Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]CC)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:25][S:26](O)(=[O:28])=[O:27]>C(Cl)(Cl)Cl>[CH2:7]([C:1]1[CH:6]=[CH:5][C:4]([S:26]([Cl:25])(=[O:28])=[O:27])=[CH:3][CH:2]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: O=S(=O)(O)Cl
Reactant: CCCCCCCCCCCCCCCCCCc1ccccc1
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCc1ccc(S(=O)(=O)Cl)cc1
Temperature: 25 °C
Reaction time: 22 h
Yield: 72 %

Procedure:
To a solution of 1-phenyloctadecane (0.76 g, 2.5 mmol) in CHCl3 (5 mL) was added chlorosulfonic acid (0.5 mL, 7.5 mmol) and the mixture was stirred at rt for 22 h. The mixture was poured on ice and extracted with CH2Cl2. The combined extracts were washed with water, a solution of NaHCO3, and water, dried (Na2SO4), and concentrated in vacuo. The residue was chromatographed on silica gel (70-230 mesh) with hexane/ethyl acetate (49:1) to give the product as a white solid (0.71 g, 1.8 mmol, 72%), mp 35-36° C.; 1H NMR (300 MHz, CDCl3) δ 0.88 (t, 3H, J=7.2 Hz), 1.25 (m, 26H), 1.62 (m, 2H), 2.72 (t, 2H, J=7.8 Hz), 7.42 (d, 2H, J=8.4 Hz), 7.95 (d, 2H, J=8.4 Hz); 13C NMR (75 MHz, CDCl3) 14.4, 22.9, 29.4, 29.64, 29.8, 29.9, 31.2, 32.2, 36.3, 127.3, 129.8, 142.0, 151.9.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][N:5]1[C:10]2[CH:11]=[CH:12][CH:13]=[C:14]([O:15][CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][O:17]3)[C:9]=2[O:8][CH2:7][C:6]1=[O:22].C(N(CC)CC)C.CS(Cl)(=O)=O.[N-:35]=[N+:36]=[N-:37].[Na+]>ClCCl.C(Cl)(Cl)Cl.CN(C=O)C.C(OCC)(=O)C>[N:35]([CH2:2][CH2:3][CH2:4][N:5]1[C:10]2[CH:11]=[CH:12][CH:13]=[C:14]([O:15][CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][O:17]3)[C:9]=2[O:8][CH2:7][C:6]1=[O:22])=[N+:36]=[N-:37]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C1COc2c(OC3CCCCO3)cccc2N1CCCO
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: [N-]=[N+]=NCCCN1C(=O)COc2c(OC3CCCCO3)cccc21
Reaction time: 2 h
Yield: 95.7 %

Procedure:
4-(3-hydroxypropyl)-3-oxo-8-(tetrahydropyran-2-yloxy)-3,4-dihydro-2H-1,4-benzoxazine (2.0 g) was dissolved in dichloromethane (20 ml), and triethylamine (1.27 ml) and a methanesulfonyl chloride (0.6 ml) were added to the resultant solution at 0° C., followed by stirring for 2 hours. The reaction solution was diluted with chloroform, washed with saturated brine, and then dried over anhydrous sodium sulfate. Then, the solvent was distilled off under reduced pressure to obtain a crude mesyl compound. The crude mesyl compound was dissolved in DMF (20 ml), and sodium azide (510 mg) was added to the resultant solution, and the mixture was stirred at room temperature for 15 hours. The reaction solution was diluted with ethyl acetate, washed with saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resultant residue was purified by column chromatography (silica gel: ethyl acetate/n-hexane=1:9) to obtain the object compound (2.07 g, yield 96%).
Reaction SMILES: C([O:8][C:9]1[CH:37]=[C:36]([O:38][CH3:39])[CH:35]=[CH:34][C:10]=1[C:11]([C:13]1[CH:18]=[C:17]([O:19][CH2:20][CH2:21][CH3:22])[CH:16]=[CH:15][C:14]=1[C:23](=[O:33])[C:24]1[CH:29]=[CH:28][C:27]2[O:30][CH2:31][O:32][C:26]=2[CH:25]=1)=[O:12])C1C=CC=CC=1.C(OCC)(=O)C>[Pd].CCCCCC>[OH:8][C:9]1[CH:37]=[C:36]([O:38][CH3:39])[CH:35]=[CH:34][C:10]=1[C:11]([C:13]1[CH:18]=[C:17]([O:19][CH2:20][CH2:21][CH3:22])[CH:16]=[CH:15][C:14]=1[C:23](=[O:33])[C:24]1[CH:29]=[CH:28][C:27]2[O:30][CH2:31][O:32][C:26]=2[CH:25]=1)=[O:12]
Reactant: CCCOc1ccc(C(=O)c2ccc3c(c2)OCO3)c(C(=O)c2ccc(OC)cc2OCc2ccccc2)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCCOc1ccc(C(=O)c2ccc3c(c2)OCO3)c(C(=O)c2ccc(OC)cc2O)c1
Reaction time: 24 h
Yield: 74 %

