Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:12]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[Cs+].[Cs+].FC(F)(F)S(O[CH2:35][C:36]([F:39])([F:38])[F:37])(=O)=O>CC#N.CN(C=O)C>[C:1]1([CH2:7][O:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[N:14]([CH2:35][C:36]([F:39])([F:38])[F:37])[C:13]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:12]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: CCOC(=O)c1cc2cc(OCc3ccccc3)ccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2cc(OCc3ccccc3)ccc2n1CC(F)(F)F
Temperature: 25 °C
Reaction time: 4 h
Yield: 61 %

Procedure:
To a solution of ethyl 5-[(phenylmethyl)oxy]-1H-indole-2-carboxylate (0.3 g, 1 mmol) in 3:2 MeCN/DMF (5 mL) was added Cs2CO3 (0.36 g, 1.1 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.26 g, 1.1 mmol). The mixture was stirred at rt, under N2, for 4 h. Additional Cs2CO3 (0.033 g, 0.1 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.023 g, 0.1 mmol) were added and stirring was continued at rt for 15 h. The mixture was partitioned between Et2O and 0.05N HCl. The organic phase was washed with 0.05N HCl and sat'd brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography (0-20% EtOAc-hexanes gradient) to afford the title compound (0.23 g, 61% yield): 1H NMR (400 MHz, CDCl3) δ 7.46 (d, J=7.1 Hz, 2H), 7.38 (t, J=7.1 Hz, 2H), 7.34-7.29 (m, 3H), 7.16-7.13 (m, 2H), 5.28 (q, J=8.5 Hz, 2H), 5.10 (s, 2H), 4.37 (q, J=7.1 Hz, 2H), 1.39 (t, J=7.1 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[C:9](B2OC(C)(C)C(C)(C)O2)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].Br[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.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>[Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[C:9]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: Brc1ccccn1
Reactant: COC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)c(Cl)cc1Cl
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: COC(=O)c1cc(-c2ccccn2)c(Cl)cc1Cl
Temperature: 110 °C
Yield: 93.6 %

Procedure:
To a solution of methyl 2,4-dichloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (Preparation 45, 5 g, 15 mmol) in dioxane (30 mL) and water (10 mL) was added 2-bromopyridine (1.73 mL, 18 mmol), tetrakis(triphenylphosphine)palladium (0) (1.75 g, 1.51 mmol) and potassium carbonate (4.18 g, 30 mmol). The reaction was heated to 110° C. The reaction was cooled, extracted into EtOAc and separated. The organic layer was washed with brine, dried over magnesium sulphate and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with 10-50% EtOAc in heptanes followed by trituration with TBME to afford the title compound (3.96 g, 93%).
Reaction SMILES: O=P(Cl)(Cl)[Cl:3].[CH3:6][C:7]1[CH2:12][C:11](=O)[CH:10]=[C:9]([C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)=[CH:16][CH:15]=2)[N:8]=1.N12CCCN=C1CCCCC2>C(Cl)Cl>[Cl:3][C:11]1[CH:12]=[C:7]([CH3:6])[N:8]=[C:9]([C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)=[CH:16][CH:15]=2)[CH:10]=1
Reactant: CC1=NC(c2ccc(Oc3ccc(F)cc3)cc2)=CC(=O)C1
Reactant: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1cc(Cl)cc(-c2ccc(Oc3ccc(F)cc3)cc2)n1

