Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[NH2:5][C:6]1[N:11]=[C:10]([CH3:12])[C:9]([Br:13])=[CH:8][CH:7]=1.[OH-].[Na+]>S(=O)(=O)(O)O>[Br:13][C:9]1[CH:8]=[C:7]([N+:1]([O-:4])=[O:2])[C:6]([NH2:5])=[N:11][C:10]=1[CH3:12]
Reactant: Cc1nc(N)ccc1Br
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: Cc1nc(N)c([N+](=O)[O-])cc1Br
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Nitric acid (2.9 ml) was added dropwise to a solution of 6-amino-3-bromo-2-methylpyridine (7.2 g) in concentrated sulfuric acid (39 ml) under ice-cooling over 30 minutes, and the mixture was stirred at the same temperature for one hour. After further stirring at room temperature for one hour, the reaction solution was poured into ice water. A 50% aqueous sodium hydroxide solution was added, and the resulting precipitate was collected by filtration, washed with distilled water and then dried under reduced pressure to give the title compound (9.0 g).
Reaction SMILES: [OH-].[NH4+:2].[N:3]([CH2:6][CH2:7][CH2:8][S:9](Cl)(=[O:11])=[O:10])=[N+:4]=[N-:5]>C(O)C>[N:3]([CH2:6][CH2:7][CH2:8][S:9]([NH2:2])(=[O:11])=[O:10])=[N+:4]=[N-:5]
Reactant: [NH4+]
Reactant: [N-]=[N+]=NCCCS(=O)(=O)Cl
Agent: [OH-]
Solvent: CCO
Product: [N-]=[N+]=NCCCS(N)(=O)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 86 %

Procedure:
Ammonium hydroxide (28%) (10 mL) was added to a solution of 3-azido-1-propanesulfonyl chloride (˜2.29 g, 12.53 mmol; obtained in step 2) in ethanol (10 mL). The reaction mixture was stirred at room temperature for 3 h then concentrated. The residual material was passed through a short silica gel column using hexanes:ethyl acetate as eluent to isolate 3-azido-1-propanesulfonamide (1.5 g, 86%).
Reaction SMILES: Br[C:2]1[C:6]2[CH:7]=[N:8][C:9]([NH2:23])=[C:10]([O:11][C@@H:12]([C:14]3[C:19]([Cl:20])=[CH:18][CH:17]=[C:16]([F:21])[C:15]=3[Cl:22])[CH3:13])[C:5]=2[O:4][CH:3]=1.[CH:24]([C:26]1[S:30][C:29](B(O)O)=[CH:28][CH:27]=1)=[O:25].C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[NH2:23][C:9]1[N:8]=[CH:7][C:6]2[C:2]([C:29]3[S:30][C:26]([CH:24]=[O:25])=[CH:27][CH:28]=3)=[CH:3][O:4][C:5]=2[C:10]=1[O:11][C@@H:12]([C:14]1[C:19]([Cl:20])=[CH:18][CH:17]=[C:16]([F:21])[C:15]=1[Cl:22])[CH3:13]
Reactant: C[C@@H](Oc1c(N)ncc2c(Br)coc12)c1c(Cl)ccc(F)c1Cl
Reactant: O=Cc1ccc(B(O)O)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: C[C@@H](Oc1c(N)ncc2c(-c3ccc(C=O)s3)coc12)c1c(Cl)ccc(F)c1Cl