Procedure:
To a solution of 1-(2-benzyloxy-4-methoxybenzoyl)-2-(3,4-methylenedioxybenzoyl)-5-prop-1-yloxybenzene (0.437 g, 0.84 mmol) in a mixture 1:1 ethyl acetate:hexane (20 ml) was added 10% Pd/C (0.040 g) and the mixture was shaken under hydrogen atmosphere at 60 psi for 24 h. The reaction mixture was filtered through a pad of celite and the filtrate dried (MgSO4). After removing the solvent under reduced pressure, flash chromatography of the residue (silica gel, 3:7 ethyl acetate:hexane) afforded the title compound as a pale yellow oil (0.270 g, 72%).
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:6]=[N:7][C:8]([O:11][C:12]2[CH:22]=[CH:21][C:15]3[CH2:16][CH2:17][NH:18][CH2:19][CH2:20][C:14]=3[CH:13]=2)=[CH:9][CH:10]=1)=[O:4].[C:23]1(=O)[CH2:26][CH2:25][CH2:24]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClCCl.C(O)(=O)C>[CH:23]1([N:18]2[CH2:19][CH2:20][C:14]3[CH:13]=[C:12]([O:11][C:8]4[CH:9]=[CH:10][C:5]([C:3]([NH:2][CH3:1])=[O:4])=[CH:6][N:7]=4)[CH:22]=[CH:21][C:15]=3[CH2:16][CH2:17]2)[CH2:26][CH2:25][CH2:24]1
Reactant: O=C1CCC1
Reactant: CNC(=O)c1ccc(Oc2ccc3c(c2)CCNCC3)nc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CNC(=O)c1ccc(Oc2ccc3c(c2)CCN(C2CCC2)CC3)nc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of N-methyl-6-(2,3,4,5-tetrahydro-1H-3-benzazepin-7-yloxy)-3-pyridinecarboxamide (D40) (1.04 g, 3.5 mmol) in dichloromethane (12 ml) containing acetic acid (240 μL) at 0° C. was treated dropwise with cyclobutanone (400 μL, 5.3 mmol) and then stirred at room temperature for 1 hour. The mixture was then cooled to 0° C. and treated portionwise with sodium triacetoxyborohydride (1.11 g, 5.3 mmol) and stirred at room temperature for 16 hours. The solution was carefully basified with 2N sodium hydroxide, stirred for 30 minutes and then extracted with dichloromethane. The combined extracts were washed with brine, dried over anhydrous sodium sulphate and concentrated in vacuo. The crude material was purified by column chromatography eluting with dichloromethane then a mixture of 0.880 ammonia:methanol:dichloromethane (1:9:90) to afford the title compound (E121); MS (ES+) m/e 352 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[C:5]([N+:10]([O-:12])=[O:11])[CH:4]=1.[F:13][C:14]([F:24])([F:23])[C:15](=O)[CH2:16][C:17](OCC)=[O:18]>>[OH:18][C:17]1[C:8]2[C:6](=[C:5]([N+:10]([O-:12])=[O:11])[CH:4]=[C:3]([O:2][CH3:1])[CH:9]=2)[N:7]=[C:15]([C:14]([F:24])([F:23])[F:13])[CH:16]=1
Reactant: COc1ccc(N)c([N+](=O)[O-])c1
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Product: COc1cc([N+](=O)[O-])c2nc(C(F)(F)F)cc(O)c2c1
Yield: 27 %

