Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[CH:7]=[CH:6][C:5]=1[CH3:13]>[Pd].CO.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8]([NH2:10])[CH:7]=[CH:6][C:5]=1[CH3:13]
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1C
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)c1cc(N)ccc1C
Yield: 99.3 %

Procedure:
A solution of 2-methyl-5-nitro-benzoic acid methyl ester (1.96 g, 10.0 mmol) in 4:1 MeOH/EtOAc (25 mL) was shaken at room temperature with a suspension of 10% Pd/C (200 mg, 0.19 mmol) under hydrogen atmosphere (35 psi) for 2 h. The catalyst was removed by filtration, and the filtrate was concentrated in vacuo to give an orange oil (1.64 g, 99%). 1H NMR (CDCl3) δ 2.47 (s, 3H), 3.62 (br s, 2H), 3.87 (s, 3H), 6.75 (dd, 1H, J=8.1, 2.7 Hz), 7.02 (d, 1H, J=8.1 Hz), 7.25 (d, 1H, J=2.7 Hz).
Reaction SMILES: C(O)(=O)C.[CH3:5][O:6][P:7]([CH2:27][NH2:28])([CH2:9][CH:10]([C:15](=[O:26])[NH:16][C@H:17]([C:22](=[O:25])[NH:23][CH3:24])[CH2:18][CH:19]([CH3:21])[CH3:20])[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:8].[CH2:29]([O:36][C:37]1[CH:47]=[CH:46][CH:45]=[C:39]2[C:40]([O:42][C:43](=O)[C:38]=12)=[O:41])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH3:5][O:6][P:7]([CH2:27][N:28]1[C:43](=[O:42])[C:38]2=[C:37]([O:36][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:47]=[CH:46][CH:45]=[C:39]2[C:40]1=[O:41])([CH2:9][CH:10]([C:15](=[O:26])[NH:16][C@H:17]([C:22](=[O:25])[NH:23][CH3:24])[CH2:18][CH:19]([CH3:21])[CH3:20])[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:8]
Reactant: O=C1OC(=O)c2c(OCc3ccccc3)cccc21
Reactant: CNC(=O)[C@H](CC(C)C)NC(=O)C(CC(C)C)CP(=O)(CN)OC
Solvent: CC(=O)O
Product: CNC(=O)[C@H](CC(C)C)NC(=O)C(CC(C)C)CP(=O)(CN1C(=O)c2cccc(OCc3ccccc3)c2C1=O)OC
Yield: 38.3 %

Procedure:
In a manner analogous to that described in Example 3(A), from 0.64 g of (aminomethyl)[(RS)-4-methyl-2-[[(S)-3-methyl-1-(methylcarbamoyl)butyl]carbamoyl]pentyl]phosphinic acid methyl ester acetate and 0.4 g of 3-(benzyloxy)phthalic anhydride, there was obtained 0.347 g of [[3-(benzyloxy)phthalimido]methyl][(RS)-4-methyl-2-[[(S)-3-methyl-1-(methylcarbamoyl)butyl]carbamoyl]pentyl]phosphinic acid methyl ester in the form of a white foam.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]3[C:31]([F:32])=[CH:30][N:29]=[C:28](Cl)[N:27]=3)[CH:21]=2)[S:15]([CH3:18])(=[O:17])=[O:16])[CH2:10][CH2:9]1)=O)(C)(C)C.[F:34][C:35]1[CH:36]=[C:37]([CH2:41][CH2:42][NH2:43])[CH:38]=[CH:39][CH:40]=1>>[F:32][C:31]1[C:26]([C:22]2[CH:21]=[C:20]([CH:25]=[CH:24][CH:23]=2)[CH2:19][N:14]([CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[S:15]([CH3:18])(=[O:16])=[O:17])=[N:27][C:28]([NH:43][CH2:42][CH2:41][C:37]2[CH:38]=[CH:39][CH:40]=[C:35]([F:34])[CH:36]=2)=[N:29][CH:30]=1
Reactant: CC(C)(C)OC(=O)N1CCC(N(Cc2cccc(-c3nc(Cl)ncc3F)c2)S(C)(=O)=O)CC1
Reactant: NCCc1cccc(F)c1
Product: CS(=O)(=O)N(Cc1cccc(-c2nc(NCCc3cccc(F)c3)ncc2F)c1)C1CCNCC1