Procedure:
To a flask containing 20 ml of POCl3 at 120° C. oil bath was carefully added a solution of 5 g (17 mmol) crude compound 4 and 2.6 ml of 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU) (17 mmol) in 20 ml of methylene chloride. After the addition, the reaction mixture was refluxed for one hour. The resulting mixture was concentrated to dryness and diluted with ethyl acetate. Saturated aqueous NaHCO3 was carefully added to the solution to adjust pH to 5-6. The organic phase was separated and the aqueous phase was extracted with the same volume of EtOAc. The combined organic phases were then washed with brine and dried with magnisium sulfate, filtered and concentrated to dryness. The residue was purified with flash chromatography (silica gel, 5% EtOAc/hexane) to get 1.8 g of compound 5 and 850 mg of a mixture of compound 5 and unreacted compound 3. 1H NMR (CDCl3): δ 7.93 (d, 2H, J=6.7 Hz), 7.48 (d, 1H, J=1.36 Hz), 7.09 (d, 1H, J=1.5 Hz), 7.00 (m, 6H), 2.59 (s, 3H). MS: 314.1
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]2[CH:11]=[C:12]([N+:19]([O-:21])=[O:20])[C:13]([C:16](N)=[O:17])=[N:14][CH:15]=2)[CH:5]=[CH:6][C:7]=1[F:8].[CH3:22][OH:23]>>[F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]2[CH:11]=[C:12]([N+:19]([O-:21])=[O:20])[C:13]([C:16]([O:23][CH3:22])=[O:17])=[N:14][CH:15]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: NC(=O)c1ncc(Cc2ccc(F)c(F)c2)cc1[N+](=O)[O-]
Reactant: CO
Product: COC(=O)c1ncc(Cc2ccc(F)c(F)c2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 5-[(3,4-difluorophenyl)methyl]-3-nitro-2-pyridinecarboxamide (2.7 g, 9.21 mmol) and MeOH (100 ml), was added dimethylformamidedimethylacetal (3.29 g, 27.62 mmol). After stirring at room temperature overnight, the solvent was evaporated using no heat, EtOAc was added and the organic layer was washed three times with brine, dried and concentrated in vacuo. The product was purified by chromatography on silica gel, eluting with 20-60% EtOAc/hexanes to afford a dark brown oil. 1H NMR (CDCl3) δ 8.71 (1H, s), 8.05 (1H, s), 7.20-7.15 (1H, m), 7.00-6.80 (2H, m), 4.10 (2H, s), 4.01 (3H, s); HRMS calcd for C14H10F2N2O4+H+: 309.0687. Found 309.0681.
Reaction SMILES: [N+]([NH:4][C:5]1[NH:10][C:9](=[O:11])[C:8]([CH2:12][C:13]2[CH:14]=[N:15][C:16]([CH3:19])=[CH:17][CH:18]=2)=[CH:7][N:6]=1)([O-])=O.N[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][OH:26]>N1C=CC=CC=1>[OH:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][NH:4][C:5]1[NH:10][C:9](=[O:11])[C:8]([CH2:12][C:13]2[CH:14]=[N:15][C:16]([CH3:19])=[CH:17][CH:18]=2)=[CH:7][N:6]=1
Reactant: Cc1ccc(Cc2cnc(N[N+](=O)[O-])[nH]c2=O)cn1
Reactant: NCCCCCO
Solvent: c1ccncc1
Product: Cc1ccc(Cc2cnc(NCCCCCO)[nH]c2=O)cn1

Procedure:
Reaction of 2-nitroamino-5-(6-methyl-3-pyridylmethyl)-4-pyrimidone with 5-aminopentanol in refluxing pyridine gives 2-(5-hydroxypentylamino)-5-(6-methyl-3-pyridylmethyl)-4-pyrimidone which can be converted into 2-[5-(O-isoureido)pentylamino]-5-(6-methyl-3-pyridylmethyl)-4-pyrimidone by the procedure of Example 5(iii).
Reaction SMILES: C[O:2][C:3](=[O:40])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH:20]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C:21]([N:23]3[CH2:28][CH2:27][N:26]([C:29](=[O:31])[CH3:30])[CH2:25][CH2:24]3)=[O:22])=[CH:15][CH:14]=2)=[CH:8][CH:7]=1.[OH-].[Li+]>C1COCC1.O>[C:29]([N:26]1[CH2:27][CH2:28][N:23]([C:21](=[O:22])[CH:20]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:19][C:16]2[CH:17]=[CH:18][C:13]([O:12][C:9]3[CH:10]=[CH:11][C:6]([CH2:5][CH2:4][C:3]([OH:40])=[O:2])=[CH:7][CH:8]=3)=[CH:14][CH:15]=2)[CH2:24][CH2:25]1)(=[O:31])[CH3:30]
Reactant: COC(=O)CCc1ccc(Oc2ccc(CC(NC(=O)OC(C)(C)C)C(=O)N3CCN(C(C)=O)CC3)cc2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)N1CCN(C(=O)C(Cc2ccc(Oc3ccc(CCC(=O)O)cc3)cc2)NC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.3 %