Procedure:
The reaction of 4-methoxy-2-nitroaniline with ethyl trifluoroacetoacetate in polyphosphoric acid at 130°-140° gave 4-hydroxy-6-methoxy-8-nitro-2-trifluoromethylquinoline. The pure compound (tan crystals, mp 138°-140° ) was obtained in 27% yield following several crystallizations of the crude product from ligroin.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH2:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([OH:17])=[CH:9][CH:8]=1)[CH3:2].Cl[CH2:20][C:21]1[C:22]([CH:37]2[CH2:39][CH2:38]2)=[N:23][C:24]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=2)=[N:25][CH:26]=1>>[CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH2:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([O:17][CH2:20][C:21]2[C:22]([CH:37]3[CH2:39][CH2:38]3)=[N:23][C:24]([C:27]3[CH:28]=[CH:29][C:30]([C:33]([F:35])([F:36])[F:34])=[CH:31][CH:32]=3)=[N:25][CH:26]=2)=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)CCc1ccc(O)c2ccccc12
Reactant: FC(F)(F)c1ccc(-c2ncc(CCl)c(C3CC3)n2)cc1
Product: CCOC(=O)CCc1ccc(OCc2cnc(-c3ccc(C(F)(F)F)cc3)nc2C2CC2)c2ccccc12

Procedure:
A] In analogy to the procedures described in example 5C] and 5D], 3-(4-hydroxy-naphthalen-1-yl)-propionic acid ethyl ester [Helvetica Chimica Acta (2001), 84(8), 2198-2211] was reacted with 5-chloromethyl-4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidine (example 9E]) to give 3-{4-[4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-ylmethoxy]-naphthalen-1-yl}-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as colorless solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[C:12](=O)([O-])[O-].[Cs+].[Cs+].IC.C(OCC)(=O)C>CN(C=O)C>[Br:1][C:2]1[C:3]([CH3:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([O:7][CH3:12])=[O:6]
Reactant: Cc1c(Br)cccc1C(=O)O
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(Br)c1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 84.8 %

Procedure:
A solution of 3-bromo-2-methylbenzoic acid (2.98 g, 13.9 mmol) in DMF (20 mL) was treated with cesium carbonate (4.56 g, 13.9 mmol) and iodomethane (0.900 mL, 14.4 mmol). The reaction mixture was stirred at room temperature for 3 hours. The solution was poured into ethyl acetate and washed with water (3×) and brine. The ethyl acetate layer was concentrated under vacuum to give methyl 3-bromo-2-methylbenzoate (Cpd FF, 2.70 g, 85% yield) as a clear oil.
Reaction SMILES: [CH3:1][N:2]1[C:6]([O:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][NH:15][CH:16]=O)[N:9]=2)=[CH:5][C:4]([C:18]([F:21])([F:20])[F:19])=[N:3]1.Cl>C1COCC1>[CH3:1][N:2]1[C:6]([O:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][NH:15][CH3:16])[N:9]=2)=[CH:5][C:4]([C:18]([F:21])([F:20])[F:19])=[N:3]1
Reactant: Cn1nc(C(F)(F)F)cc1Oc1cccc(CNC=O)n1
Agent: Cl
Solvent: C1CCOC1
Product: CNCc1cccc(Oc2cc(C(F)(F)F)nn2C)n1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
4.40 g (14.7 mmol) of 2-(1-methyl-3-trifluoromethylpyrazol-5-yloxy)-6-(formylaminomethyl)-pyridine were dissolvej in 45 ml of anhydrous THF under an inert gas atmosphere and at 0° C. 4.17 ml (44.0 mmol) of borane dimethylsulfide complex were added to the solution. The mixture was heated at 50° C. for 2.5 h. After cooling to room temperature, the reaction solution was admixed with 100 ml of 2 N HCl, stirred for 1 h and then extracted with ethyl acetate. The aqueous phase was rendered alkaline with 2 N NaOH and subjected to repeated extraction with ethyl acetate. The extracts were dried over MgSO4 and concentrated to dryness.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:37])=[C:9]([CH2:11][O:12][C:13]2[CH:34]=[CH:33][C:16]([CH2:17][O:18]/[N:19]=[C:20](/[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)\[CH2:21][CH2:22][C:23]([O:25]C)=[O:24])=[CH:15][C:14]=2[O:35][CH3:36])[N:10]=1.C(O)C.[OH-].[Na+].Cl>O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:37])=[C:9]([CH2:11][O:12][C:13]2[CH:34]=[CH:33][C:16]([CH2:17][O:18]/[N:19]=[C:20](/[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)\[CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[CH:15][C:14]=2[O:35][CH3:36])[N:10]=1
Reactant: COC(=O)CC/C(=N\OCc1ccc(OCc2nc(-c3ccco3)oc2C)c(OC)c1)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1cc(CO/N=C(\CCC(=O)O)c2ccccc2)ccc1OCc1nc(-c2ccco2)oc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 93 %