Procedure:
A mixture of 3-bromo-7-[(R)-1-(2,6-dichloro-3-fluorophenyl)-ethoxy]-furo[3,2-c]pyridine-6-ylamine (100.0 mg, 0.238 mmol), 5-formyl-2-thiopheneboronic acid (55.7 mg, 0.357 mmol), Pd(PPh3)4 (10.0 mg, 0.01 mmol), potassium carbonate (98.7 mg, 0.714 mmol) and 4:1 dioxane:water (10 mL) was heated to 90° C. overnight. The material was concentrated in vacuo, redissolved in DCM and transferred to a separatory funnel, extracting with sat. NaHCO3. The organic layer was dry-loaded onto silica gel for column chromatography, eluting with 2% MeOH/DCM. The fractions containing the pure product were concentrated in vacuo to afford the title compound as a yellow solid. 1H NMR (400 MHz, CD3OD): δ=1.90 (d, J=6.8 Hz, 3H), 6.53 (q, J=6.7 Hz, 1H), 7.20-7.25 (m, 1H), 7.41 (dd, J=8.8, 4.8 Hz, 1H), 7.59 (d, J=3.8 Hz, 1H), 7.94 (d, J=4.0 Hz, 1H), 8.13 (s, 1H), 8.28 (s, 1H), 9.89 (s, 1H). MS (ES+): m/z 450.92 (100) [MH+]. HPLC: tR=3.75 min (ZQ3, polar—5 min).
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[O:23]1[CH2:28][CH:27]=[C:26](B2OC(C)(C)C(C)(C)O2)[CH2:25][CH2:24]1.C([O-])([O-])=O.[Na+].[Na+].CCO>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[Br:1][C:2]1[C:3]([C:26]2[CH2:27][CH2:28][O:23][CH2:24][CH:25]=2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8]
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(Cl)c(Br)c1
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(C2=CCOCC2)c(Br)c1
Temperature: 70 °C
Reaction time: 18 h

Procedure:
5-Bromo-6-chloro-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 44.2, 462 mg, 1.11 mmol), 2-(3,6-dihydro-2h-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (262 mg, 1.22 mmol), Pd(Ph3P)4 (64.1 mg, 0.056 mmol), Na2CO3 (3 mL of 2 M, 5.99 mmol), EtOH (1 mL) and toluene (3 mL) were added to a vial, which was sealed, evacuated/purged with argon and the RM was stirred at 70° C. for 18 h. The RM was diluted with EtOAc, washed with brine, dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give the crude product which was purified by flash chromatography (RediSep® Silica gel column, 12 g, n-heptane/EtOAc, from 10% B to 100% EtOAc) to afford the title compound. HPLC (Condition 3) tR=6.04 min, UPLC-MS (Condition 2) m/z=443.1 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].Br[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CO>CN(C)C=O.[Cu]>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:6][N:7]=1
Reactant: Cc1ccc(O)cn1
Reactant: Brc1ccccc1
Agent: [Cu]
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CO
Solvent: CN(C)C=O
Product: Cc1ccc(Oc2ccccc2)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 6-methylpyridin-3-ol (25.2 g, 231 mmol) in N,N-dimethylformamide (100 ml) was added potassium tert-butoxide (25.9 g, 231 mmol), and the mixture was stirred at room temperature for 1 hr. The reaction solution was evaporated under reduced pressure and diluted with N,N-dimethylformamide (100 ml). A copper powder (3.7 g, 58 mmol) and bromobenzene (36.3 g, 231 mmol) were added, and the mixture was stirred at 120° C. overnight. Methanol was added to the reaction solution and insoluble material was filtered off using celite. The filtrate was diluted with water (500 ml) and the mixture was extracted with ethyl acetate (500 ml×2). The extract was washed successively with water and saturated brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to give the objective substance (31 g, 72%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C:10]([N:12]([CH2:28][CH:29]([CH3:31])[CH3:30])[C@H:13]3[CH2:18][C@@H:17]([CH2:19][OH:20])[CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14]3)=[O:11])[N:7]([CH2:32][CH2:33][CH2:34][CH2:35][O:36][CH3:37])[C:6]=2[CH:38]=1.[ClH:39].CO>>[ClH:39].[ClH:39].[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C:10]([N:12]([C@H:13]3[CH2:18][C@@H:17]([CH2:19][OH:20])[CH2:16][NH:15][CH2:14]3)[CH2:28][CH:29]([CH3:31])[CH3:30])=[O:11])[N:7]([CH2:32][CH2:33][CH2:34][CH2:35][O:36][CH3:37])[C:6]=2[CH:38]=1
Reactant: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](CO)CN(C(=O)OC(C)(C)C)C2)nc2ccc(F)cc21
Agent: Cl
Solvent: CO
Product: COCCCCn1c(C(=O)N(CC(C)C)[C@@H]2CNC[C@H](CO)C2)nc2ccc(F)cc21
Temperature: 25 °C
Reaction time: 72 h

