Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:15][C:14](=[O:16])[O:13][C:11](=[O:12])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].C([N:19]([CH2:22]C)[CH2:20][CH3:21])C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:10][C:11]([N:19]([CH2:20][C:21]2[CH:3]=[CH:4][CH:9]=[CH:10][C:11]=2[O:13][CH3:14])[CH3:22])=[O:12])[CH2:15][C:14]([OH:13])=[O:16])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CCN(CC)CC
Reactant: O=C1CC(c2ccc(Cl)c(Cl)c2)CC(=O)O1
Solvent: ClCCl
Product: COc1ccccc1CN(C)C(=O)CC(CC(=O)O)c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
3-(3,4-Dichlorophenyl)glutaric anhydride (5.9 g) in CH2Cl2 (80 mL) at 0° C. was treated sequentially with N-methyl-N-[2-methoxyphenyl)methyl]amine (3.8 g), triethylamine (3.5 mL) and N,N-dimethylaminopyridine (278 mg). The mixture was stirred at 0° C. for two hours then allowed to warm to room temperature and stirred for 20 hours. The reaction mixture was washed with 1N HCl (1×100 mL) and brine (1×100 mL). The organic layers were dried over MgSO4, filtered and concentrated to afford the title compound (9.3 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[C@H:14]([OH:25])[CH2:15][O:16][C@@H:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH3:18])=[CH:4][CH:3]=1.[CH2:26]([O:28][C:29]([C:31]1([C:34]2[CH:39]=[CH:38][C:37](B3OC(C)(C)C(C)(C)O3)=[CH:36][CH:35]=2)[CH2:33][CH2:32]1)=[O:30])[CH3:27]>>[CH2:26]([O:28][C:29]([C:31]1([C:34]2[CH:39]=[CH:38][C:37]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[C@H:14]([OH:25])[CH2:15][O:16][C@@H:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH3:18])=[CH:4][CH:3]=3)=[CH:36][CH:35]=2)[CH2:32][CH2:33]1)=[O:30])[CH3:27]
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1[C@H](O)CO[C@H](C)c1ccccc1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4[C@H](O)CO[C@H](C)c4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 110, Step 3, using (S)-1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-2-((R)-1-phenyl-ethoxy)-ethanol and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([O:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[F:21])[CH2:10][CH:9]1[C:22](O)=[O:23])=[O:7])([CH3:4])([CH3:3])[CH3:2].CSC.O>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([O:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[F:21])[CH2:10][CH:9]1[CH2:22][OH:23])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC(Oc2ccc(F)cc2F)CC1C(=O)O
Solvent: C1CCOC1
Solvent: O
Solvent: CSC
Product: CC(C)(C)OC(=O)N1CC(Oc2ccc(F)cc2F)CC1CO
Temperature: 25 °C
Yield: 71.9 %

Procedure:
To a stirred solution of 1-(tert-butoxycarbonyl)-4-(2,4-difluorophenoxy)pyrrolidine-2-carboxylic acid (2.55 g, 7.43 mmol) in THF (50 ml) was added BH3.DMS (452 ul, 7.43 mmol). The mixture was heated at reflux overnight. After cooling to room temperature, the mixture was concntrated in vacuo and quenced by the addition of H2O (100 ml). The mixture was extracted with CHCl3 (2×200 ml), dried over MgSO4, and evaporated. The residue was chromatographed on silica gel with CHCl3-EtOAc (4:1) as eluent to give 1-(tert-butoxycarbonyl)-4-(2,4-difluorophenoxy)-2-pyrrolidinylmethanol (1.76 g, 72%) as a colorless oil. 1H-NMR (CDCl3) δ1.45 (s, 9 H), 2.28-2.36 (m, 2 H), 3.58-4.99 (series of m, 8 H), 6.74-6.90 (m, 3 H).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:5])[CH3:4].[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14]Cl)=[CH:9][CH:8]=1.O>C1(C)C=CC=CC=1>[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][NH:1][CH2:2][CH:3]([OH:5])[CH3:4])=[CH:9][CH:8]=1
Reactant: ClCCc1ccc(Cl)cc1
Reactant: CC(O)CN
Solvent: Cc1ccccc1
Solvent: O
Product: CC(O)CNCCc1ccc(Cl)cc1
Temperature: 84 °C
Reaction time: 0.25 h