Procedure:
A mixture of methyl E-4-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]-3-methoxybenzyloxyimino]-4-phenylbutyrate (1.55 g, ethanol (10 ml) and 1N aqueous sodium hydroxide (5 ml) was stirred at room temperature for 2 hours. The reaction mixture was poured into water and acidified with 1N hydrochloric acid to give E-4-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]-3-methoxybenzyloxyimino]-4-phenylbutyric acid as crystals (1.40 g, yield 93%). Recrystallization from ethanol-isopropyl ether gave colorless prisms. m.p. 131-132° C.
Reaction SMILES: Br[C:2]1[C:7]([NH2:8])=[C:6]([CH2:9][S:10][CH3:11])[C:5]([F:12])=[C:4]([F:13])[CH:3]=1.[CH3:14][N:15](P(N(C)C)(N(C)C)=O)C.[Cu](C#N)C#N.C(N)CN>O>[NH2:8][C:7]1[C:6]([CH2:9][S:10][CH3:11])=[C:5]([F:12])[C:4]([F:13])=[CH:3][C:2]=1[C:14]#[N:15]
Reactant: CN(C)P(=O)(N(C)C)N(C)C
Reactant: CSCc1c(N)c(Br)cc(F)c1F
Agent: N#C[Cu]C#N
Solvent: NCCN
Solvent: O
Product: CSCc1c(N)c(C#N)cc(F)c1F
Temperature: 150 °C
Yield: 35.4 %

Procedure:
A mixture of 6-bromo-3,4-difluoro-2-methylthiomethylaniline (99 g), HMPA (130 g) and copper cyanide (48 g) is heated at 150° C. for 4 hours. After cooling, the reaction mixture is poured into a solution of ethylenediamine (50 ml) in water (500 ml), and the mixture is heated at 60° C. for one hour. After cooling, the mixture is extracted with ethyl acetate, and the extract is dried over magnesium sulfate and concentrated. The resulting residue is purified by silica gel column chromatography (solvent, dichloromethane: n-hexane=1:1), and the product is recrystallized from ethanol to give 2-amino-4,5-difluoro-3-methylthiomethylbenzonitrile (28 g), as a white crystal, m.p. 109°-110° C.
Reaction SMILES: Cl[C:2]1[N:21]=[C:5]2[C:6]([NH:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[S:17]([CH3:20])(=[O:19])=[O:18])=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[N:22]1([CH2:27][CH2:28][O:29][C:30]2[CH:35]=[CH:34][C:33]([NH2:36])=[CH:32][CH:31]=2)[CH2:26][CH2:25][CH2:24][CH2:23]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:20][S:17]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[NH:10][C:6]1[C:5]2[N:4]([N:3]=[C:2]([NH:36][C:33]3[CH:34]=[CH:35][C:30]([O:29][CH2:28][CH2:27][N:22]4[CH2:26][CH2:25][CH2:24][CH2:23]4)=[CH:31][CH:32]=3)[N:21]=2)[CH:9]=[CH:8][CH:7]=1)(=[O:19])=[O:18]
Reactant: CS(=O)(=O)c1ccccc1Nc1cccn2nc(Cl)nc12
Reactant: Nc1ccc(OCCN2CCCC2)cc1
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CS(=O)(=O)c1ccccc1Nc1cccn2nc(Nc3ccc(OCCN4CCCC4)cc3)nc12

