1712, 1348, 1162; ESI-MS 569 (M++1).
Reaction SMILES: [C:1]([Mg]Br)#[CH:2].[CH3:5][N:6]1[CH:10]=[N:9][C:8]([C:11](=[O:13])[CH3:12])=[N:7]1>C1COCC1>[CH3:5][N:6]1[CH:10]=[N:9][C:8]([C:11]([OH:13])([C:1]#[CH:2])[CH3:12])=[N:7]1
Reactant: C#C[Mg]Br
Reactant: CC(=O)c1ncn(C)n1
Solvent: C1CCOC1
Product: C#CC(C)(O)c1ncn(C)n1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of ethynylmagnesium bromide (0.5M in THF, 4.32 mL, 2.16 mmol) at 0° C. was added 1-(1-methyl-1,2,4-triazol-3-yl)ethanone (180 mg, 1.44 mmol) in THF (5 mL) slowly. The reaction mixture was allowed to warm to RT and stirred for a further 1.5 hr. The reaction mixture was quenched with saturated aqueous NH4Cl solution (10 mL) and the organics were removed in vacuo. The product was extracted into EtOAc (×2) and the combined organics were dried (Na2SO4), filtered and concentrated in vacuo. Purification by column chromatography eluting with 2-10% methanol in DCM afforded the title compound: 1H NMR (500 MHz, CDCl3) delta 1.93 (3H, s), 2.62 (1H, s), 3.53 (1H, s), 3.93 (3H, s), 8.01 (1H, s); LC-MS: m/z=+152.0 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][NH2:9])=[CH:4][CH:3]=1.Cl.C(=O)([O-])[O-].[K+].[K+].C([O:19][CH:20]=[C:21]([C:27](OCC)=O)[C:22]([O:24][CH2:25][CH3:26])=[O:23])C>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:20](=[O:19])[C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:27][NH:9]2)=[CH:4][CH:3]=1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: NNc1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCOC(=O)c1c[nH]n(-c2ccc(F)cc2)c1=O
Temperature: 25 °C
Yield: 48.8 %

Procedure:
To a suspension of (4-fluorophenyl)hydrazine•hydrochloride (3 g, 18 mmol) and water (75 mL) were added potassium carbonate (5.6 g, 40 mmol) and diethyl ethoxymethylenemalonate (4.8 g, 22 mmol), and the mixture was heated under reflux for 7 hr. After cooling to room temperature, the mixture was washed with ethyl acetate. 6N Aqueous hydrochloric acid solution was added to the separated aqueous layer under ice-cooling. The precipitated solid was collected by filtration, washed with water and ethyl acetate/hexane (1/10), and dried under reduced pressure to give the title compound (2.2 g, 48%) as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([NH:13]C(=O)C)[C:10]([Cl:17])=[CH:9][C:4]=1[C:5]([O:7]C)=[O:6].[OH-].[Na+].Cl>C(O)C.O>[CH3:1][O:2][C:3]1[CH:12]=[C:11]([NH2:13])[C:10]([Cl:17])=[CH:9][C:4]=1[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1cc(Cl)c(NC(C)=O)cc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1cc(N)c(Cl)cc1C(=O)O
Yield: 84 %

Procedure:
25.75 grs (0.1 mol) methyl 2-methoxy-4-acetamido-5-chlorobenzoate were introduced into a 500 ml flask, suspended in 100 ml ethanol. 40 grs NaOH, dissolved in 150 cc of water, were added and the mixture was heated under reflux for 2.5 hours. The mixture was diluted with water and made acid with concentrated HCl. The white solid which precipitated was collected and recrystallized from methanol. Weight: 17 grs m.p. = 213°-215° C. Yield = 84%.
Reaction SMILES: C(N(CC)CC)C.[C:8]([C:10]1[CH:11]=[C:12]([CH:20]=[CH:21][N:22]=1)[CH2:13][C:14](=O)[CH2:15][C:16](=O)C)#[N:9].Cl.[F:24][C:25]1[CH:30]=[CH:29][C:28]([NH:31][NH2:32])=[CH:27][CH:26]=1>C(O)C>[C:8]([C:10]1[CH:11]=[C:12]([C:13]2[N:31]([C:28]3[CH:29]=[CH:30][C:25]([F:24])=[CH:26][CH:27]=3)[N:32]=[C:15]([CH3:16])[CH:14]=2)[CH:20]=[CH:21][N:22]=1)#[N:9]
Reactant: CC(=O)CC(=O)Cc1ccnc(C#N)c1
Reactant: NNc1ccc(F)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1cc(-c2ccnc(C#N)c2)n(-c2ccc(F)cc2)n1
Yield: 52.8 %

Procedure:
Triethylamine (4.6 mL, 0.033 mol) was added dropwise to a mixture of 1-(2-cyanoisonicotinyl)-1,3-butanedione (6.0 g, 0.032 mol) and 4-fluorophenylhydrazine hydrochloride (5.37 g, 0.033 mol) in 100 mL of ethanol. The reaction mixture was heated at reflux overnight (about eighteen hours). The solvent was removed and the residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated and the crude was purified by recrystallization from ether/hexane to give 4.7 g (53% yield) of product as a yellow solid: mp: 94-95° C.; Anal. Calc'd. for C16H11FN4: C, 69.06; H, 3.98; N, 20.13. Found: C, 68.52; H, 3.89; N, 19.73.