Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: BrC1C=C[C:5]([N:8]2[CH2:13][C@H:12](C)[NH:11][C@H:10]([CH3:15])[CH2:9]2)=CC=1.I[C:17]1[CH:22]=[CH:21][C:20]([I:23])=[CH:19][CH:18]=1.CN(C)[C@@H]1CCNC1>>[I:23][C:20]1[CH:21]=[CH:22][C:17]([N:11]2[CH2:10][CH2:15][C@@H:13]([N:8]([CH3:5])[CH3:9])[CH2:12]2)=[CH:18][CH:19]=1
Reactant: C[C@@H]1CN(c2ccc(Br)cc2)C[C@H](C)N1
Reactant: Ic1ccc(I)cc1
Agent: CN(C)[C@@H]1CCNC1
Product: CN(C)[C@@H]1CCN(c2ccc(I)cc2)C1

Procedure:
The title compound was synthesized according to the synthesis of 1-(4-bromophenyl)-cis-3,5-dimethylpiperazine, except reacting 1,4-diiodobenzene (2.41 g, 7.30 mmol) with (R)—N,N-dimethylpyrrolidin-3-amine (1.0 g, 8.8 mmol). The title compound was purified by silica gel chromatography (MeOH/CH2Cl2, 2:98 to 12:88) as a yellow solid (1.17 g, 51%). 1H NMR (400 MHz, MeOD) δ 7.42 (d, J=8.2 Hz, 2H), 6.39 (d, J=8.0 Hz, 2H), 3.51-3.47 (m, 1H), 3.44-3.39 (m, 1H), 3.29-3.24 (m, 1H), 3.13-3.09 (m, 2H), 3.00-2.87 (m, 1H), 2.35 (s, 6H), 2.35-2.26 (m, 1H), 1.96-1.86 (m, 1H); MS ESI 317.0 [M+H]+, calcd for [C12H17IN2+H]+ 317.04.
Reaction SMILES: C([NH:4][C:5]1[CH:6]=[C:7]([N:11]2[C:16](=[O:17])[C:15]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:14][C:13]3[CH:25]=[CH:26][CH:27]=[N:28][C:12]2=3)[CH:8]=[CH:9][CH:10]=1)(=O)C.C(=O)(O)[O-].[Na+]>Cl>[NH2:4][C:5]1[CH:6]=[C:7]([N:11]2[C:16](=[O:17])[C:15]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:14][C:13]3[CH:25]=[CH:26][CH:27]=[N:28][C:12]2=3)[CH:8]=[CH:9][CH:10]=1
Reactant: CC(=O)Nc1cccc(-n2c(=O)c(Cc3ccccc3)nc3cccnc32)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Nc1cccc(-n2c(=O)c(Cc3ccccc3)nc3cccnc32)c1
Yield: 94.5 %

Procedure:
A mixture of 4-(3-acetamidophenyl)-2-benzyl-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (6.03 g) in 3N hydrochloric acid (150 ml) was refluxed for 1 hour. Sodium bicarbonate was added thereto until the mixture was alkaline. The mixture was extracted with ethyl acetate and the organic solution was washed with water and brine, dried over magnesium sulfate and concentrated to give the solids. The solids were collected and washed with ethanol to give 4-(3-aminophenyl)-2-benzyl-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (5.05 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13](O)[CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][CH:9]=2)=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:41]1(=[O:51])[NH:45][C:44](=[O:46])[C:43]2=[CH:47][CH:48]=[CH:49][CH:50]=[C:42]12.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[O:46]=[C:44]1[C:43]2[C:42](=[CH:50][CH:49]=[CH:48][CH:47]=2)[C:41](=[O:51])[N:45]1[CH:13]1[CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][CH:9]=[C:8]1[C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc(F)cc2)C(O)C1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc(F)cc2)C(N2C(=O)c3ccccc3C2=O)C1
Yield: 84 %