Procedure:
tert-Butyl (3S,5R)-3-[{[6-fluoro-1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]-5-(hydroxymethyl)piperidine-1-carboxylate (182 mg) was dissolved in 10-20% hydrogen chloride-methanol (5 ml), and the mixture was stirred at room temperature for 3 days. The reaction mixture was concentrated to give the object product (169 mg).
Reaction SMILES: [CH2:1]([C:8]([C:23]#[N:24])([CH2:12][C:13](=[O:22])[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=1)C(O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>O.O1CCOCC1>[CH2:1]([CH:8]([CH2:12][C:13]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=1)=[O:22])[C:23]#[N:24])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#CC(CC(=O)c1ccc(Cl)c(Cl)c1)(Cc1ccccc1)C(=O)O
Solvent: O
Solvent: C1COCCO1
Product: N#CC(CC(=O)c1ccc(Cl)c(Cl)c1)Cc1ccccc1

Procedure:
A solution of 2-benzyl-2-cyano-4-oxo-4-(3,4-dichlorophenyl)-butanoic acid (5 g, 13.8 mmol) in 10% water/1,4-dioxane (250 ml) was refluxed for about 24 hours. The solvents were removed under reduced pressure and the residue was purified by flash chromatography, using cyclohexane/ethyl acetate 0÷15 as eluent. The title compound was obtained as a colourless solid (2.7 g, 62%) (m.p. 101°-102° C.)
Reaction SMILES: [CH2:1]([N:5]1[C:14]2[C:9](=[N:10][CH:11]=[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH:13]=2)[C:8]([OH:23])=[C:7]([C:24](OCC)=[O:25])[C:6]1=[O:29])[CH2:2][CH2:3][CH3:4].[NH2:30][CH2:31][C:32]([CH3:36])([CH3:35])[CH2:33][OH:34]>>[CH2:1]([N:5]1[C:14]2[C:9](=[N:10][CH:11]=[C:12]([CH2:15][C:16]3[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=3)[CH:13]=2)[C:8]([OH:23])=[C:7]([C:24]([NH:30][CH2:31][C:32]([CH3:36])([CH3:35])[CH2:33][OH:34])=[O:25])[C:6]1=[O:29])[CH2:2][CH2:3][CH3:4]
Reactant: CC(C)(CN)CO
Reactant: CCCCn1c(=O)c(C(=O)OCC)c(O)c2ncc(Cc3ccc(F)cc3)cc21
Product: CCCCn1c(=O)c(C(=O)NCC(C)(C)CO)c(O)c2ncc(Cc3ccc(F)cc3)cc21
Yield: 53 %

Procedure:
In a similar manner to that described in example 196, from ethyl 1-butyl-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (30 mg, 0.075 mmol) and 3-amino-2,2-dimethyl-1-propanol (0.05 mL) was prepared 1-butyl-7-[(4-fluorophenyl)methyl]-4-hydroxy-N-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide (18 mg, 53% yield) as a white solid after purification by reverse phase HPLC. 1H NMR (CDCl3) δ 10.51 (br s, 1 H), 8.56 (s, 1 H), 7.27 (s, 1 H), 7.17-7.13 (m, 2 H), 7.05-7.01 (m, 2 H), 4.14 (s, 2 H), 4.08 (m, 2 H), 3.39 (m, 1 H), 3.30 (m, 2 H), 3.22 (m, 2 H), 1.51 (m, 2 H), 1.33 (m, 2 H), 0.94 (s, 6 H), 0.90 (m, 3 H); MS m/z 456 M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:8](F)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[C:12]1([Mg]Br)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1COCC1>[C:12]1([S:8]([C:4]2[CH:3]=[C:2]([Br:1])[CH:7]=[CH:6][CH:5]=2)(=[O:10])=[O:9])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=S(=O)(F)c1cccc(Br)c1
Reactant: Br[Mg]c1ccccc1
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)c1cccc(Br)c1
Temperature: 25 °C
Yield: 87.8 %