Procedure:
The amide compound 18 (2.3 g, 4.15 mmol) was dissolved in THF (20 mL) and diluted with water (20 mL). Lithium hydroxide (0.4 g, 17.0 mmol) was added and the reaction mixture was stirred at room temperature for about 2 h. The THF was evaporated and the resulting aqueous layer was acidified with 2.0 M HCl and extracted into EtOAc (2×30 mL). The organic layer was washed with water (1×40 mL) and brine (1×40 mL), dried and concentrated to yield the desired acid compound 19 (2.0 g, 89%). 1H NMR (400 MHz, DMSO-d6): 7.16 (overlapped d, J=8.4 Hz, 2H), 7.15 (overlapped d, J=8.8 Hz, 2H), 6.91 (d, J=8.0 Hz, 2H), 6.86 (d, J=8.0 Hz, 2H), 5.47 (dd, J=12.8 and 8.4 Hz, 1H), 4.81 (m, 1H), 4.81 (m, 1H), 3.32-3.57 (m, 6H), 2.92-3.00 (m, 6H), 2.66 (t, J=6.8 Hz, 2H), 2.08 (d, J=7.6 Hz, 3H), 1.43 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH:5]=[CH:4][C:3]=1[C:15]1[CH:24]=[C:23]([C:25]([OH:27])=O)[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([F:28])[CH:21]=2)[N:16]=1.CN1CCOCC1.ClC1N=C(OC)N=C(OC)N=1.[N:47]1([CH2:52][CH2:53][NH2:54])[CH2:51][CH2:50][CH2:49][CH2:48]1>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][N:9]2[CH2:10][CH2:11][O:12][CH2:13][CH2:14]2)[CH:5]=[CH:4][C:3]=1[C:15]1[CH:24]=[C:23]([C:25]([NH:54][CH2:53][CH2:52][N:47]2[CH2:51][CH2:50][CH2:49][CH2:48]2)=[O:27])[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([F:28])[CH:21]=2)[N:16]=1
Reactant: NCCN1CCCC1
Reactant: O=C(O)c1cc(-c2ccc(CN3CCOCC3)cc2Cl)nc2ccc(F)cc12
Agent: COc1nc(Cl)nc(OC)n1
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: O=C(NCCN1CCCC1)c1cc(-c2ccc(CN3CCOCC3)cc2Cl)nc2ccc(F)cc12
Reaction time: 1 h
Yield: 60.5 %

Procedure:
A mixture of 2-(2-chloro-4-(morpholinomethyl)phenyl)-6-fluoroquinoline-4-carboxylic acid (303 mg, 0.76 mmol) (preparation 18) in DCM (6 ml) was prepared at room temperature and N-methylmorpholine (0.166 ml, 1.51 mmol) and 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT) (159 mg, 0.91 mmol) added and the mixture stirred for 1 h in a sealed vial. 2-(Pyrrolidin-1-yl)ethanamine (0.143 ml, 1.13 mmol) was then added and the mixture stirred in a sealed vial for 17 h. The mixture was then diluted with DCM (5 ml) and the organic layers washed with water (2×3 ml) and filtered through a phase separator and the organic layers concentrated under reduced pressure and purified by column chromatography (0-10% 7M NH3 in MeOH/DCM) to afford an off white solid. Analysis by 1HNMR showed impurities and the mixture was further purified by mass directed autopreparative HPLC to afford the desired product as an off-white solid (228 mg, 0.46 mmol, 61%).
Reaction SMILES: [CH2:1]([N:5]([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].CO.[CH3:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][Cl:22])=[CH:19][CH:18]=1.O>C1(C)C=CC=CC=1>[Cl-:22].[CH2:10]([N+:5]([CH2:1][CH2:2][CH2:3][CH3:4])([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:21][C:20]1[CH:23]=[CH:24][C:17]([CH3:16])=[CH:18][CH:19]=1)[CH2:11][CH2:12][CH3:13]
Reactant: Cc1ccc(CCl)cc1
Reactant: CCCCN(CCCC)CCCC
Solvent: CO
Solvent: O
Solvent: Cc1ccccc1
Product: CCCC[N+](CCCC)(CCCC)Cc1ccc(C)cc1
Product: [Cl-]
Temperature: 65 °C
Reaction time: 1 h