Procedure:
Into a 4-L jacketed reactor, equipped with an overhead stirrer, a thermocouple, a condenser and a nitrogen inlet was charged 1-amino-2-propanol (1094 mL, 14.2 mol). Stirring was commenced and the reactor jacket was heated to 95° C. (84° C. internal temperature). 1-Chloro-4-(2-chloroethyl)benzene (˜496 g, 2.833 mol) (501 g of the mixture containing N,N-dimethylformamide from Step A) was added dropwise over ˜80 min at an internal temperature of 84 to 99° C. On completion of the addition the reaction was stirred at 90 to 95° C. for 2 h and then cooled to 85° C. Water (500 mL) and toluene (1 L) were added while maintaining the internal temperature at 70 to 75° C. Stirring was continued at that temperature for another 15 min and then stirring was discontinued and the phases were allowed to separate at 70 to 75° C. The aqueous phase was extracted with toluene (2×500 mL) at 70 to 75° C. The organic phases were combined, cooled to 50° C. and stirred at that temperature overnight. The solution was then heated to 60° C., washed with water (500 mL) and concentrated under reduced pressure at 58 to 65° C. After approximately 650 mL of distillate had been removed, fresh toluene (650 mL) was added. The water content of the resulting solution was determined to be 0.0854% by Karl Fischer titration and the solution was immediately carried forward to Step C.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:5])[CH3:4].[OH-].[Na+].O.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17]Cl)=[CH:12][CH:11]=1>>[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][NH:1][CH2:2][CH:3]([OH:5])[CH3:4])=[CH:12][CH:11]=1
Reactant: ClCCc1ccc(Cl)cc1
Reactant: CC(O)CN
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(O)CNCCc1ccc(Cl)cc1
Temperature: 120 °C

Procedure:
In a 500-mL round-bottom flask equipped with magnetic stirring, a thermocouple, a condenser, and a nitrogen bubbler vented to a caustic scrubber, 1-aminopropan-2-ol (60.2 g, 802 mmol) was heated to 120° C. The solution of 1-chloro-4-(2-chloroethyl)benzene in toluene prepared in Step A was added dropwise over 70 min at 114° C. to 120° C. and upon completion of the addition, the mixture was stirred at reflux for a further 2 h and then allowed to cool to 72° C. Aqueous NaOH (50%, 12.83 g, 160 mmol) and water (25 mL) were added and the mixture was stirred at 70 to 73° C. for approximately 5 minutes. The phases were allowed to separate, the aqueous phase was removed, and the organic phase washed at 80° C. (bath) for approximately 5 min with water (4×25 mL). The combined aqueous phases were extracted with toluene (37 mL) at 80° C. (bath). The combined organic phases were concentrated under reduced pressure at 60° C. (bath) and then at room temperature overnight to leave the title compound as a white solid.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1B(O)O.Br[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C([O-])([O-])=O.[Cs+].[Cs+].C1(C)C=CC=CC=1>CCO>[C:10]1([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Brc1ccccc1
Reactant: OB(O)c1ccco1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: c1ccc(-c2ccco2)cc1
Temperature: 140 °C

Procedure:
Furan-2-boronic acid (22) (3.6 g, 32.14 mmol) was coupled to bromobenzene (21) (4.2 g, 26.79 mmol) using Method E, except that Cs2CO3 (17.47 g, 53.58 mmol), Pd(PPha)4 (6.20 g, 0.54 mmol), toluene (25 mL) and EtOH (25 mL) were used and the reaction heated in a CEM Discover microwave at 140° C. (200 W, 200 psi). The crude product was purified by dry-flash chromatography eluting with EtOAc in heptane to yield the title compound. Yield: 2.94 g, 62%; LC tr 1.50 min; HPLC Purity: 84%
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:8]1[CH:12]=[CH:11][CH:10]=[C:9]1B(O)O>>[C:2]1([C:9]2[O:8][CH:12]=[CH:11][CH:10]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1ccco1
Reactant: Brc1ccccc1
Product: c1ccc(-c2ccco2)cc1