Procedure:
To a tetrahydrofuran solution (10 mL) of tert-butyl 4-(4-fluorophenyl)-5-hydroxy-5,6-dihydropyridine-1(2H)-carboxylate (1.00 g, 3.41 mmol) synthesized in Reference Synthesis Example 354, triphenylphosphine (0.894 g, 3.41 mmol), and phthalimide (0.501 g, 3.41 mmol), diisopropyl azodicarboxylate (1.9 M, toluene solution) (1.97 mL, 3.75 mmol) was added dropwise and the resultant mixture was stirred at room temperature for 1 day. After completion of the reaction, the reaction solution was concentrated and the resultant residue was purified by silica gel column chromatography to obtain the title compound (1.21 g, yield 84%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH3:23])=[C:6]([CH:22]=1)[C:7]([NH:9][C:10]1[C:11]([CH3:21])=[C:12]([CH:17]=[CH:18][C:19]=1[CH3:20])[C:13]([O:15][CH3:16])=[O:14])=[O:8].[C:24]([Si:28]([CH3:37])([CH3:36])[O:29][CH:30]1[CH2:35][CH2:34][CH2:33][NH:32][CH2:31]1)([CH3:27])([CH3:26])[CH3:25].C([O-])([O-])=O.[Cs+].[Cs+].COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Si:28]([O:29][CH:30]1[CH2:35][CH2:34][CH2:33][N:32]([C:2]2[CH:3]=[CH:4][C:5]([CH3:23])=[C:6]([CH:22]=2)[C:7]([NH:9][C:10]2[C:11]([CH3:21])=[C:12]([CH:17]=[CH:18][C:19]=2[CH3:20])[C:13]([O:15][CH3:16])=[O:14])=[O:8])[CH2:31]1)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:37])[CH3:36]
Reactant: COC(=O)c1ccc(C)c(NC(=O)c2cc(Br)ccc2C)c1C
Reactant: CC(C)(C)[Si](C)(C)OC1CCCNC1
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: COC(=O)c1ccc(C)c(NC(=O)c2cc(N3CCCC(O[Si](C)(C)C(C)(C)C)C3)ccc2C)c1C
Temperature: 100 °C
Reaction time: 16 h
Yield: 59.3 %

Procedure:
To a solution of methyl 3-[(5-bromo-2-methyl-benzoyl)amino]-2,4-dimethyl-benzoate (0.5 g, 1.32 mmol), tert-butyl-dimethyl-(3-piperidyloxy)silane (0.425 g, 1.98 mmol) and Cs2CO3 (1.28 g, 3.96 mmol) in 1,4-dioxane (15 ml) is added Pd2(dba)3 (0.12 g, 0.132 mmol) followed by S-Phos (0.054 g, 0.132 mmol). The reaction mixture is purged with nitrogen for 5 minutes and then heated at 100° C. After 16 hours, the reaction is cooled to ambient temperature, filtered through Celite™, and washed with EtOAc. The combined filtrates are dried over sodium sulfate, filtered, and concentrated under reduced pressure and purified by flash chromatography (silica gel) using 10% EtOAc in hexane to afford the title compound as a brown semi-solid (0.4 g, 60%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Cl[CH2:15][CH2:16][CH:17]1[O:21][C:20](=[O:22])[N:19]([CH3:23])[CH2:18]1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+]>C(O)CCC.CC(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:15][CH2:16][CH:17]3[O:21][C:20](=[O:22])[N:19]([CH3:23])[CH2:18]3)[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: CN1CC(CCCl)OC1=O
Reactant: Clc1ccc(N2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCCCO
Solvent: CC(C)O
Product: CN1CC(CCN2CCN(c3ccc(Cl)cc3)CC2)OC1=O
Yield: 72.9 %