Procedure:
Into a 3 l round bottom flask, 176.5 g of tri-n-butylamine and 200 ml of methyl alcohol were charged and heated to 65° C. with stirring. Then, 134.1 g of p-methylbenzyl chloride was added thereto over a period of one hour. Then, this solution was stirred at 65° C. for 10 hours. The heating was stopped, and the solution was cooled to 30° C. Then, 1113 ml of water and 82.4 g of toluene were added thereto, and the mixture was stirred at 30° C. for 30 minutes. Then, the toluene layer was removed to obtain an aqueous solution of tri-n-butyl-p-methylbenzylammonium chloride. To this aqueous solution, 0.3 g of NaHCO3 was added to adjust the pH to 6.8.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=1.[NH:17]1[CH2:20][CH:19]([N:21]2[CH2:26][CH2:25][N:24]([C:27]([C:29]3[S:30][CH:31]=[CH:32][N:33]=3)=[O:28])[CH2:23][CH2:22]2)[CH2:18]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>O.CN(C=O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][C:8]1[CH:9]=[CH:10][C:11]([C:12]([N:17]2[CH2:18][CH:19]([N:21]3[CH2:22][CH2:23][N:24]([C:27]([C:29]4[S:30][CH:31]=[CH:32][N:33]=4)=[O:28])[CH2:25][CH2:26]3)[CH2:20]2)=[O:14])=[CH:15][CH:16]=1
Reactant: O=C(O)c1ccc(Oc2ccccn2)cc1
Reactant: O=C(c1nccs1)N1CCN(C2CNC2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(c1ccc(Oc2ccccn2)cc1)N1CC(N2CCN(C(=O)c3nccs3)CC2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 44c (60 mg, 0.28 mmol), 5e (105 mg, 0.36 mmol), HATU (159 mg, 0.42 mmol), Et3N (1 mL), and DMF (3 mL) was stirred at room temperature overnight, and then poured into water (10 mL). The mixture was extracted with EtOAc. The extracts were washed with brine, dried over Na2SO4 and concentrated. The residue was purified by flash column chromatography (silica gel, 7% MeOH/CH2Cl2) to give 98 mg of Cpd 913. MS m/z (M+H+) 450.0.
Reaction SMILES: Cl.[CH2:2]([NH2:5])[CH2:3][CH3:4].[NH2:6][C:7]1[S:8][C:9]2[CH2:15][CH2:14][CH2:13][C:12](=O)[C:10]=2[N:11]=1.C(N)CC.C([BH3-])#N.[Na+]>CO.O.Cl>[NH2:6][C:7]1[S:8][C:9]2[CH2:15][CH:14]([NH:5][CH2:2][CH2:3][CH3:4])[CH2:13][CH2:12][C:10]=2[N:11]=1
Reactant: CCCN
Reactant: Nc1nc2c(s1)CCCC2=O
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCCNC1CCc2nc(N)sc2C1
Temperature: 25 °C
Reaction time: 70 h

Procedure:
3.0 g of propylamine hydrochloride was dissolved in 60 mL of methanol and 2.2 g of 2-amino-oxo-4,5,6,7-tetrahydrobenzothiazole was added. 1.1 mL of propylamine was poured into the mixture to set pH within the range 6.5-7.0. Then 0.7 g of sodium cyanoborohydride was added and the reaction mixture was stirred for 70 hours under nitrogen atmosphere and at ambient temperature. The reaction mixture was diluted with 50 mL of water and 10 mL of conc. hydrochloric acid. Solvents were removed by evaporation, the yellow residue was stirred with ethanol and the solid was removed by filtration. The filtrate was made alkaline with potassium hydroxide solution and the precipitate was again removed by filtration. Filtrate was several times evaporated with ethanol to remove propylamine. The residue was dissolved in hot ethanol and resulting crystals were collected and dried. Reaction product was characterised by NMR spectra.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([N:6]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8](=O)[C:7]2=[O:16])=[CH:2]1.[F:17][C:18]([F:27])([F:26])[C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][CH:25]=1)[NH2:22]>>[S:1]1[CH:5]=[CH:4][C:3]([N:6]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8](=[N:22][C:21]3[CH:23]=[CH:24][CH:25]=[C:19]([C:18]([F:17])([F:26])[F:27])[CH:20]=3)[C:7]2=[O:16])=[CH:2]1
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: O=C1C(=O)N(c2ccsc2)c2ccccc21
Product: O=C1C(=Nc2cccc(C(F)(F)F)c2)c2ccccc2N1c1ccsc1
Temperature: 140 °C
Yield: 18.2 %