Procedure:
To a stirred solution of 3-bromophenylsulfonyl fluoride (D1) (1 g, 4.18 mmol) in dry THF (20 ml) at −78° C., under argon was added phenylmagnesium bromide (1 M, 1.4 ml, 4.18 mmol) dropwise. The reaction was left to warm to room temperature overnight and then quenched with ammonium chloride (50 ml), extracted with ethyl acetate (3×40 ml) and the combined organic extracts dried (Na2SO4). Solvents were evaporated in vacuo to give a colourless solid (1.09 g, 88%).
Reaction SMILES: [C:1](Cl)(=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][S:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12](Cl)=[O:13].[Cl:21][C:22]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:23]=1[NH2:24]>ClCCl.N1C=CC=CC=1>[Cl:21][C:22]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:23]=1[NH:24][C:1](=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][S:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]([NH:24][C:23]1[CH:25]=[CH:26][C:27]([Cl:29])=[CH:28][C:22]=1[Cl:21])=[O:13]
Reactant: O=C(Cl)c1ccccc1SSc1ccccc1C(=O)Cl
Reactant: Nc1ccc(Cl)cc1Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1ccc(Cl)cc1Cl)c1ccccc1SSc1ccccc1C(=O)Nc1ccc(Cl)cc1Cl
Yield: 18.5 %

Procedure:
This compound was prepared according to the general method of Example 77 using 2,2'-dithiobisbenzoyl chloride (2.00 g, 5.83 mmol) in 50 mL of dichloromethane and 2,4-dichloroaniline (1.89 g, 11.7 mmol) in 15 mL of pyridine. The crude product was triturated with a hot mixture of ethyl acetate, ethanol and methanol (1:1:1) and filtered to yield 0.64 g of the title compound, mp 227-228° C.
Reaction SMILES: [C:1]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C(Cl)=O.[F:17][C:18]1[CH:23]=[CH:22][C:21]([O:24]C)=[CH:20][CH:19]=1.[Al+3].[Cl-].[Cl-].[Cl-]>ClCCl.CN(C=O)C>[F:17][C:18]1[CH:19]=[CH:20][C:21]([OH:24])=[C:22]([C:8](=[O:10])[CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:23]=1
Reactant: O=C(O)Cc1ccccc1
Reactant: COc1ccc(F)cc1
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cc1ccccc1)c1cc(F)ccc1O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 56 %

Procedure:
Phenylacetic acid (8.09 g, 59.46 mmoles) was dissolved in 15 ml dichloromethane. To this mixture, oxalylchloride (5.2 ml, 59.46 mmoles) and DMF (3 drops) were added at 0° C. and stirred for 30 min. The solvent was evaporated and dissolved in 15 ml dichloromethane. To this mixture, 4-fluoroanisole (5.0 g, 39.64 mmoles) was added and cooled to 0° C. At 0° C. AlCl3 (7.92 g, 59.46 mmoles) was added and the reaction mixture was warmed to RT and stirred for 12 h. The reaction mixture was quenched by the addition of 2N HCl, extracted with ethyl acetate, dried over sodium sulphate and concentrated. The crude product was purified by column chromatography with ethyl acetate:petroleum ether to afford the title compound as off-white solid (5.1 g, 56% yield. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): δ 11.43(s,1H), 7.77(dd, J=9.5,3.2Hz, 1H), 7.42(dt, J=8.7,3.2Hz, 1H), 7.33(t, J=7.3Hz, 2H), 7.26(m, 3H), 7.01(q, J=4.6 Hz, 1H),4.42(s, 2H).
Reaction SMILES: C([O:5][C:6]([CH2:8][NH:9][C:10]1[CH:11]=[C:12]([S:16]([NH2:19])(=[O:18])=[O:17])[CH:13]=[CH:14][CH:15]=1)=[O:7])(C)(C)C.[Cl:20][C:21]1[CH:22]=[C:23]([NH:31][C:32](OC2C=CC=CC=2)=[O:33])[C:24](=[CH:29][CH:30]=1)[C:25](OC)=[O:26]>>[C:6]([CH2:8][NH:9][C:10]1[CH:11]=[C:12]([S:16]([N:19]2[C:25](=[O:26])[C:24]3[C:23](=[CH:22][C:21]([Cl:20])=[CH:30][CH:29]=3)[NH:31][C:32]2=[O:33])(=[O:17])=[O:18])[CH:13]=[CH:14][CH:15]=1)([OH:5])=[O:7]
Reactant: COC(=O)c1ccc(Cl)cc1NC(=O)Oc1ccccc1
Reactant: CC(C)(C)OC(=O)CNc1cccc(S(N)(=O)=O)c1
Product: O=C(O)CNc1cccc(S(=O)(=O)n2c(=O)[nH]c3cc(Cl)ccc3c2=O)c1
Yield: 9 %