Procedure:
Intermediate 77 was coupled with 2-(3-fluoro-phenyl)-ethylamine following procedure Q. The resulting product was deprotected following procedure R. LC-MS showed the product had the expected M+H+ of 502. 1H NMR (Varian 300 MHz, CD3OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.26 (d, 1H), 8.19 (s, 1H), 7.98 (d, 1H), 7.49 (m, 2H), 7.08 (m, 3H), 6.87 (m, 1H), 4.55 (s, 2H), 3.91 (m, 1H), 3.64 (t, 2H), 3.34 (m, 2H), 3.03 (s, 3H), 3.00 (m, 2H), 2.92 (t, 2H), 1.91 (m, 4H).
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([Br:26])=[CH:24][N:23]=[C:22](S(C)(=O)=O)[N:21]=3)[C@H:14]2[CH3:31])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Cl.[F:35][C:36]1([F:40])[CH2:39][NH:38][CH2:37]1.C(N(CC)CC)C>C1COCC1>[F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([Br:26])=[CH:24][N:23]=[C:22]([N:38]4[CH2:39][C:36]([F:40])([F:35])[CH2:37]4)[N:21]=3)[C@H:14]2[CH3:31])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: FC1(F)CNC1
Reactant: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1nc(S(C)(=O)=O)ncc1Br
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1nc(N2CC(F)(F)C2)ncc1Br

Procedure:
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[5-bromo-2-(methylsulfonyl)pyrimidin-4-yl]methyl}-4-methyl-1,3-oxazolidin-2-one (1.4428 g, 2.57 mmol) from Step A, 3,3-difluoroazetidine hydrochloride (0.997 g, 7.70 mmol), triethylamine (1.788 ml, 12.83 mmol) and THF (25 mL) were heated in a 63° C. oil bath overnight. The reaction crude was purified by flash chromatography (SiO2, Isolute Flash Si; 100 g prepacked cartridge). The column was eluted by an EtOAc/hexanes mixture (0% to 40%). Related fractions were pooled and evaporated to afford a light yellow solid foam as the titled compound. LCMS calc.=574.03. found=575.09 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:19][C:20]2[CH:25]=[CH:24][C:23](=[O:26])[N:22]([CH3:27])[N:21]=2)[C:9]2[C:10]([C:16]([OH:18])=O)=[N:11][N:12]([CH3:15])[C:13]=2[CH3:14])=[CH:4][CH:3]=1>C(Cl)Cl.CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:9]3[C:10](=[N:11][N:12]([CH3:15])[C:13]=3[CH3:14])[C:16](=[O:18])[N:19]2[C:20]2[CH:25]=[CH:24][C:23](=[O:26])[N:22]([CH3:27])[N:21]=2)=[CH:4][CH:3]=1
Reactant: Cc1c(C(Nc2ccc(=O)n(C)n2)c2ccc(Cl)cc2)c(C(=O)O)nn1C
Solvent: ClCCl
Solvent: CO
Product: Cc1c2c(nn1C)C(=O)N(c1ccc(=O)n(C)n1)C2c1ccc(Cl)cc1

Procedure:
The title compound was prepared in analogy to the procedure described in Example 1 using 4-((4-chlorophenyl)(1-methyl-6-oxo-1,6-dihydropyridazin-3-ylamino)methyl)-1,5-dimethyl-1H-pyrazole-3-carboxylic acid Step 32.3). tR: 3.94 min (HPLC 1); tR: 0.87 min (LC-MS 2); ESI-MS: 370 [M+H]+ (LC-MS 2); Rf=0.56 (CH2Cl2/MeOH 9:1); 1H NMR (400 MHz, DMSO-d6) δ ppm 2.05 (s, 3H) 3.44 (s, 3H) 3.84 (s, 3H) 6.29 (s, 1H) 6.96 (d, J=9.8 Hz, 1H) 7.29-7.41 (m, 4H) 8.21 (d, J=9.8 Hz, 1H).
Reaction SMILES: [CH3:1][Si:2]([CH3:14])([CH3:13])[O:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]#[CH:12])=[CH:7][CH:6]=1.[CH2:15]([CH:20]1[CH2:25][CH2:24][CH:23]([CH2:26][CH:27]=[O:28])[CH2:22][CH2:21]1)[CH2:16][CH2:17][CH2:18][CH3:19].Cl>C1COCC1>[CH3:1][Si:2]([CH3:13])([CH3:14])[O:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][CH:27]([OH:28])[CH2:26][C@H:23]2[CH2:24][CH2:25][C@H:20]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:21][CH2:22]2)=[CH:7][CH:6]=1
Reactant: CCCCCC1CCC(CC=O)CC1
Reactant: C#Cc1ccc(CO[Si](C)(C)C)cc1
Agent: Cl
Solvent: C1CCOC1
Product: CCCCC[C@H]1CC[C@H](CC(O)C#Cc2ccc(CO[Si](C)(C)C)cc2)CC1
Temperature: 25 °C