Procedure:
Bromobenzene (1.5 g, 9.55 mmol) was coupled to 2-furylboronic acid (1.75 g, 15.6 mmol) using Method E. The crude compound was purified by column chromatography using a stepped gradient of 5-10% EtOAc in heptane to give the title compound.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:9][C:10]([CH2:12][CH:13]1[CH2:22][CH2:21][C:16]2([O:20][CH2:19][CH2:18][O:17]2)[CH2:15][CH2:14]1)=O)C>C1COCC1>[O:17]1[C:16]2([CH2:21][CH2:22][CH:13]([CH2:12][CH2:10][OH:9])[CH2:14][CH2:15]2)[O:20][CH2:19][CH2:18]1
Reactant: CCOC(=O)CC1CCC2(CC1)OCCO2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCCC1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 97.9 %

Procedure:
To a mixture of lithium aluminum hydride (42.5 g, 1.12 mol) in THF (1200 mL) is carefully added crude 8-ethoxycarbonylmethyl-1,4-dioxaspiro[4.5]decane (174.7 g) in THF solution (640 mL) at 0° C. under argon atmosphere. After stirring for 10 min at ambient temperature, Na2SO4-10H2O (360.9 g) is added at 0° C., and the mixture is stirred for additional 3 hours. Insoluble matter is filtered and washed with EtOAc, and the filtrate is concentrated in vacuo to afford crude 2-(1,4-dioxaspiro[4.5]dec-8-yl)ethanol (139.5 g). The crude product is used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.Br[C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1.C(=O)([O-])[O-].[Na+].[Na+].O>C(O)C.C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(Br)cc1
Reactant: Brc1cccnc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: Brc1ccc(-c2cccnc2)cc1
Yield: 17.2 %