Procedure:
This compound was prepared according to the procedure of Example 2. A mixture of 4.9 g (0.025 mol) of 1-(4-chlorophenyl)piperazine, 4.1 g (0.025 mol) of 5-(2-chloroethyl)-3-methyl-2-oxazolidinone, 8.0 g (0.075 mol) of anhydrous sodium carbonate and 0.4 g of potassium iodide in 150 mL of 1-butanol gave 5.9 g (73%) of white solid, mp 113°-114° C. (2-propanol).
Reaction SMILES: [OH:1][CH:2]1[CH2:6][C:5]2([CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[CH2:4][CH:3]1[NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16].FC(F)(F)S(O[C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[C:33]([O:36][CH3:37])[N:34]=2)[N:29]=[CH:28][CH:27]=1)(=O)=O>CN(C=O)C>[OH:1][C@@H:2]1[CH2:6][C:5]2([CH2:11][CH2:10][N:9]([C:26]3[C:35]4[C:30](=[CH:31][CH:32]=[C:33]([O:36][CH3:37])[N:34]=4)[N:29]=[CH:28][CH:27]=3)[CH2:8][CH2:7]2)[CH2:4][C@@H:3]1[NH:12][C:13](=[O:19])[O:14][C:15]([CH3:16])([CH3:18])[CH3:17]
Reactant: CC(C)(C)OC(=O)NC1CC2(CCNCC2)CC1O
Reactant: COc1ccc2nccc(OS(=O)(=O)C(F)(F)F)c2n1
Solvent: CN(C)C=O
Product: COc1ccc2nccc(N3CCC4(CC3)C[C@@H](O)[C@@H](NC(=O)OC(C)(C)C)C4)c2n1
Reaction time: 12 h
Yield: 74.9 %

Procedure:
A solution of 1,1-dimethylethyl (3-hydroxy-8-azaspiro[4.5]dec-2-yl)carbamate (185 mg, 0.685 mmol) and 6-(methyloxy)-1,5-naphthyridin-4-yl trifluoromethanesulfonate (211 mg, 0.685 mmol) in DMF (1 mL) were stirred at 90° C. After 12 h, the solution was concentrated and the residue purified via column chromatography (silica, 1-2% MeOH in DCM (1% NH4OH)) yielding the title compound (220 mg, 75%) as a white foam: LCMS (ES) m/e 430 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][NH:10][C:11](=[O:13])[CH3:12])[CH:5]=[CH:6][C:7]=1[Cl:8].[C:14](OCC)(=O)[CH2:15]C(C)=O.P(Cl)(Cl)Cl>>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH:14]([CH3:15])[CH2:12][C:11]([OH:13])=[N:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CCOC(=O)CC(C)=O
Reactant: CC(=O)NNc1ccc(Cl)c(Cl)c1
Solvent: ClP(Cl)Cl
Product: CC1CC(O)=NN1c1ccc(Cl)c(Cl)c1
Temperature: 50 °C
Yield: 41 %

Procedure:
To a mixture of (V) (5.0 g, 22.8 mmol) and ethyl acetoacetate (2.97 g 22.8 mmol) was slowly added PCl3 (3.13 g, 22.8 mmol). The mixture was warmed to 50° C. for 1.5 h, poured into ice water (150 ml), and the resulting precipitate was collected on a sintered glass funnel and recrystallized from EtOH to yield (VI) (2.29 g, 41%) as white crystals, mp 208-211° C. (lit. 208-209° C.), TLC CHCl3/MeOH 9:1.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]([CH3:16])[C:12]([N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][S:18]2(=[O:24])=[O:23])=[N:11][C:10]=1[C:25]([OH:27])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].ClC=[N+](C)C.[F:34][C:35]1[CH:41]=[CH:40][C:38]([NH2:39])=[CH:37][CH:36]=1.N1C=CC=CC=1>ClCCl>[F:34][C:35]1[CH:41]=[CH:40][C:38]([NH:39][C:25]([C:10]2[N:11]=[C:12]([N:17]3[CH2:22][CH2:21][CH2:20][CH2:19][S:18]3(=[O:24])=[O:23])[N:13]([CH3:16])[C:14](=[O:15])[C:9]=2[O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:27])=[CH:37][CH:36]=1
Reactant: Nc1ccc(F)cc1
Reactant: Cn1c(N2CCCCS2(=O)=O)nc(C(=O)O)c(OCc2ccccc2)c1=O
Agent: C[N+](C)=CCl
Agent: [Cl-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cn1c(N2CCCCS2(=O)=O)nc(C(=O)Nc2ccc(F)cc2)c(OCc2ccccc2)c1=O
Reaction time: 0.25 h
Yield: 108.8 %