Procedure:
4-Trimethylsilyloxymethylphenylacetylene (20 mmol) was dissolved in THF (20 ml), followed by dropwise adding n-butyllithium-hexane solution (1.61M, 12.4 ml) while stirring the above solution under ice-cooling, stirring the reaction solution under ice-cooling for 30 minutes, dropwise adding a solution of 2-(4-pentylcyclohexyl)acetaldehyde (4.0 g) in THF (10 ml), raising the temperature of the reaction solution up to room temperature after completion of the dropwise addition, stirring for 5 hours, adding dilute hydrochloric acid (5 ml) to the resulting raw solution, extracting with ethyl acetate (150 ml), washing the organic phase with water, drying over anhydrous MgSO4, concentrating under reduced pressure to obtain a brown oil, and recrystallizing it from a mixed solution of ethyl acetate-heptane, to obtain 1-(4-trimethylsilyloxymethylphenyl)-4-(trans-4-pentylcyclohexyl)-1-butyn-3-ol (white crystals) (5.0 g).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:6][C:7]2[C:12]([C:13]=1I)=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:4].[C:15]([Cu])#[N:16]>CN(C=O)C.C1COCC1.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.[Fe+2]>[CH3:1][O:2][C:3]([C:5]1[NH:6][C:7]2[C:12]([C:13]=1[C:15]#[N:16])=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:4]
Reactant: COC(=O)c1[nH]c2ccccc2c1I
Reactant: N#C[Cu]
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COC(=O)c1[nH]c2ccccc2c1C#N
Temperature: 80 °C

Procedure:
To a solution of 2 g 3-Iodo-1H-indole-2-carboxylic acid methyl ester in 10 ml DMF and 20 ml THF, 1.5 g CuCN, 434 mg Et4NCN and 461 mg DPPF were added and the mixture was purged with argon for 15 min. Then, 254 mg Pd2(dba)3 were introduced and the reaction was heated to 80° C. for 5 h. Finally, 10 ml saturated NaHCO3 solution were added and the mixture was filtered through a chem elut® cartridge by elution with DCM. After subsequent removal of the solvent under reduced pressure the residue was purified by chromatography on silica gel with ethylacetate as eluent. The fractions containing the product were evaporated to yield a white solid. Yield: 1.2 g.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[CH:7][C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].[CH2:16]([O:18][C:19]1[CH:29]=[CH:28][C:22]([CH:23](O)[C:24](O)=[O:25])=[CH:21][CH:20]=1)[CH3:17]>>[C:11]([C:9]1[CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]2[O:15][C:24](=[O:25])[CH:23]([C:22]3[CH:28]=[CH:29][C:19]([O:18][CH2:16][CH3:17])=[CH:20][CH:21]=3)[C:7]=2[CH:8]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)c1ccc(O)c(C(C)(C)C)c1
Reactant: CCOc1ccc(C(O)C(=O)O)cc1
Product: CCOc1ccc(C2C(=O)Oc3c2cc(C(C)(C)C)cc3C(C)(C)C)cc1
Reaction time: 2 h
Yield: 92.1 %

Procedure:
A mixture of 309 g (1.50 mol) of 2,4-di-tert-butylphenol and 196.2 g (1.0 mol) of 4-ethoxymandelic acid is stirred at 140°-150° C. for 2 hours under a nitrogen atmosphere. Stirring at 150° C. is then continued for 1.5 hours under a slight vacuum (50 mbar). Excess 2,4-di-tert-butylphenol is distilled off in a high vacuum. Crystallisation of the residue from 150 ml of xylene and 250 ml of ethanol gives 337.7 g (92%) of 5,7-di-tert-butyl-3-(4-ethoxyphenyl)benzofuran-2-one, melting point 132°-134° C. (compound (101), Table 1).
Reaction SMILES: [C:1](O)(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]C.C(OC(=O)C)(=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Pd].O1CCCC1>[CH2:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCCCCCCCCC(=O)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(=O)OC(C)=O
Solvent: C1CCOC1
Product: C=CCCCCCCCCCCC
Temperature: 255 °C
Yield: 1308.4 %