Procedure:
A solution of 4-bromobenzeneboronic acid (6.0 g) in absolute ethanol (15 ml) was added slowly to a stirred mixture of a solution of 3-bromopyridine (4.7 g) in toluene (30 ml), a saturated aqueous solution of sodium carbonate (10 ml) and tetrakistriphenylphosphine palladium [0] (1.0 g) under an atmosphere of argon. The mixture was then heated to reflux and stirred at reflux under an atmosphere of argon for 6 hours. The mixture was cooled and water (50 ml) added. The resulting mixture was extracted with ethyl acetate (3×30 ml). The ethyl acetate extracts were combined, and then extracted with 2N aqueous hydrochloric acid (3×20 ml). The acidic extracts were combined, cooled by the addition of ice and basified by the addition of sodium hydroxide solution to give a pH of 9. The mixture was then extracted with ethyl acetate (3×30 ml). These ethyl acetate extracts were combined, dried (MgSO4) and evaporated to afford 3-(4-bromophenyl)pyridine as a colourless oil (1.2 g); NMR (CDCl3): 7.3-7.5(3H, m), 7.6(2H, d), 7.85(1H, d of t), 8.6(1H, d of d) and 8.8(1H, d).
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:13]2[C:12](=O)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=O)[C:4]=2[CH:3]=1.C(O)(C)C.O1CCCC1.[BH4-].[Na+]>O>[Br:1][C:2]1[CH:15]=[CH:14][C:13]2[C:4](=[CH:5][C:6]3[C:11]([CH:12]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH:3]=1
Reactant: O=C1c2ccccc2C(=O)c2cc(Br)ccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(C)O
Product: Brc1ccc2cc3ccccc3cc2c1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
2-Bromoanthraquinone 10 (8.50 g, 0.0296 mol, 1 equiv) and a 50:50 mixture of isopropyl alcohol and tetrahydrofuran (200 mL) were stirred for 10 minutes at 0° C. forming a yellow suspension. NaBH4 (6.70 g, 0.177 mol, 6.0 equiv.) was added to the suspension at 0° C. The mixture was stirred at 0° C. for three hours, turning red in color. The solution was then warmed to room temperature. Additional NaBH4 (3.35 g, 0.089 mol, 3.0 equiv.) was added to the solution at room temperature and the solution was stirred at room temperature for 12 hours, turning into an orange suspension. Deionized water (10 mL) was added to the solution at room temperature and the solution was stirred at room temperature for an additional 12 hours. The consumption of 2-bromoanthraquinone 10 was monitored by thin-layer chromatography (35% CHCl3/hexane, Rf=0.33). Once the consumption of 2-bromoanthraquinone 10 stopped entirely (it was never fully consumed), the volatiles were removed by rotary evaporation. 3 M HCl was slowly added to the solution until bubbling ceased, then additional 3 M HCl (30 mL) was added. The solution was heated at reflux for 6 hours, turning into an opaque, yellow suspension in the process. The mixture was cooled to room temperature, turning into a transparent solution containing yellow-brown crystals. The contents underwent rotary evaporation as much water as possible. The contents were then vacuum-filtered and washed using deionized water to remove any water, acid and ionic salt, leaving behind a yellow-brown colored solid. The vacuum-filtration receiving flask was changed and the solid was washed with CH2Cl2 through the filter paper. The CH2Cl2 was removed through rotary evaporation. The remaining solid was purified through column chromatography (100% hexane, Rf=0.27), providing 2-bromoanthracene 11 as a white, powdery solid (2.00 g, 26%). 1H NMR (CDCl3): δ 8.42 (s, 1H), 8.34 (s, 1H), 8.18 (d, 1H), 8.01 (m, 2H), 7.87 (d, 1H), 7.50 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]1[N:14]([CH3:15])[C:13]2[CH:16]=[CH:17][C:18]([C:20]([OH:22])=[O:21])=[CH:19][C:12]=2[N:11]=1.CN(C(O[N:31]1[N:39]=[N:38][C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O.C(OCC)(=O)C>[N:38]1([O:21][C:20]([C:18]2[CH:17]=[CH:16][C:13]3[N:14]([CH3:15])[C:10]([NH:9][C:3]4[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=4[Cl:1])=[N:11][C:12]=3[CH:19]=2)=[O:22])[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[N:31]=[N:39]1
Reactant: Cn1c(Nc2c(Cl)cccc2Cl)nc2cc(C(=O)O)ccc21
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cn1c(Nc2c(Cl)cccc2Cl)nc2cc(C(=O)On3nnc4ccccc43)ccc21
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of 2-(2,6-dichloro-phenylamino)-1-methyl-1H-benzimidazole-5-carboxylic acid (0.50 g, 1.5 mmol), HBTU (0.56 g, 1.5 mmol) and TEA (0.42 mL, 3.0 mmol) in 8 mL DMF was stirred for 3 days at ambient temperature. The mixture was diluted with water and ethyl acetate. The organic phase was washed with water and brine, dried and concentrated i.vac.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH3:10])[C:5](Br)=[CH:4][N:3]=1.[F:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.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>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH3:10])[C:5]([C:15]2[CH:16]=[C:17]([C:19]([F:21])([F:20])[F:22])[CH:18]=[C:13]([F:12])[CH:14]=2)=[CH:4][N:3]=1
Reactant: Cc1c(Br)cnc(N)c1C#N
Reactant: OB(O)c1cc(F)cc(C(F)(F)F)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: [K+]
Solvent: Cc1ccccc1
Product: Cc1c(-c2cc(F)cc(C(F)(F)F)c2)cnc(N)c1C#N

Procedure:
This compound is prepared in a manner analogous to that of Step D of Example 4, using 1.7 grams (0.008 mole) of 2-amino-5-bromo-3-cyano-4-methylpyridine, 2.5 grams (0.01 2 mole) of 3-fluoro-5-trifluoromethylphenylboronic acid, 4.3 grams (0.031 mole) of potassium carbonate and 0.3 gram of tetrakis(triphenylphosphine)palladium(0) in 150 mL of toluene, yielding 2-amino-3-cyano-4-methyl-5-[3-fluoro-5-trifluoromethylphenyl]pyridine.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:10]([OH:12])=[O:11])=[N:4][C:5](Br)=[C:6]([F:8])[CH:7]=1.[F:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH3:23])=[CH:16][C:15]=1B(O)O>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[NH2:1][C:2]1[C:3]([C:10]([OH:12])=[O:11])=[N:4][C:5]([C:19]2[CH:18]=[C:17]([O:20][CH2:21][CH2:22][CH3:23])[CH:16]=[CH:15][C:14]=2[F:13])=[C:6]([F:8])[CH:7]=1
Reactant: Nc1cc(F)c(Br)nc1C(=O)O
Reactant: CCCOc1ccc(F)c(B(O)O)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClCCl
Product: CCCOc1ccc(F)c(-c2nc(C(=O)O)c(N)cc2F)c1
Yield: 28 %