Procedure:
1.62 g (5.65 mmol) of 3-t-butoxycarbonylmethylaminobenzenesulfonamide and 1.73 g (5.65 mmol) of methyl 4-chloro-2-N-phenoxycarbonylanthranilate were treated in the same way as in Example 7 to obtain 209 mg (yield 9%: 4 steps) of the above-identified compound. Properties: colorless crystal, Melting point: >200° C. (decomposition), PMR (δ ppm, DMSO-d6): 3.86 (2H, s), 6.88 (1H, s), 7.12 (1H, s), 7.24 (1H, d), 7.30–7.38 (3H, m), 7.86 (1H, d), 11.61 (1H, br).
Reaction SMILES: [CH2:1]([N:12]([CH2:24][C:25]([OH:27])=[O:26])[CH2:13][CH2:14][N:15]([CH2:20][C:21]([OH:23])=O)[CH2:16][C:17]([OH:19])=[O:18])[CH2:2][N:3]([CH2:8][C:9]([OH:11])=[O:10])[CH2:4][C:5]([OH:7])=O.C(OC(=O)C)(=O)C>N1C=CC=CC=1>[CH2:20]1[N:15]([CH2:14][CH2:13][NH+:12]([CH2:24][C:25]([O-:27])=[O:26])[CH2:1][CH2:2][N:3]2[CH2:8][C:9](=[O:10])[O:11][C:5](=[O:7])[CH2:4]2)[CH2:16][C:17](=[O:19])[O:18][C:21]1=[O:23]
Reactant: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CCN(CC(=O)O)CC(=O)O
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: O=C([O-])C[NH+](CCN1CC(=O)OC(=O)C1)CCN1CC(=O)OC(=O)C1

Procedure:
DTPA (78.6 g.) was heated to about 70° C. with a mixture of acetic anhydride (75.6 ml) and anhydrous pyridine (102.2 ml) for 18 hours and 65.9 g. of diethylenetriamine pentaacetic acid dianhydride ("DTPADA") was obtained. DTPADA (64.3 g.) was then heated with an excess of 2,6-dimethylaniline (50.2 g) in anhydrous pryridine (1200 ml) and refluxed at a temperature of about 115° C. for 2 hours. The reaction mixture was then cooled and added to 1500 ml of ethyl acetate. The resulting mixture was chilled for about 16 hours to a temperature of about 4° C. The precipitate was collected, washed with ethyl acetate and dried under vacuum at 97° C. and 0.5 mm for about 16 hours. About 59.8 g of N,N"-bis (2,6-dimethylcarbaniloylmethylene) diethylenetriamine triacetic acid ("DTPA-bis 2,6-dimethylaniline") was obtained as the monohydrate. The melting point was determined to be 195°-199° C. and elemental analysis determined for C30H43N5O9 was 58.4% C, 6.76% H, and 11.22% N.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[CH:16][C:17]3[N:23]([S:24]([CH3:27])(=[O:26])=[O:25])[CH2:22][CH2:21][C:20]([C:28]([O:30]C)=[O:29])=[CH:19][C:18]=3[CH:32]=2)=[CH:10][CH:9]=1)[CH3:2].[OH-].[Na+]>CO.C1COCC1>[CH2:1]([O:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[CH:15]=[CH:16][C:17]3[N:23]([S:24]([CH3:27])(=[O:25])=[O:26])[CH2:22][CH2:21][C:20]([C:28]([OH:30])=[O:29])=[CH:19][C:18]=3[CH:32]=2)=[CH:12][CH:13]=1)[CH3:2]
Reactant: CCOCCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3S(C)(=O)=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCOCCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 107.8 %