Procedure:
A mixture of myristic acid (90.0 g, 0.394 mol) and acetic anhydride (40.2 g, 0.394 mol) was heated under reduced pressure (150 torr) using an oil bath maintained at 255° C. A small amount of a tetrahydrofuran solution containing dichlorobis(triphenylphosphine)palladium (0.453 g, 6.45×10-4 mol) and triphenylphosphine (2.97 g, 0.0113 mol) was then added to the reactor in order to initiate the decarbonylation reaction. The olefin product immediately distilled from the reaction mixture into a receiver. As material distilled from the reactor, it was continuously replaced with an equimolar mixture of myristic acid and acetic anhydride at a rate that maintained the initial level of the reactor contents throughout the course of the entire reaction. The solution of Pd-catalyst was added in a slow, continuous manner in order to keep the reaction temperature between ca. 215°-220° C. The decarbonylation reaction proceeded rapidly until the catalyst supply was exhausted, whereupon the reaction temperature gradually reached ca. 245° C. and conversion of myristic acid ceased. The combined product was washed with water and distilled to afford 940 g of 1-tridecene (bp 90° C./10 torr), which GC analysis showed to be 96.3% of the αolefin. TON=7985.
Reaction SMILES: [C:1]([C:6]1[C:7](=[O:19])[O:8][C:9]2([CH2:17][CH2:16][CH:15]([CH3:18])[CH2:14][CH2:13]2)[CH2:10][C:11]=1[OH:12])(=O)[CH2:2][CH2:3][CH3:4].Cl.[CH2:21]([O:23][NH2:24])[CH3:22]>C(N(CC)CC)C>[CH2:21]([O:23][N:24]=[C:1]([C:6]1[C:7](=[O:19])[O:8][C:9]2([CH2:17][CH2:16][CH:15]([CH3:18])[CH2:14][CH2:13]2)[CH2:10][C:11]=1[OH:12])[CH2:2][CH2:3][CH3:4])[CH3:22]
Reactant: CCON
Reactant: CCCC(=O)C1=C(O)CC2(CCC(C)CC2)OC1=O
Agent: Cl
Solvent: CCN(CC)CC
Product: CCCC(=NOCC)C1=C(O)CC2(CCC(C)CC2)OC1=O
Yield: 86.2 %

Procedure:
The acylated compound (8.20) (1.00 g, 3.75 mmol) was oximated with ethoxyamine hydrochloride (0.39 g, 4.0 mmol) in the presence of triethylamine as described in Part (c) of the general procedure above, to afford the title compound (4.9) (1.00 g, 86%) as a mobile pale yellow oil. (Found: M, 309.196. C17H27NO4 requires 309.194.) 1H n.m.r. δ (CDCl3) 14.80, very broad s, 1H; 4.08, q, J 7 Hz, OCH2CH3 ; 3.00, t, J 7.5 Hz, CH2CH2CH3 ; 2.68, s, 2H5; 2.2-1.2 complex, 11H; 1.30, t, J 7.5 Hz, OCH2CH3 ; 1.15-0.7, m, CH2CH2CH3 & CH3.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[N:10]([C:16]1[CH:21]=[CH:20][C:19]([N:22]3[CH2:26][CH2:25][C@@H:24]([N:27]([CH3:29])[CH3:28])[CH2:23]3)=[C:18]([F:30])[CH:17]=1)[CH2:9][CH2:8]2)=[O:4].[OH-].[Na+].CO>O>[CH3:28][N:27]([CH3:29])[C@@H:24]1[CH2:25][CH2:26][N:22]([C:19]2[CH:20]=[CH:21][C:16]([N:10]3[CH2:9][CH2:8][C:7]4[C:12](=[CH:13][CH:14]=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=4)[C:11]3=[O:15])=[CH:17][C:18]=2[F:30])[CH2:23]1
Reactant: COC(=O)c1ccc2c(c1)CCN(c1ccc(N3CC[C@@H](N(C)C)C3)c(F)c1)C2=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CN(C)[C@@H]1CCN(c2ccc(N3CCc4cc(C(=O)O)ccc4C3=O)cc2F)C1