Procedure:
Method 1 was followed using 3-amino-6-bromo-5-fluoropicolinic acid (1.0 equiv.) and 2-fluoro-5-propoxyphenylboronic acid (1.3 equiv.) and Pd(dppf)Cl2-DCM (0.05 equiv.) to give 3-amino-5-fluoro-6-(2-fluoro-5-propoxyphenyl)picolinic acid in 28% yield. LC/MS=309.1 (M+H), Rt=1.00 min.
Reaction SMILES: F[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CN1CCOCC1>COCCO>[NH:14]([C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Nc1ccccc1
Reactant: O=C(O)c1ccc(F)c([N+](=O)[O-])c1
Solvent: COCCO
Solvent: CN1CCOCC1
Product: O=C(O)c1ccc(Nc2ccccc2)c([N+](=O)[O-])c1

Procedure:
4-Fluoro-3-nitrobenzoic acid (0.27 mol), an aniline (0.32 mol) and NMM (32.5 mL) in 2-methoxyethanol (750 mL) were stirred at reflux under argon for 24 h. The suspension was concentrated under reduced pressure and the residue was sonicated with 1M HCl (aq) over 1.5 h. The resultant orange solid was isolated by filtration, washed with water dried, then sonicated with t-butyl methyl ether, isolated by filtration and dried. Where necessary, the product was further purified by recrystallisation to yield the 4-anilino-3-nitrobenzoic acid: e.g. 4-(3-bromophenyl amino)-3-nitrobenzoic acid. (In some cases, for example with heteroaromatic anilines, NMN may be omitted from the reaction mixture).
Reaction SMILES: [F:1][CH:2]([F:5])[CH2:3]Cl.[C:6]1(=[O:12])[NH:10][C:9](=[O:11])[CH2:8][CH2:7]1.C(=O)([O-])[O-].[K+].[K+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[F:1][CH:2]([F:5])[CH2:3][N:10]1[C:6](=[O:12])[CH2:7][CH2:8][C:9]1=[O:11]
Reactant: FC(F)CCl
Reactant: O=C1CCC(=O)N1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Product: O=C1CCC(=O)N1CC(F)F
Temperature: 120 °C
Reaction time: 16 h
Yield: 117.8 %

Procedure:
An amount of 204.9 g (1.9 mol) of 2,2-difluoro-1-chloroethane, 3.22 g (9.9 mmol) of tetra(n-butyl)ammonium bromide and 20 g (0.19 mol) of succinimide are treated with 83.6 g (0.599 mol) of potassium carbonate. The reaction mixture is stirred in an autoclave under pressure at 120° C. for 16 h. After the end of the reaction, cooling is carried out to ambient temperature and the reaction mixture is subsequently filtered. The filter residue is washed with dichloromethane and the solvent is removed under vacuum. An amount of 36.5 g of 1-(2,2-difluoroethyl)pyrrolidine-2,5-dione with a purity of 85% is obtained. This corresponds to a yield of 95% of theory.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1)[CH:6]=O.[N+:13]([CH3:16])([O-:15])=[O:14].[OH-].[Na+]>O.CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:6]=[CH:16]/[N+:13]([O-:15])=[O:14])[CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1
Reactant: C[N+](=O)[O-]
Reactant: COc1cc(C=O)cc(OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1cc(/C=C/[N+](=O)[O-])cc(OC)c1
Temperature: 0 °C

Procedure:
A solution of 3,5-dimethoxybenzaldehyde (34.5 g., 0.208 mole) and nitromethane (12.69 g., 0.208 mole) in 40 ml. of MeOH was cooled to 0° under N2 . A solution was prepared by dissolving NaOH (8.43 g., 0.211 mole) in 10 ml. of H2O then diluting to 20 ml. with ice-water. This solution was then added dropwise to the methanol mixture. After 15 minutes the reaction was diluted with ice-H2O and added slowly to a solution of 40 ml. concentrated HC1in 60 ml. H2O. The resulting precipitate (44 g.) was filtered and recrystallized from methanol to give 28.6 g. of product, m.p. 132°; reported, J. Org. Chem. 27, p. 376 (1962), m.p. 133.5-134.5.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][NH2:6].[C:10]([N:17]1[CH2:22][CH2:21][C:20](=O)[CH2:19][CH2:18]1)([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11]>>[C:13]([O:12][C:10]([N:17]1[CH2:22][CH2:21][CH:20]([NH:6][CH2:5][C:4]2[CH:7]=[CH:8][CH:9]=[C:2]([CH3:1])[CH:3]=2)[CH2:19][CH2:18]1)=[O:11])([CH3:16])([CH3:14])[CH3:15]
Reactant: Cc1cccc(CN)c1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Product: Cc1cccc(CNC2CCN(C(=O)OC(C)(C)C)CC2)c1
Yield: 81.6 %