Procedure:
N(8)-(2-Methanesulfonyl-phenyl)-N(2)-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-[1,2,4]triazolo[1,5-a]pyridine-2,8-diamine was prepared from (2-chloro-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-(2-methanesulfonyl-phenyl)-amine (75.0 mg, 0.232 mmol) and 4-(2-pyrrolidin-1-yl-ethoxy)-phenylamine (58.0 mg, 0.281 mmol)(prepared as described in J. Med. Chem., 2006, 49, 4451-4454) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (25.0 mg, 0.0457 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a yellow foam (0.064 g, 56%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.46 (s, 1H), 8.11 (d, J=6.7 Hz, 1H), 7.98 (dd, J=7.9, 1.1 Hz, 1H), 7.57-7.50 (m, 2H), 7.48 (d, J=9.0 Hz, 2H), 7.28-7.24 (m, 1H), 7.14-7.09 (m, 1H), 6.93 (d, J=9.0 Hz, 2H), 6.79 (t, J=6.4 Hz, 1H), 6.68 (s, 1H), 4.10 (t, J=6.1 Hz, 2H), 3.14 (s, 3H), 2.90 (t, J=5.9 Hz, 2H), 2.68-2.58 (m, 4H), 1.86-1.76 (m, 4H). MS=493 (MH)+.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19]CC1C=CC=CC=1)[CH:15]([CH2:27][C:28]1[CH:33]=[C:32]([I:34])[C:31]([O:35]C)=[C:30]([I:37])[CH:29]=1)[NH:14][CH2:13][CH2:12]2)C1C=CC=CC=1.COC1C(OC)=C(OC)C=C(CC2NCCC3C2=CC(O)=C(O)C=3)C=1.Cl.B(Br)(Br)Br>>[OH:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[OH:19])[CH:15]([CH2:27][C:28]1[CH:33]=[C:32]([I:34])[C:31]([OH:35])=[C:30]([I:37])[CH:29]=1)[NH:14][CH2:13][CH2:12]2
Reactant: COc1c(I)cc(CC2NCCc3cc(OCc4ccccc4)c(OCc4ccccc4)cc32)cc1I
Agent: BrB(Br)Br
Agent: COc1cc(CC2NCCc3cc(O)c(O)cc32)cc(OC)c1OC
Agent: Cl
Product: Oc1cc2c(cc1O)C(Cc1cc(I)c(O)c(I)c1)NCC2