Procedure:
A mixture of 2-[4-((R)-3-dimethylaminopyrrolidin-1-yl)-3-fluorophenyl]-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-carboxylic acid methyl ester (0.80 g), sodium hydroxide (78 mg), methanol (20 mL) and water (10 mL) was boiled under reflux for 2 hours and then concentrated. The product with the molecular weight of 397.45 (C22H24FN3O3) was obtained in this way; MS (ESI): 398 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([N+:19]([O-])=O)[CH:17]=[CH:18][C:13]=2[N:12]([CH3:22])[C:11](=[O:23])[CH:10]([CH3:24])[N:9]=1>Cl>[NH2:19][C:16]1[CH:17]=[CH:18][C:13]2[N:12]([CH3:22])[C:11](=[O:23])[CH:10]([CH3:24])[N:9]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])[C:14]=2[CH:15]=1
Reactant: CC1N=C(c2ccccc2F)c2cc([N+](=O)[O-])ccc2N(C)C1=O
Agent: Cl
Product: CC1N=C(c2ccccc2F)c2cc(N)ccc2N(C)C1=O
Reaction time: 0.25 h

Procedure:
85 g (0.26 M) of rac-5-(o-fluorophenyl)-1,3-dihydro-1,3-dimethyl-7-nitro-2H-1,4-benzodiazepin-2-one are dissolved in 700 ml of concentrated hydrochloric acid and treated slowly with 180 g of stannous chloride. After about 15 minutes, the mixture is cooled with ice and then concentrated on a rotary evaporator. The residue is dissolved in ice-water, slowly made alkaline with 200 g of sodium carbonate in 1 liter of water and extracted several times with methylene chloride. The organic solution is dried over sodium sulphate, filtered and concentrated. The residue is crystallised from ethyl acetate and there is obtained rac-7-amino-5(o-fluorophenyl)-1,3-dihydro-1,3-dimethyl-2H-1,4-benzodiazepin-2-one which melts at 178°-180° C.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11](O)=[O:12])[CH2:7][CH2:6]1.S(Cl)([Cl:18])=O>>[F:1][C:2]([F:15])([F:14])[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]([Cl:18])=[O:12])[CH2:7][CH2:6]1
Reactant: O=C(O)C1CCN(CCC(F)(F)F)CC1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)C1CCN(CCC(F)(F)F)CC1
Temperature: 80 °C
Yield: 68 %

Procedure:
A suspension of 1-(3,3,3-trifluoropropyl)piperidine-4-carboxylic acid (4.40 g, 20.0 mmol) in thionyl chloride (20 mL) was heat to 80° C. for 15 h. The solution was cooled and concentrated in vacuo to yield a brown foam (3.0 g, 68%).
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[C:6]3[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][N:7]3[C:15]=2[CH3:16])[CH2:3][CH2:2]1.[F:17][C:18]([F:31])([F:30])[C:19]1[N:24]=[CH:23][C:22]([CH2:25][CH2:26][C:27](O)=[O:28])=[CH:21][CH:20]=1>>[CH:1]1([C:4]2[N:5]=[C:6]3[CH:11]=[CH:10][C:9]([NH:12][C:27](=[O:28])[CH2:26][CH2:25][C:22]4[CH:23]=[N:24][C:19]([C:18]([F:17])([F:30])[F:31])=[CH:20][CH:21]=4)=[CH:8][N:7]3[C:15]=2[CH3:16])[CH2:3][CH2:2]1
Reactant: Cc1c(C2CC2)nc2ccc([N+](=O)[O-])cn12
Reactant: O=C(O)CCc1ccc(C(F)(F)F)nc1
Product: Cc1c(C2CC2)nc2ccc(NC(=O)CCc3ccc(C(F)(F)F)nc3)cn12