Procedure:
A solution of 5-benzyloxy-2-(1,1-dioxo-1λ6-[1,2]thiazinan-2-yl)-1-methyl-6-oxo-1,6-dihydro-pyrimidine-4-carboxylic acid (0.200 g, 0.51 mmol) in dichloromethane (20 ml) was treated at 25° C. with (chloromethylene)dimethylammonium chloride (0.080 g, 0.62 mmol) and the resulting mixture was stirred for 15 min. Then a solution of 4-fluoroaniline (0.117 g, 1.06 mmol) and pyridine (0.1 ml, 1.2 mmol) in dichloromethane (2 ml) was added and the reaction mixture was stirred for another 45 min. The mixture was quenched by addition of ethyl acetate and pH 6 phosphate buffer. The organic phase was then washed with saturated sodium bicarbonate, brine and dried over anhydrous magnesium sulfate. Evaporation of the solvent and chromatography of the residue on silica gel (elution toluene-ethyl acetate 7:3) gave 0.270 g (88% yield) of the title amide as white crystals; mp 201–202° C.(ethyl acetate). 1HNMR 400 MHz (CDCl3) δ (ppm): 1.65–1.69 and 2.35–2.7 (1H and 3H, 2 m, 2×CH2), 3.2–3.25 (1H, m, CH), 3.59–3.73 (2H, m, CH2), 3.68 (3H, s, NCH3), 3.99–4.07 (1H, m, CH), 5.47 (2H, AB system, JAB=10.8 Hz, Δν=49.8 Hz, OCH2), 6.93 (2H, m, aromatics), 7.22 (2H, m, aromatics), 7.39–7.52 (5H, m, aromatics) Anal. Calcd for C23H23FN4O5S: C, 56.78; H, 4.77; N, 11.52. Found: C, 56.83; H, 4.58; N, 11.53.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][CH:5]1[C:9](=[O:10])[N:8]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[C:7](=[O:20])[NH:6]1.[H-].[Na+].[CH3:24]I>CN(C=O)C>[CH3:1][O:2][C:3](=[O:21])[CH2:4][CH:5]1[C:9](=[O:10])[N:8]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[C:7](=[O:20])[N:6]1[CH3:24]
Reactant: CI
Reactant: COC(=O)CC1NC(=O)N(Cc2ccc(OC)cc2)C1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CC1C(=O)N(Cc2ccc(OC)cc2)C(=O)N1C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 72.3 %

Procedure:
A 0° C. solution of compound [1-(4-methoxy-benzyl)-2,5-dioxo-imidazolidin-4-yl]-acetic acid methyl ester (9.84 g, 33.7 mmol) in DMF (30 mL) was treated with sodium hydride (60% dispersion, 1.37 g, 34.3 mmol) and warmed to room temperature and stirred under N2 for 20 minutes. The resultant mixture was cooled to 0° C. and then treated with methyl iodide (6.16 g, 43.4 mmol) and then warmed to room temperature and stirred for 16 h. The reaction was quenched with aqueous 1 N HCl (60 mL) and then worked up extractively with EtOAc and water. The organic layer was dried (MgSO4) and the solvent removed in vacuo to give crude product that was purified by flash chromatography using 3:1 hexanes:actetone to afford 7.46 g (85%) [1-(4-methoxy-benzyl)-3-methyl-2,5-dioxo-imidazolidin-4-yl]-acetic acid methyl ester. MS (ES+) Calc'd for C15H19N2O5 (M+1) 307. Found m/z 307 (100%). 1H NMR.
Reaction SMILES: [C:1]1([NH:7][C:8]([C:10]2[CH:15]=[C:14](I)[CH:13]=[C:12]([CH3:17])[C:11]=2[NH:18][C:19]([C:21]2[N:22]([C:30]3[C:35]([Cl:36])=[CH:34][CH:33]=[CH:32][N:31]=3)[N:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=2)=[O:20])=[O:9])([CH:4]2[CH2:6][CH2:5]2)[CH2:3][CH2:2]1.[C:37]([Cu])#[N:38]>O1CCCC1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:1]1([NH:7][C:8]([C:10]2[CH:15]=[C:14]([C:37]#[N:38])[CH:13]=[C:12]([CH3:17])[C:11]=2[NH:18][C:19]([C:21]2[N:22]([C:30]3[C:35]([Cl:36])=[CH:34][CH:33]=[CH:32][N:31]=3)[N:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=2)=[O:20])=[O:9])([CH:4]2[CH2:6][CH2:5]2)[CH2:3][CH2:2]1
Reactant: Cc1cc(I)cc(C(=O)NC2(C3CC3)CC2)c1NC(=O)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Reactant: N#C[Cu]
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cc(C#N)cc(C(=O)NC2(C3CC3)CC2)c1NC(=O)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 101.2 %