Procedure:
Using general procedure A, 3-methylbenzylamine (198 μL, 1.58 mmol) and 1-Boc-4-piperidone (300 mg, 1.51 mmol) afforded 4-(3-methylbenzylamino)-piperidine-1-carboxylic acid tert-butyl ester as a white solid (375 mg, 82%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]([OH:11])=O)[CH2:8][CH2:7]1)=[O:5])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>C(Cl)Cl>[C:37]1([NH:36][C:9]([C:6]2([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:7][CH2:8]2)=[O:11])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: Nc1ccccc1
Reactant: CCOC(=O)C1(C(=O)O)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)C1(C(=O)Nc2ccccc2)CC1
Reaction time: 0.17 h
Yield: 88.8 %

Procedure:
To a solution of 1-(ethoxycarbonyl)cyclopropane carboxylic acid (7.4 g, 46.84 mmol) in dry CH2Cl2 (70 mL) was added HATU (35.62 g, 93.67 mmol) at 0° C. After stirring for 10 minutes, a solution of the aniline (8.71 g, 93.67 mmol) and Et3N-(9.48 g, 93.67 mmol) in dry CH2Cl2 (30 mL) was then added and the reaction mixture was continued to stir at 40° C. for 24 hrs. The reaction mixture was quenched with water (30 mL) and extracted with CH2Cl2 (100 mL×3). The combined organic phases were dried over anhydrous Na2SO4, filtered and the filtrate was concentrated in vacuo. The residue was chromatographed with a silica gel column (1:5 (v/v) EtOAc/n-hexane) to afford the title compound as a pale yellow solid (9.7 g, 89%).
Reaction SMILES: [CH:1]12[CH2:6][CH:5]1[CH2:4][N:3]([C:7]1[N:12]=[C:11]([NH:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([Cl:23])[CH:16]=3)[C:10]([C:24](O)=[O:25])=[CH:9][N:8]=1)[CH2:2]2.[N:27]1([CH2:33][CH2:34][NH2:35])[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>C1COCC1.O>[CH:1]12[CH2:6][CH:5]1[CH2:4][N:3]([C:7]1[N:12]=[C:11]([NH:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([Cl:23])[CH:16]=3)[C:10]([C:24]([NH:35][CH2:34][CH2:33][N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[O:25])=[CH:9][N:8]=1)[CH2:2]2
Reactant: NCCN1CCOCC1
Reactant: COc1ccc(CNc2nc(N3CC4CC4C3)ncc2C(=O)O)cc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc(CNc2nc(N3CC4CC4C3)ncc2C(=O)NCCN2CCOCC2)cc1Cl
Reaction time: 4 h
Yield: 36.4 %

Procedure:
In THF (10 mL) were dissolved 2-(3-azabicyclo[3.1.0]hexan-3-yl)-4-((3-chloro-4-methoxybenzyl)amino)-pyrimidine-5-carboxylic acid (150 mg, 0.40 mmol) and 2-morpholinylethylamine (59 mg, 0.45 mmol). HATU (190 mg, 0.50 mmol) and triethylamine (101 mg, 1 mmol) were then added. The reaction was conducted at ambient temperature for 4 h. Then the reaction mixture was diluted with water and extracted with DCM. The organic phase was dried, concentrated, and purified by silica gel column chromatography (DCM/methanol=20/1) to give 2-(3-azabicyclo[3.1.0]hexan-3-yl)-4-((3-chloro-4-methoxybenzyl)amino)-N-(2-morpholinylethyl)pyrimidine-5-formamide as a white solid (71 mg, 36.5% yield).