Procedure:
While reaction of 10a with acetic anhydride at room temperature did not give the desired 4′-acetamido derivative 13, heating 10a in acetic anhydride at reflux resulted in the diacetylation product 16(Scheme 3). Similar diacetylation has been reported with the reaction of 2,6-dibromo-4-toluidine with refluxing acetic anhydride while lower temperatures gave a mixture of mono and diacetylated products. Ulffers, F.; von Janson, A. Diacetylderivate einger Amine der aromatischen Reihe Ber. 1894, 27, 93-101. With this in mind, mono-acetylation was accomplished by reacting 10a with 5 equivalents of acetyl chloride in the presence of 4-dimethylaminopyridine (DMAP) and triethylamine at room temperature to afford 13. Basic hydrolysis of the trifluoroacetyl protecting group of 10a and 13gave 20c and 14, respectively. The methoxy derivatives 20c, 14, and 6c were demethylated with BBr3 to afford the desired trimetoquinol analogs 21c, 15, and 27, respectively, as hydrobromide salts (Sch m 1 and 3). In a similar manner, the 6,7-dibenzyloxy-1-(3,5-diiodo-4-methoxybenzyl)-1,2,3,4-tetrahydro-isoquinoline, Harrold, M. W.; Gerhardt,. M. A.; Romstedt, K.; Feller, D. R.; Miller, D. D. Synthesis and platelet antiaggregatory activity of trimetoquinol analogs as endoperoxide/thromboxane A2 antagonists Drug Des Deliv 1987, 1, 193-207, was dealkylated with BBr3 to give 6,7-dihydroxy-1-(3,5-diiodo-4-hydroxybenzyl)-1,2,3,4-tetrahydroisoquinoline (18) the desmethyl analog of 2. Diazotization of 10a (Scheme 3) followed by reaction of the diazonium salt with H3PO2 or potassium iodide (KI) gave the diiodo and triiodo derivatives, 19a and 19b, respectively. Basic hydrolysis of the trifluoroacetyl group of 19a,b as before gave 20a,b. Demethylation of 20a,b with BBr3 proceeded smoothly to give 21a,b. Compound 9a was acylated with acetic anhydride in refluxing benzene to give 22which was deprotected in the same manner as 14to give 23(Scheme 4).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=1)[C:7]([NH:9][NH2:10])=[O:8])([O-:3])=[O:2].[C:14]1([CH3:23])[CH:19]=[CH:18][C:17]([C:20](Cl)=[O:21])=[CH:16][CH:15]=1>N1C=CC=CC=1>[CH3:23][C:14]1[CH:19]=[CH:18][C:17]([C:20]([NH:10][NH:9][C:7](=[O:8])[C:6]2[CH:11]=[CH:12][CH:13]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)=[O:21])=[CH:16][CH:15]=1
Reactant: NNC(=O)c1cccc([N+](=O)[O-])c1
Reactant: Cc1ccc(C(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(C(=O)NNC(=O)c2cccc([N+](=O)[O-])c2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 3-nitrobenzhydrazide (2.16 g, 11.92 mmol) in pyridine (40 ml) cooled to 0° C. in an ice bath is added dropwise p-toluoyl chloride (1.94 g, 11.92 mmol). The mixture is allowed to warm to room temperature and stirred for 12 hours. The mixture is quenched with 350 mL of water and stirred for thirty minutes. The precipitate is filtered and dried in a vacuum oven to yield 1-[(4-methyl)benzoyl]-2-(3-nitrobenzoyl)hydrazine as a pale yellow solid. (2.94 g, 82%).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[CH:12][C:13](=[O:24])[N:14]2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])=[C:9]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[Cl:31])[CH:8]=1)(=O)=O.[NH2:34][CH:35]([CH2:38][OH:39])[CH2:36][OH:37].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(Cl)(Cl)Cl.O>[Cl:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[N:14]1[C:15]2[C:10](=[C:9]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[Cl:31])[CH:8]=[C:7]([NH:34][CH:35]([CH2:38][OH:39])[CH2:36][OH:37])[CH:16]=2)[CH:11]=[CH:12][C:13]1=[O:24]
Reactant: NC(CO)CO
Reactant: O=c1ccc2c(-c3ccccc3Cl)cc(OS(=O)(=O)C(F)(F)F)cc2n1-c1ccccc1Cl
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Product: O=c1ccc2c(-c3ccccc3Cl)cc(NC(CO)CO)cc2n1-c1ccccc1Cl
Yield: 15.8 %

Procedure:
1,5-bis(2-chlorophenyl)-2-oxo-1,2-dihydro-7-quinolinyl trifluoromethanesulfonate (50 mg, 0.097 mmol), serinol (44 mg, 0.483 mmol), racemic BINAP (74 mg, 0.19 mmol), palladium(II) acetate (17 mg, 0.076 mmol), and cesium carbonate (0.14 g, 0.43 mmol) in 1,4-dioxan (2 ml) were heated in a Smith creator microwave at 130° for 15 min. Water (3 ml) and chloroform (4 ml) were added to the reaction mixture, which was then passed through a hydrophobic frit, and blown down under a stream of nitrogen. The residue was purified by mass directed autoprep to afford the title compound as a gum (7 mg, 16%).
Reaction SMILES: N([O-])=O.[Na+].S(=O)(=O)(O)O.[N+:10]([C:13]1[CH:19]=[C:18]([I:20])[C:16](N)=[C:15]([I:21])[CH:14]=1)([O-:12])=[O:11]>C(O)(=O)C.C(O)C>[I:20][C:18]1[CH:19]=[C:13]([N+:10]([O-:12])=[O:11])[CH:14]=[C:15]([I:21])[CH:16]=1
Reactant: Nc1c(I)cc([N+](=O)[O-])cc1I
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: O=[N+]([O-])c1cc(I)cc(I)c1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
13.8 g (0.2 M) of sodium nitrite was added portionwise slowly to 96 mL of conc. sulfuric acid at 0° C. The resulting thick mixture was stirred at 0° C. for 10 minutes. A suspension of 68.25 g (0.175 M) of finely powdered 4-nitro-2,6-diiodoaniline in 175 mL of glacial acetic acid was added cautiously portionwise to the above mixture at 0° C. After the addition, the mixture was stirred 30 mins. The resulting slurry was then added slowly to a vigorously stirred suspension of 4 g of cuprous oxide in 420 mL of absolute ethanol over a period of 25 mins. Vigorous effervescence was observed during this addition. The resulting mixture was stirred 20 mins. at room temperature and then heated to reflux for 30 minutes. After cooling, this reaction mixture was poured onto a large amount of ice. The solid which separated was filtered, and washed with water. This solid was dissolved in a minimum amount of chloroform, dried over anhyd. magnesium sulfate, and the solvent was removed to give 62 g of 3,5-diiodnitrobenzene as a yellow solid. ##STR135##
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11]CCOCCOCCCC)[CH2:2][CH2:3][CH3:4]>C(O)(=O)C>[CH2:1]([O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][OH:11])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOCCOCCOCCOCCCC
Solvent: CC(=O)O
Product: CCCCOCCOCCO