Procedure:
To a solution of 3.29 g (5.23 mmol) 2-(3-chloro-pyridin-2-yl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid [2-(bicyclopropyl-1 -ylcarbamoyl)-4-iodo-6-methyl-phenyl]-amide in 50 ml tetrahydrofuran is added 1.19 g (6.25 mmol) Cul, 0.30 g tetrakis(triphenylphosphine) palladium and 2.78 g (31.0 mmol) CuCN. The mixture is heated 1 h at 80° C. and turns dark green. After cooling down, the mixture is filtered on Hyflo and evaporated. The residue is dissolved in 15 ml DMF and poured into 100 ml water containing 5 g NaHCO3. After 30 min stirring, the crystals are filtered, washed with water and a mixture of hexane/acetone (1:3) to afford 2.8 g of the title compound.
Reaction SMILES: [F:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[C:3]=1[C:12](Cl)=[O:13].[CH3:15][CH:16]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[NH2:28])[CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19].C(N(CC)CC)C>O1CCCC1>[F:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[C:3]=1[C:12]([NH:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[CH:16]([CH3:15])[CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:13]
Reactant: Cn1nc(C(F)(F)F)c(C(=O)Cl)c1F
Reactant: CC(CC(C)(C)C)c1ccccc1N
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(CC(C)(C)C)c1ccccc1NC(=O)c1c(C(F)(F)F)nn(C)c1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 92.6 %

Procedure:
At from 0° C. to −10° C., a solution comprising 8.1 g (42.4 mmol) of 5-fluoro-1-methyl-3-(trifluoromethyl)pyrazole-4-carbonyl chloride in 80 ml of tetrahydrofuran is added dropwise to a solution comprising 6.5 g (28.3 mmol) of 2-(1,3,3-trimethylbutyl)phenylamine and 5.7 g (56.6 mmol) of triethylamine in 200 ml of tetrahydrofuran. The reaction mixture is stirred at 0° C. for 1 h. For work-up, the mixture is filtered through silica gel and concentrated. Purification on silica gel (petroleum ether/ethyl acetate 3:1) gives 10.1 g (94% of theory) of [5-fluoro-1-methyl-3-(trifluoromethyl)pyrazol-4-yl]-N-[2-(1,3,3-trimethylbutyl)phenyl]carbox-amide of log P (pH 2.3)=4.14.
Reaction SMILES: [CH3:1][O:2][CH2:3]Cl.[H-].[Na+].[CH3:7][NH:8][C:9]([N:11]1[C:15]([CH3:16])=[CH:14][C:13]([O:17][C:18]2[C:23]([Cl:24])=[CH:22][C:21]([C:25]([F:28])([F:27])[F:26])=[CH:20][N:19]=2)=[N:12]1)=[O:10].O>CN(C=O)C>[CH3:7][N:8]([CH2:3][O:2][CH3:1])[C:9]([N:11]1[C:15]([CH3:16])=[CH:14][C:13]([O:17][C:18]2[C:23]([Cl:24])=[CH:22][C:21]([C:25]([F:27])([F:28])[F:26])=[CH:20][N:19]=2)=[N:12]1)=[O:10]
Reactant: COCCl
Reactant: CNC(=O)n1nc(Oc2ncc(C(F)(F)F)cc2Cl)cc1C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCN(C)C(=O)n1nc(Oc2ncc(C(F)(F)F)cc2Cl)cc1C
Reaction time: 8 h
Yield: 23.8 %