Procedure:
A mixture of 1-(3-thienyl)-2H-indole-2,3-dione (25 mg, 0.11 mmol) (prepared as described below) and 3-trifluoromethylaniline (14 uL, 0.11 mmol) was heated neat at 140° C. for 2 h. The crude material was purified by preparative TLC using a mixture of 3:7 ethyl acetate and hexane as the eluent, giving the desired product as a yellow solid (7.3 mg, 0.02 mmol, 22%). 1H NMR (400 MHz) δ 7.62–7.19 (m, 9H), 6.94 (d, J=8.0, 1H), 6.76 (t, J=7.6, 1H); ESI-MS m/z found 373 (MH+).
Reaction SMILES: C[O:2][C:3](=[O:27])[CH2:4][C:5]1[C:9]2[C:10]([Cl:26])=[CH:11][C:12]([O:14][CH2:15][C:16]3[N:20]([CH3:21])[N:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=3)=[CH:13][C:8]=2[S:7][CH:6]=1.[OH-].[Na+].C1COCC1.Cl>O.CO>[Cl:26][C:10]1[C:9]2[C:5]([CH2:4][C:3]([OH:27])=[O:2])=[CH:6][S:7][C:8]=2[CH:13]=[C:12]([O:14][CH2:15][C:16]2[N:20]([CH3:21])[N:19]=[C:18]([C:22]([F:24])([F:23])[F:25])[CH:17]=2)[CH:11]=1
Reactant: COC(=O)Cc1csc2cc(OCc3cc(C(F)(F)F)nn3C)cc(Cl)c12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cn1nc(C(F)(F)F)cc1COc1cc(Cl)c2c(CC(=O)O)csc2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 95.3 %

Procedure:
A mixture of methyl(4-chloro-6-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)methoxy)-1-benzothiophen-3-yl)acetate (1.9 g), 1N NaOH (10 mL), THF (10 mL) and MeOH (10 mL) was stirred at room temperature for 4 h. To the mixture were added 1N HCl (10 mL) and water, and the mixture was extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO4 and concentrated in vacuo. The residual solid was washed with hexane to give the crystals (1.75 g). The crystals were recrystallized from acetone-heptane to give the title compound.
Reaction SMILES: [OH:1][S:2]([OH:5])(=[O:4])=[O:3].[Br:6][C:7]1[N:8]=[C:9]2[C:15]([CH2:16][OH:17])=[CH:14][NH:13][C:10]2=[N:11][CH:12]=1.[CH3:18][C:19]([CH3:21])=[O:20].OS(O)(=O)=O.[O:27]=[Cr:28](=[O:30])=[O:29]>O.CC(C)=O>[CH3:18][C:19]([CH3:21])=[O:20].[OH:4][S:2]([OH:5])(=[O:3])=[O:1].[O:27]=[Cr:28](=[O:30])=[O:29].[Br:6][C:7]1[N:8]=[C:9]2[C:15]([CH:16]=[O:17])=[CH:14][NH:13][C:10]2=[N:11][CH:12]=1
Reactant: OCc1c[nH]c2ncc(Br)nc12
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Solvent: O
Product: O=Cc1c[nH]c2ncc(Br)nc12
Reaction time: 0.25 h