Procedure:
the 2-(2-butoxyethoxy)-ethyl ether of acetic acid
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH2:7][CH3:8])[N:5]=[C:4]([CH3:9])[CH:3]=1.I[C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]([OH:15])=[O:14].CN(C=O)C.C([O-])([O-])=O.[K+].[K+]>C(O)(=O)C>[CH2:7]([N:6]1[C:2]([NH:1][C:11]2[C:12](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:13]([OH:15])=[O:14])=[CH:3][C:4]([CH3:9])=[N:5]1)[CH3:8]
Reactant: CCn1nc(C)cc1N
Reactant: O=C(O)c1ccccc1I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CCn1nc(C)cc1Nc1ccccc1C(=O)O
Temperature: 25 °C
Yield: 48.2 %

Procedure:
A mixture of 5-amino-1-ethyl-3-methylpyrazole (7.5 g, 0.06 mol), 2-iodobenzoic acid (14.88 g, 0.06 mol), DMF (50 ml) Cu(OAc)2.H2 (0.5 g) and K2CO3 (8.3 g, 0.06 mol) was refluxed under a nitrogen atmosphere for 20 hours. The reaction mixture was cooled to room temperature and then was poured into ice-water. The mixture was neutralized with acetic acid and the resulting solid was collected by filtration, washed with water and dried to afford 7.1 g (48%) of N-(1-ethyl-3-methylpyrazol-5-yl)anthranilic acid.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]([CH:9]([OH:13])[C:10]([OH:12])=O)[CH:6]=[N:7][CH:8]=1.[C:14]1([CH:20]([NH2:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C1C=NC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C1COCC1.C(OCC)(=O)C>[CH:20]([NH:27][C:10](=[O:12])[CH:9]([C:5]1[CH:6]=[N:7][CH:8]=[C:3]([Br:2])[CH:4]=1)[OH:13])([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(O)C(O)c1cncc(Br)c1
Reactant: NC(c1ccccc1)c1ccccc1
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(NC(c1ccccc1)c1ccccc1)C(O)c1cncc(Br)c1
Temperature: 60 °C
Yield: 84.5 %

Procedure:
(5-Bromo-pyridin-3-yl)-hydroxy-acetic acid HCl salt (1.19 g, 4.47 mmol), diphenylmethylamine (1.3 g, 5.36 mmol), HOAT (2.0 g, 5.36 mmol) and DIEA (1.94 mL, 11.17 mmol) were all combined in THF (43.0 mL) and heated in a closed vial for 20 min at 60° C. The solution was diluted with ethyl acetate and washed with saturated sodium bicarbonate (1×) and brine (1×). The material was purified by silica gel chromatography using a gradient of hexanes and ethyl acetate (0-100%) to afford N-benzhydryl-2-(5-bromo-pyridin-3-yl)-2-hydroxy-acetamide (1.5 g, 73.5%) as a waxy white solid. MS: m/z 397 (M+H+).