Procedure:
Conducting the operations similar to those of Example 1 using 2-cyclopropyl-3-methyl-6-nitroimidazo[1,2-a]pyridine and 3-[6-(trifluoromethyl)-3-pyridyl]propionic acid, the title compound was obtained as white solid.
Reaction SMILES: [CH:1]1([NH:7][C:8]2[C:9]3[CH:25]=[N:24][N:23]([CH2:26][CH3:27])[C:10]=3[N:11]=[CH:12][C:13]=2[C:14]2[CH2:18][C:17]3([CH2:22][CH2:21][S:20][CH2:19]3)[O:16][N:15]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O.I([O-])(=O)(=O)=[O:30].[Na+]>CO>[CH:1]1([NH:7][C:8]2[C:9]3[CH:25]=[N:24][N:23]([CH2:26][CH3:27])[C:10]=3[N:11]=[CH:12][C:13]=2[C:14]2[CH2:18][C:17]3([CH2:22][CH2:21][S:20](=[O:30])[CH2:19]3)[O:16][N:15]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCn1ncc2c(NC3CCCCC3)c(C3=NOC4(CCSC4)C3)cnc21
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCn1ncc2c(NC3CCCCC3)c(C3=NOC4(CCS(=O)C4)C3)cnc21
Reaction time: 0.08 h

Procedure:
N-cyclohexyl-1-ethyl-5-(1-oxa-7-thia-2-azaspiro[4.4]non-2-en-3-yl)-1H-pyrazolo[3,4-b]pyridin-4-amine (70 mg, 0.00018 mole) (example 13) was taken in methanol and stirring was done for about five minutes. Water (1 ml) was added. Sodium periodate (38 mg, 0.00018 mole) was added. The reaction mixture was stirred at room temperature for about 5 h. Filtration was done and the residue was washed with dichloromethane. The organic layer was dried over anhydrous sodium sulphate and concentrated in vacuo. Purification was done by preparative thin layer chromatography using ethyl acetate (60%) in hexane.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]([NH:8][C:9]1[C:10]([I:36])=[C:11]([CH2:25][CH:26]([O:32][C:33](=[O:35])[CH3:34])[CH2:27][O:28][C:29](=[O:31])[CH3:30])[C:12]([I:24])=[C:13]([NH:16][C:17](=[O:23])[CH2:18][O:19][C:20](=[O:22])[CH3:21])[C:14]=1[I:15])=[O:7])(=[O:3])[CH3:2].[C:37]([O:40][CH2:41][CH2:42]Br)(=[O:39])[CH3:38].C(=O)([O-])[O-].[Cs+].[Cs+]>>[C:1]([O:4][CH2:5][C:6]([NH:8][C:9]1[C:14]([I:15])=[C:13]([N:16]([CH2:42][CH2:41][O:40][C:37](=[O:39])[CH3:38])[C:17](=[O:23])[CH2:18][O:19][C:20](=[O:22])[CH3:21])[C:12]([I:24])=[C:11]([CH2:25][CH:26]([O:32][C:33](=[O:35])[CH3:34])[CH2:27][O:28][C:29](=[O:31])[CH3:30])[C:10]=1[I:36])=[O:7])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC(=O)Nc1c(I)c(CC(COC(C)=O)OC(C)=O)c(I)c(NC(=O)COC(C)=O)c1I
Reactant: CC(=O)OCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CC(=O)OCCN(C(=O)COC(C)=O)c1c(I)c(CC(COC(C)=O)OC(C)=O)c(I)c(NC(=O)COC(C)=O)c1I
Yield: 12 %

Procedure:
3,5-Bis-(acetoxyacetamido)-2,4,6-triiodo-(2,3-diacetoxypropyl)benzene, Example 71 a, was alkylated using 2-bromoethyl acetate in the presence of cesium carbonate according to the general procedure given in Example 25a. The reaction product was purified by HPLC to give the two products. 5-Acetoxyacetamido-3-[N-(2-acetoxyethyl)-acetoxyacetamido]-2,4,6-triiodo-(2,3-diacetoxypropyl)benzene was isolated in 12% yield.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([CH3:13])[CH:5]=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8].[I:14]N1C(=O)CCC1=O>CN(C=O)C>[NH2:1][C:2]1[N:3]=[C:4]([CH3:13])[C:5]([I:14])=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)c1cc(C)nc(N)c1
Reactant: O=C1CCC(=O)N1I
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(N)nc(C)c1I
Temperature: 60 °C
Reaction time: 8 h
Yield: 56.5 %