Procedure:
Chloromethyl methyl ether (0.16 g, 2.0 mmol) was added to a solution of sodium hydride (60% in oil, 0.09 g, 2.2 mmol) and N-methyl-3-(3-chloro-5-trifluoromethylpyridin-2-yloxy)-5-methylpyrazole-1-carboxamide (0.67 g, 2.0 mmol) in DMF (10 ml) at 0° C., and while the mixture was allowed to have room temperature gradually, the mixture was stirred overnight. After completion of the reaction, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 ml×3). An organic layer was washed with water, dried over anhydrous magnesium sulfate and filtered to remove a desiccant. The solvent was distilled off from the filtrate under reduced pressure. The resultant crude product was purified with a silica gel column (ethyl acetate/hexane=1/5), to give a colorless viscous substance of N-methyl-N-methoxymethyl-3-(3-chloro-5-trifluoromethylpyridin-2-yloxy)-5-methylpyrazole-1-carboxamide (0.18 g, yield: 23.8%). 1H-NMR (CDCl3, TMS, ppm): δ 1.87 (s, 3H), 3.52 (s, 3H), 3.53 (s, 3H), 5.18 (s, 2H), 5.46 (s, 1H), 7.80-7.95 (m, 1H), 8.50-8.65 (m, 1H).
Reaction SMILES: [CH:1]([O:14][C:15]([C:17]1([O:22][N:23]=[C:24]([C:28]2[N:29]=[C:30]([NH:33][C:34]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[S:31][CH:32]=2)[C:25](O)=[O:26])[CH2:21][CH2:20][CH2:19][CH2:18]1)=[O:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:53][CH:54]1[C:79](=[O:80])[N:56]2[C:57]([C:63]([O:65][CH:66]([C:73]3[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=3)[C:67]3[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=3)=[O:64])=[C:58]([CH2:61][Cl:62])[CH2:59][S:60][C@H:55]12.CN(C)C1C=CC=CC=1.P(Cl)(Cl)(Cl)=O>C(Cl)Cl.O.C(Cl)(Cl)Cl>[CH:1]([O:14][C:15]([C:17]1([O:22][N:23]=[C:24]([C:28]2[N:29]=[C:30]([NH:33][C:34]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)[S:31][CH:32]=2)[C:25]([NH:53][CH:54]2[C:79](=[O:80])[N:56]3[C:57]([C:63]([O:65][CH:66]([C:67]4[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=4)[C:73]4[CH:74]=[CH:75][CH:76]=[CH:77][CH:78]=4)=[O:64])=[C:58]([CH2:61][Cl:62])[CH2:59][S:60][C@H:55]23)=[O:26])[CH2:21][CH2:20][CH2:19][CH2:18]1)=[O:16])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS[C@H]12
Reactant: O=C(O)C(=NOC1(C(=O)OC(c2ccccc2)c2ccccc2)CCCC1)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Solvent: ClC(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)c1ccccc1
Product: O=C(NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS[C@H]12)C(=NOC1(C(=O)OC(c2ccccc2)c2ccccc2)CCCC1)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reaction time: 4 h

Procedure:
2.12 g (3 mmol) of 2-(1-benzhydryloxycarbonyl-1-cyclopentyloxyimino)-2-(2-tritylaminothiazol-4-yl)acetic acid (syn-isomer) and 1.24 g (3 mmol) of benzhydryl 7-amino-3-chloromethyl-3-cephem-4-carboxylate were dissolved in 50 ml of methylene chloride, and 1.2 ml (9.6 mmol) of N,N-dimethylaniline was added thereto under cooling with ice. Then, 0.29 ml (3.15 mmol) of phosphorus oxychloride was dropwise added thereto and the reaction solution was stirred at the same temperature for 4 hours. To the reaction solution, 30 ml of chloroform and 30 ml of water were added. The organic layer was washed with water and a saturated sodium chloride aqueous solution, then dried over anhydrous sodium sulfate and concentrated to obtain benzhydryl 7-[2-(1-benzhydryloxycarbonyl-1-cyclopentyloxyimino)-2-(2-tritylaminothiazol-4-yl)acetamido]-3-chloromethyl-3-cephem-4-carboxylate (syn-isomer), which was used for the next reaction without purification.
Reaction SMILES: [CH3:1]N(C)CCNC.[CH:8]([N:11]([CH:39](C)C)[CH2:12][CH2:13][NH:14][C:15]([N:17]1[CH2:26][CH2:25][C:24]2[C:19](=[CH:20][C:21]([O:29][CH3:30])=[C:22]([O:27][CH3:28])[CH:23]=2)[CH:18]1[C:31]1[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=1)=[O:16])(C)C>>[CH3:28][O:27][C:22]1[CH:23]=[C:24]2[C:19](=[CH:20][C:21]=1[O:29][CH3:30])[CH:18]([C:31]1[CH:32]=[CH:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=1)[N:17]([C:15]([N:14]([CH2:13][CH2:12][N:11]([CH3:39])[CH3:8])[CH3:1])=[O:16])[CH2:26][CH2:25]2
Reactant: COc1ccc(C2c3cc(OC)c(OC)cc3CCN2C(=O)NCCN(C(C)C)C(C)C)cc1
Reactant: CNCCN(C)C
Product: COc1ccc(C2c3cc(OC)c(OC)cc3CCN2C(=O)N(C)CCN(C)C)cc1