Procedure:
A stock solution of Jones reagent (2.67 M) was prepared by carefully adding concentrated H2SO4 (2.3 mL) to CrO3 (2.67 g) then diluting to 10 mL with H2O. To a partial suspension of (2-bromo-5H-pyrrolo[2,3-b]pyrazin-7-yl)-methanol (4.6 g, 20.1 mmol) in acetone (300 mL) was slowly added Jones reagent (9 mL, 24.0 mmol). During the addition the starting material gradually dissolved and a thick green precipitate was formed. The reaction mixture was stirred for 15 min then quenched with i-PrOH (2 mL) and filtered over Celite, rinsing with acetone. The filtrate was concentrated to provide 4.76 g of 2-bromo-5H-pyrrolo[2,3-b]pyrazine-7-carbaldehyde as a yellow-orange solid that was used without further purification. To a solution of this solid in DMF (50 mL) at 0° C. was added NaH (60% in mineral oil, 1.2 g, 30.1 mmol). The reaction mixture was stirred at room temperature for 30 min then cooled back to 0° C. and 2-(trimethylsilyl)ethoxymethyl chloride (4.3 mL, 24.1 mmol) was slowly added. The reaction mixture was warmed to room temperature and stirred for 1 h then quenched with H2O and extracted with EtOAc (3×). The combined organics were washed with H2O (3×) and brine then dried over MgSO4 and concentrated. The residue was purified by SiO2 chromatography (20% to 30% EtOAc/hexanes) to isolate 3.82 g (53%) of 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbaldehyde as a yellow solid.
Reaction SMILES: F[C:2]1[C:3]([CH3:15])=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([F:14])([F:13])[F:12])[C:5]([OH:7])=[O:6].[H-].[Na+].[CH3:18][S-:19].[Na+].O>CN(C)C=O>[CH3:15][C:3]1[C:2]([S:19][CH3:18])=[C:10]([C:11]([F:14])([F:13])[F:12])[CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6]
Reactant: Cc1c(C(=O)O)ccc(C(F)(F)F)c1F
Reactant: C[S-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CSc1c(C(F)(F)F)ccc(C(=O)O)c1C
Temperature: 80 °C
Reaction time: 0.17 h

Procedure:
300 mg (1.35 mmol) of 3-fluoro-2-methyl-4-trifluoromethylbenzoic acid were initially charged in 5 ml of N,N-dimethylformamide, and 59 mg (purity 60% by weight, 1.49 mmol) of NaH were added. The mixture was stirred for 10 min, and 199 mg (purity 95% by weight, 2.70 mmol) of sodium thiomethoxide were then added. The mixture was stirred at RT for 1.5 h and then heated at 80° C. for 16 h. The reaction mixture was cooled and, for workup, poured into water and extracted with ethyl acetate, and the aqueous phase was then acidified with concentrated HCl. The mixture was extracted twice with t-butyl methyl ether, dried and concentrated. This gave 310 mg of the product.
Reaction SMILES: [I:1][C:2]1[C:11]([N+:12]([O-])=O)=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([C:15]([F:18])([F:17])[F:16])[CH:3]=1.[I:19][C:20]1[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[C:22]([C:30]([F:33])([F:32])[F:31])[C:21]=1[N+:34]([O-])=O>C(O)(=O)C.[Fe]>[NH2:12][C:11]1[C:2]([I:1])=[CH:3][C:4]([C:15]([F:16])([F:17])[F:18])=[C:5]([CH:10]=1)[C:6]([O:8][CH3:9])=[O:7].[NH2:34][C:21]1[C:22]([C:30]([F:33])([F:31])[F:32])=[C:23]([CH:28]=[CH:29][C:20]=1[I:19])[C:24]([O:26][CH3:27])=[O:25]
Reactant: COC(=O)c1cc([N+](=O)[O-])c(I)cc1C(F)(F)F
Reactant: COC(=O)c1ccc(I)c([N+](=O)[O-])c1C(F)(F)F
Agent: [Fe]
Solvent: CC(=O)O
Product: COC(=O)c1cc(N)c(I)cc1C(F)(F)F
Product: COC(=O)c1ccc(I)c(N)c1C(F)(F)F
Temperature: 25 °C