Procedure:
Ethyl 6-amino-2-methylisonicotinate (2.00 g, 11.1 mmol) was dissolved in DMF (20 mL), and the solution was stirred overnight at 60° C. after adding N-iodosuccinimide (2.50 g, 11.1 mmol). The reaction mixture was stirred at 60° C. for 5 hours after adding N-iodosuccinimide (1.25 g, 5.55 mmol). The reaction mixture was allowed to cool to room temperature, and extracted with a mixed solvent of ethyl acetate and hexane after adding a sodium hydrogen carbonate aqueous solution. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=80/20→50/50) to give ethyl 6-amino-3-iodo-2-methylisonicotinate (1.92 g, yield 57%).
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([S:12]([NH:15][CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])(=[O:14])=[O:13])[CH:8]=2)[O:3]1.Br[CH2:26][C:27]1[CH:28]=[C:29]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:30]=[CH:31][CH:32]=1>C(#N)C>[C:29]1([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:30]=[CH:31][CH:32]=[C:27]([CH2:26][N:15]([CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[S:12]([C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][CH:6]=2)[O:3][C:2]([CH3:24])([CH3:1])[CH2:11][CH2:10]3)(=[O:14])=[O:13])[CH:28]=1
Reactant: BrCc1cccc(-c2ccccc2)c1
Reactant: CC(C)(C)OC(=O)CNS(=O)(=O)c1ccc2c(c1)CCC(C)(C)O2
Solvent: CC#N
Product: CC(C)(C)OC(=O)CN(Cc1cccc(-c2ccccc2)c1)S(=O)(=O)c1ccc2c(c1)CCC(C)(C)O2
Temperature: 90 °C
Yield: 89 %

Procedure:
To a solution of tert-butyl 2-(2,2-dimethylchroman-6-sulfonamido)acetate (20 mg, 0.056 mmol) in acetonitrile (1 mL) was added 3-(bromomethyl)biphenyl (19.47 mg, 0.079 mmol) and resin-supportedBEMP (42.9 mg, 0.084 mmol). The mixture was heated in an oil bath at 90° C. overnight. The reaction mixture was filtered, and the filtrate was concentrated to give an orange residue, which was purified by preparative HPLC using MeCN—H2O-0.1% TFA as the solvent to obtain tert-butyl 2-(N-(biphenyl-3-ylmethyl)-2,2-dimethylchroman-6-sulfonamido)acetate as an oil (26 mg, 84% yield). 1H NMR (500 MHz, CDCl3) δ 7.64-7.60 (m, 2H), 7.54-7.49 (m, 3H), 7.44-7.40 (m, 3H), 7.38 (dd, J=9.4, 5.8 Hz, 1H), 7.33 (ddd, J=6.7, 4.0, 1.2 Hz, 1H), 7.22 (d, J=7.7 Hz, 1H), 4.57 (s, 2H), 3.84 (s, 2H), 2.78 (t, J=6.7 Hz, 2H), 1.80 (t, J=6.7LRMS [ESI, MNa+] m/z calcd for C30H35NO5SNa 544.21. found 544.32. To the solution of tert-butyl 2-(N-(biphenyl-3-ylmethyl)-2,2-dimethylchroman-6-sulfonamido)acetate (23 mg, 0.044 mmol) in DCM (1 mL) was added trifluoroacetic acid (0.102 mL, 1.323 mmol). The mixture was stirred at RT for 1 hour. The reaction mixture was concentrated to give a reddish residue, which was purified by preparative HPLC using MeCN—H2O-0.1% TFA as the solvent to obtain the product as a white powder (17 mg, 82% yield). 1H NMR (500 MHz, CDCl3) δ 7.61 (d, J=6.3 Hz, 1H), 7.60 (s, 1H), 7.51 (d, 1H), 7.50 (d, J=7.4 Hz, 2H), 7.41 (dd, J=13.4, 5.5 Hz, 2H), 7.39 (s, 1H), 7.36 (d, J=7.7 Hz, 1H), 7.34 (t, J=7.3 Hz, 1H), 7.19 (d, J=7.6 Hz, 1H), 6.87-6.83 (m, 1H), 4.52 (s, 2H), 3.97 (s, 2H), 2.77 (t, J=6.7 Hz, 2H), 1.79 (t, J=6.7 Hz, 2H), 1.33 (s, 6H). LRMS [ESI, (M−H)−] m/z calcd for C26H26NO5S 464.15, found 464.32.