Procedure:
Substitution of an equivalent quantity of N,N,N'-trimethylethylenediamine for the 2-diisopropylaminoethylamine used above and substantial repetition of the foregoing procedure affords 6,7-dimethoxy-N-(2-dimethylaminoethyl)-1-(4-methoxyphenyl)-N-methyl-3,4-dihydro-2(1H)-isoquinolinecarboxamide.
Reaction SMILES: OS(O)(=O)=O.[C:6]([C:10]1[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=1[NH2:12])([CH3:9])([CH3:8])[CH3:7].[N+:17]([O-])([O-:19])=[O:18].[K+]>O>[C:6]([C:10]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:11]=1[NH2:12])([CH3:9])([CH3:7])[CH3:8]
Reactant: CC(C)(C)c1ccccc1N
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Product: CC(C)(C)c1ccc([N+](=O)[O-])cc1N
Temperature: -10 °C

Procedure:
To H2SO4 (98%, 389 mL) in a 500 mL 3-neck flask was added 2-tert-butyl aniline (40.6 mL). The reaction was cooled to −10° C. and KNO3 in 3.89 g aliquots was added every 6 min for a total of 10 aliquots. Tried to maintain temperature at −5° C. to −10° C. After final addition of KNO3, stirred the reaction for five min then it was poured onto ice (50 g). The black mix was diluted with H2O and extracted with EtOAc. The aqueous layer was basified with solid NaOH slowly then extracted with EtOAc (2×). The combined organic layers were washed with 6N NaOH and then with a mix of 6N NaOH and brine, dried over Na2SO4, filtered and concentrated in vacuo to obtain crude 2-tert-butyl-5-nitro-aniline as a dark red-black oil which solidified when standing at RT. The crude material was triturated with about 130 mL hexanes. After decanting the hexanes, the material was dried to obtain a dark-red black solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:28][C:29]([F:32])([F:31])[F:30])=[C:8]([NH:10][C:11]2[N:20]=[CH:19][C:18]3[CH2:17][CH2:16][C:15]4[C:21]([C:25]([NH2:27])=[O:26])=[N:22][N:23]([CH3:24])[C:14]=4[C:13]=3[N:12]=2)[CH:9]=1)([O-])=O.CO>O.[Fe]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([O:28][C:29]([F:30])([F:32])[F:31])=[C:8]([NH:10][C:11]2[N:20]=[CH:19][C:18]3[CH2:17][CH2:16][C:15]4[C:21]([C:25]([NH2:27])=[O:26])=[N:22][N:23]([CH3:24])[C:14]=4[C:13]=3[N:12]=2)[CH:9]=1
Reactant: Cn1nc(C(N)=O)c2c1-c1nc(Nc3cc([N+](=O)[O-])ccc3OC(F)(F)F)ncc1CC2
Agent: [Fe]
Solvent: CO
Solvent: O
Product: Cn1nc(C(N)=O)c2c1-c1nc(Nc3cc(N)ccc3OC(F)(F)F)ncc1CC2

Procedure:
To a suspension of 8-(5-nitro-2-trifluoromethoxy-phenylamino)-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide (630 mg, 1.4 mmol) in methanol (6 mL) ammonium chloride (240 mg, 4.3 mmol) in water (25 mL) and iron (397 mg, 7.4 mmol) were added. The mixture was heated under reflux for 3 hours until HPLC revealed the disappearance of the starting material. The solvent was removed and the crude was diluted with trifluoroethanol. Iron was removed and the filtrate was concentrated to give the final compound as a light brown solid in quantitative yield.