Procedure:
A mixture of methyl 4-iodo-5-nitro-2-(trifluoromethyl)benzoate (desired) and methyl 4-iodo-3-nitro-2-(trifluoromethyl)benzoate as obtained in step 3 (1.7 g, 4.53 mmol) in acetic acid (20 mL) was treated with iron powder (1.5 g, 26.8 mmol) at 45° C. for 2 h. The reaction mixture was cooled to ambient temperature and was filtered through celite. The filter cake was washed with ethyl acetate and the filtrate was concentrated. The residue was diluted with ethyl acetate, washed with saturated sodium bicarbonate and brine, dried over sodium sulfate, then filtered and concentrated to afford a brown oil which was purified by column chromatography (silica gel, 10-30% ethyl acetate in hexanes) to afford the two regioisomers methyl 5-amino-4-iodo-2-(trifluoromethyl)benzoate (major) and methyl 3-amino-4-iodo-2-(trifluoromethyl)benzoate (minor) in a 4:1 ratio (1.484 g, 4.30 mmol, 95% yield). 1H NMR for desired (major) isomer (400 MHz, CDCl3): δ 7.96 (s, 1H), 7.06 (s, 1H), 4.55 (br s, 2H), 3.90 (s, 3H); GCMS for C9H7F31NO2: 345 (M+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=[C:8]([C:16]([OH:18])=O)[CH:7]=1)=[O:5])[CH3:2].[CH2:19]([O:21][C:22]([N:24]1[CH2:29][CH2:28][N:27]([C:30](=[O:42])[C@@H:31]([NH2:41])[CH2:32][CH2:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:26][CH2:25]1)=[O:23])[CH3:20].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C.O>[CH2:1]([O:3][C:4]([C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=[C:8]([C:16](=[O:18])[NH:41][C@H:31]([C:30]([N:27]2[CH2:28][CH2:29][N:24]([C:22]([O:21][CH2:19][CH3:20])=[O:23])[CH2:25][CH2:26]2)=[O:42])[CH2:32][CH2:33][C:34]([O:36][C:37]([CH3:39])([CH3:40])[CH3:38])=[O:35])[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(C(=O)O)nc2ccccc12
Reactant: CCOC(=O)N1CCN(C(=O)[C@@H](N)CCC(=O)OC(C)(C)C)CC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCCl
Product: CCOC(=O)c1cc(C(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(=O)N2CCN(C(=O)OCC)CC2)nc2ccccc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2 g of Quinoline-2,4-dicarboxylic acid 4-ethyl ester and 2.8 g of 4-((S)-2-Amino-4-tert-butoxycarbonyl-butyryl)-piperazine-1-carboxylic acid ethyl ester in 21 ml of DMF, 1.3 g of HOBT and 1.6 g of EDC was added and the reaction mixture was stirred for 16 h at RT. Then, the reaction mixture was diluted with water and extracted with DCM. The organic phase was dried over MgSO4 and the solvents were removed under reduced pressure. The crude product was purified by chromatography on silica gel eluting with a gradient of n-heptane/ethyl acetate. The fractions containing the product were combined and the solvent evaporated under reduced pressure. Yield: 1.1 g.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10][S:11][CH2:12][CH2:13][NH2:14])=[CH:7][CH:6]=1)[CH3:3].CS[C:17](SC)=[CH:18][N+:19]([O-:21])=[O:20]>C(#N)C>[CH3:3][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10][S:11][CH2:12][CH2:13][NH:14][C:17]([NH:2][CH2:4][CH2:5][O:9][CH3:8])=[CH:18][N+:19]([O-:21])=[O:20])=[CH:7][CH:6]=1)[CH3:1]
Reactant: CN(C)Cc1ccc(CSCCN)o1
Reactant: CSC(=C[N+](=O)[O-])SC
Solvent: CC#N
Product: COCCNC(=C[N+](=O)[O-])NCCSCc1ccc(CN(C)C)o1
Yield: 55.9 %

Procedure:
2-[[[5-(Dimethylamino)methyl-2-furanyl]methyl]thio]ethanamine (2.14 g) and 1,1-bis(methylthio)-2-nitroethene (1.65 g) were refluxed in acetonitrile for 8 hr. Solvents were removed and an ethanolic solution of 2-methoxyethylamine (0.75 g) added. After refluxing for a further 8 hr, removal of solvents gave an oil. This was purified by column chromatography to give N-[2-[[[5-(dimethylamino)methyl-2-furanyl]methyl]thio]ethyl]-N'-(2-methoxyethyl)-2-nitro-1,1-ethenediamine (1.0 g). NMR τ (CDCl3) 7.73 s (6H); 7-7.5 m (2H); 6.2-7 m (11H); 6.23 s (2H); 3.81 s (2H); 3.42 s (1H).