Procedure:
In methanol (25 ml) and THF (25 ml) was dissolved methyl 7-[4-(3-ethoxypropoxy)phenyl]-1-methanesulfonyl-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.22 g). To the solution was added 1N sodium hydroxide solution (5 ml), and the mixture was stirred at room temperature overnight and concentrated. To the residue was added water, and the mixture was neutralized with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate, and the solvent was evaporated to give 7-[4-(3-ethoxypropoxy)phenyl]-1-methanesulfonyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.23 g) as pale yellow crystals.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[O:10][N:9]=2)[CH:5]=[N:6][CH:7]=1.B1([C:25]2[CH:30]=[CH:29][CH:28]=[N:27][CH:26]=2)OCCCO1.COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:11]1[O:10][N:9]=[C:8]([C:4]2[CH:5]=[N:6][CH:7]=[C:2]([C:25]3[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=3)[CH:3]=2)[N:12]=1
Reactant: c1cncc(B2OCCCO2)c1
Reactant: Brc1cncc(-c2noc(-c3ccccn3)n2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: ClCCl
Product: c1ccc(-c2nc(-c3cncc(-c4cccnc4)c3)no2)nc1
Yield: 43.1 %

Procedure:
A mixture of 3-(5-bromo-pyrid-3-yl)-5-(2-pyridyl)-1,2,4-oxadiazole 30.3 mg, 0.1 mmol), pyridine-3-boronic acid 1,3-propanediol cyclic ester (32.5 mg, 0.2 mmol), and tetrakis(triphenylphosphine)palladium(0) (Pd(PPh3)4, 15 mg, 0.013 mmol), in a solution of ethylene glycol dimethyl ether (1 mL) and 2M sodium carbonate (1 mL) was heated in a sealed vial at 100° C. for 1 hour. The reaction was cooled, diluted with dichloromethane, washed with water and saturated brine, filtered, and concentrated. Silica gel chromatography using 50% ethyl acetate in hexane and 100% ethyl acetate afforded 13 mg (43.2%) 5-(2-pyridyl)-3-[5-(3-pyridyl)-pyrid-3-yl]-1,2,4-oxadiazole. 1H-NMR (CDCl3), δ (ppm): 9.49 (d, 1H), 9.01 (d, 1H), 8.93 (dd, 2H), 8.72 (t, 2H), 8.35 (d, 2H), 8.00 (dt, 1H), 7.59 (m, 1H), 7.47 (dd, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]([N:15]3C(=O)C4C(=CC=CC=4)C3=O)[CH:11]=[CH:12][C:13]=2[CH3:14])=[C:5]([CH3:26])[CH:4]=1.O.NN>CCO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]([NH2:15])[CH:11]=[CH:12][C:13]=2[CH3:14])=[C:5]([CH3:26])[CH:4]=1
Reactant: COc1ccc(-c2c(C)ccn2N2C(=O)c3ccccc3C2=O)c(C)c1
Agent: NN
Solvent: CCO
Solvent: O
Product: COc1ccc(-c2c(C)ccn2N)c(C)c1
Temperature: 25 °C
Yield: 93.7 %

Procedure:
To a suspension of 2-[2-(4-methoxy-2-methylphenyl)-3-methyl-1H-pyrrol-1-yl]-1H-isoindole-1,3(2H)-dione (0.40 g, 1.15 mmol) in EtOH was added hydrazine monohydrate (0.14 mL, 2.89 mmol) at room temperature. The reaction mixture was heated at reflux for 1 h. After cooling down to room temperature, the mixture was filtered. The filtrate was concentrated in vacuo to dryness and the residue was subjected to column chromatography (silica gel, 1/4 EtOAc/heptane) to give 0.233 g (93%) of clear oil as the title compound: 1H NMR (400 MHz, CDCl3) δ 7.17 (d, J=8 Hz, 1H), 6.89 (s, 1H), 6.84–6.79 (m, 2H), 6.00 (s, 1H), 3.87 (s, 3H), 2.16 (s, 3H), 1.93 (s, 3H); MS m/z 217.1 (M++H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12]([O:14]C)=[O:13])[CH:9]=[C:8]([F:16])[C:3]=1[C:4]([O:6][CH3:7])=[O:5].[OH-].[Na+]>O1CCCC1>[Cl:1][C:2]1[CH:11]=[C:10]([CH:9]=[C:8]([F:16])[C:3]=1[C:4]([O:6][CH3:7])=[O:5])[C:12]([OH:14])=[O:13]
Reactant: COC(=O)c1cc(F)c(C(=O)OC)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COC(=O)c1c(F)cc(C(=O)O)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.9 %

Procedure:
To a solution of dimethyl 2-chloro-6-fluoroterephthalate (6.19 g, 25.1 mmol) in tetrahydrofuran (75 mL) was added a solution of 1 N NaOH (27.6 mmol, 27.6 mL). The reaction mixture was stirred at room temperature for 30 min. After the volatiles were removed under reduced pressure, water (30 mL) was added. The aqueous solution was acidified with 1 N HCl to pH 3.0. A white solid precipitated and was collected by filtration, washed with water and diethyl ether, dried in high vacuum to afford the title compound as a white solid (5.54 g, 95% yield). 1H NMR (400 MHz, CDCl3) δ 7.96 (s, 1H), 7.76 (dd, J=8.8, 1.3 Hz, 1H), 4.01 (s, 3H). LCMS (APCI+) 233.0 [M+H]+.
Reaction SMILES: [NH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1)[NH2:2].Cl[C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=[N:15][C:14]=1[C:23](OC)=[O:24]>C(O)C>[O:24]=[C:23]1[C:14]2[N:15]=[N:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:22]=3[C:13]=2[NH:2][N:1]1[C:3]1[CH:4]=[CH:5][C:6]([C:7]([OH:9])=[O:8])=[CH:10][CH:11]=1
Reactant: COC(=O)c1nnc2ccccc2c1Cl
Reactant: NNc1ccc(C(=O)O)cc1
Solvent: CCO
Product: O=C(O)c1ccc(-n2[nH]c3c(nnc4ccccc43)c2=O)cc1
Temperature: 47.5 °C
Reaction time: 1 h

Procedure:
4-Hydrazinobenzoic acid (68.4 mg, 0.45 mmol) was mixed at room temperature with ethanol (5 ml) to give a crème-coloured suspension. Methyl 4-chlorocinnoline-3-carboxylate (100 mg, 0.45 mmol) was added and the mixture was heated to 45-50° C. for 1 h. The reaction mixture was cooled to room temperature and the solvent was removed under vacuum. Ethyl acetate (10 ml) was added to the residue. The mixture was stirred at room temperature for 1 h. The solids were collected by filtration and dried under vacuum. The title compound was isolated as a brown powder (120 mg, 0.39 mmol, 86%). LCMS: m/z 307 [M+H]+. NMR [DMSO-d6]: δ=7.69-7.77 (m, 1Haryl); 7.81-7.90 (m, 2Haryl); 8.05 (d, J=8.85, 2Haryl); 8.20 (d, J=7.92 Hz, 1Haryl); 8.33 (d, J=8.85 Hz, 2Haryl); 14.64 (s, NH).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[Br:8][C:9]1[C:10]([CH3:20])=[CH:11][C:12]([OH:19])=[C:13]([CH:18]=1)[C:14]([O:16][CH3:17])=[O:15]>N1C=CC=CC=1>[C:1]([O:19][C:12]1[CH:11]=[C:10]([CH3:20])[C:9]([Br:8])=[CH:18][C:13]=1[C:14]([O:16][CH3:17])=[O:15])(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)c1cc(Br)c(C)cc1O
Solvent: c1ccncc1
Product: COC(=O)c1cc(Br)c(C)cc1OC(C)=O
Reaction time: 4 h
Yield: 97.4 %

Procedure:
Acetic anhydride (3.06 mL, 32.5 mmol) was added to a solution of methyl 5-bromo-2-hydroxy-4-methylbenzoate (3.98 g, 16.24 mmol), which may be prepared according to procedure described in Description 2, in Pyridine (10 mL) was added. The reaction mixture was stirred for four hours. The solvent was removed in vacuo and the residue was purified by SP4 (10-20% EtOAc/hexane) to yield the desired compound as oil (4.54 g, 97% yield).