Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([Cl:12])=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].O.[NH2:14][NH2:15]>O1CCOCC1>[Cl:12][C:5]1[N:4]=[N:3][C:2]([NH:14][NH2:15])=[C:7]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:6]=1
Reactant: CS(=O)(=O)c1cc(Cl)nnc1Cl
Reactant: NN
Solvent: O
Solvent: C1COCCO1
Product: CS(=O)(=O)c1cc(Cl)nnc1NN
Temperature: 25 °C
Reaction time: 4 h

Procedure:
3,6-Dichloro-4-methanesulfonylpyridazine(W4.126; 660 mg, 2.9 mmol) was dissolved in 1,4-dioxane (5 ml) and hydrazine hydrate (295 μl, 5.8 mmol) was added. The mixture was stirred at RT for 4 h, then concentrated, and the residue was purified by flash chromatography (dichloromethane:ethyl acetate). Yield: 200 mg
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][C:3]=1[NH:16][NH:17]C(OC(C)(C)C)=O.[F:25][C:26]([F:39])([F:38])[C:27]1[CH:37]=[CH:36][C:30]([C:31]([N:33]=[C:34]=[O:35])=O)=[CH:29][CH:28]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][C:3]=1[N:16]1[C:34](=[O:35])[NH:33][C:31]([C:30]2[CH:36]=[CH:37][C:27]([C:26]([F:39])([F:38])[F:25])=[CH:28][CH:29]=2)=[N:17]1
Reactant: O=C=NC(=O)c1ccc(C(F)(F)F)cc1
Reactant: CC(C)(C)OC(=O)NNc1cc(CNC(=O)C(C)(C)C)ccc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(-n2nc(-c3ccc(C(F)(F)F)cc3)[nH]c2=O)c1
Yield: 36.8 %

Procedure:
The title compound was prepared according to the procedure described in Example-83 by using tert-butyl 2-(2-chloro-5-{[(2,2-dimethylpropanoyl)amino]methyl}phenyl)hydrazinecarboxylate (Intermediate-94, 0.150 g, 0.420 mmol), 4-(trifluoromethyl)benzoyl isocyanate (Intermediate-59, 0.181 g, 0.84 mmol), DCM (15 mL), and trifluoro acetic acid (3.0 mL) to afford 0.070 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 1.13 (s, 9H), 4.29 (d, J=5.4 Hz, 2H), 7.36 (d, J=8.7 Hz, 1H), 7.45 (s, 1H), 7.62 (d, J=8.4 Hz, 1H), 7.92 (d, J=8.4 Hz, 2H), 8.06 (d, J=8.4 Hz, 2H), 8.19 (m, 1H), 12.79 (s, 1H); MS (m/z): 456.59 (M+H)+.
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([NH:11][CH:12]([C:14]2[CH:15]=[C:16]([C:32]([O:34]C)=[O:33])[CH:17]=[C:18]3[C:23]=2[O:22][C:21]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][C@@H:25]2[CH3:30])=[CH:20][C:19]3=[O:31])[CH3:13])[CH:7]=[C:8]([F:10])[CH:9]=1.C1COCC1.Cl>CO>[F:3][C:4]1[CH:5]=[C:6]([NH:11][CH:12]([C:14]2[CH:15]=[C:16]([C:32]([OH:34])=[O:33])[CH:17]=[C:18]3[C:23]=2[O:22][C:21]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][C@@H:25]2[CH3:30])=[CH:20][C:19]3=[O:31])[CH3:13])[CH:7]=[C:8]([F:10])[CH:9]=1
Reactant: COC(=O)c1cc(C(C)Nc2cc(F)cc(F)c2)c2oc(N3CCOC[C@@H]3C)cc(=O)c2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(Nc1cc(F)cc(F)c1)c1cc(C(=O)O)cc2c(=O)cc(N3CCOC[C@@H]3C)oc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.4 %

Procedure:
2N NaOH (0.206 mL, 0.41 mmol) was added to a stirred suspension of methyl 8-(1-(3,5-difluorophenylamino)ethyl)-2-((S)-3-methylmorpholino)-4-oxo-4H-chromene-6-carboxylate (90 mg, 0.20 mmol) in MeOH (1 mL)/THF (1 mL) and cooled with an ice-water bath. The resulting suspension was stirred at RT for 2 hours. The reaction was incomplete thus the temperature was increased to 35° C. and stirred for an additional hour. The reaction mixture was cooled with an ice bath, the pH was adjusted to 2-3 with hydrochloric acid 1M and the volatils were evaporated. The resulting precipitate was collected by filtration, dried, triturated with diethyl ether, collected by filtration and dried again under vacuum to give 8-(1-(3,5-difluorophenylamino)ethyl)-2-((S)-3-methylmorpholino)-4-oxo-4H-chromene-6-carboxylic acid (75 mg, 86%). Mass Spectrum: M+H+ 445.
Reaction SMILES: Cl.[CH2:2]1[C:7]2([CH2:12][CH2:11][CH:10]([CH2:13][C:14]([O:16][CH3:17])=[O:15])[CH2:9][CH2:8]2)[CH2:6][CH2:5][NH:4][CH2:3]1.CCN(C(C)C)C(C)C.Cl[C:28]([O:30][CH:31]1[CH:38]2[CH2:39][CH:34]3[CH2:35][CH:36]([CH2:40][CH:32]1[CH2:33]3)[CH2:37]2)=[O:29].Cl>C(Cl)Cl>[CH3:17][O:16][C:14](=[O:15])[CH2:13][CH:10]1[CH2:11][CH2:12][C:7]2([CH2:2][CH2:3][N:4]([C:28]([O:30][CH:31]3[CH:32]4[CH2:40][CH:36]5[CH2:35][CH:34]([CH2:39][CH:38]3[CH2:37]5)[CH2:33]4)=[O:29])[CH2:5][CH2:6]2)[CH2:8][CH2:9]1
Reactant: COC(=O)CC1CCC2(CCNCC2)CC1
Reactant: O=C(Cl)OC1C2CC3CC(C2)CC1C3
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CC1CCC2(CC1)CCN(C(=O)OC1C3CC4CC(C3)CC1C4)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.3 %

Procedure:
A vial was charged with methyl 2-(3-azaspiro[5.5]undecan-9-yl)acetate HCl salt (31 mg, 0.12 mmol) and DIEA (45 μL, 0.25 mmol). A solution of 2-adamantyl chloroformate (25 mg, 0.12 mmol) in CH2Cl2 (2 mL) was added and the mixture was stirred overnight at rt. A 10-mL Chem-Elut cartridge was wetted with 5% aq HCl (6 mL) and allowed to stand for 5 min. The reaction mixture was applied to the cartridge and eluted with ether (20 mL). The eluate was evaporated to dryness and the residue was purified by preparative HPLC to afford (2-adamantyl) 9-(2-methoxy-2-oxoethyl)-3-azaspiro[5.5]undecane-3-carboxylate (35 mg, 74%). LC-MS Method 1 tR=2.52 min, m/z=404; 1H NMR (CDCl3) δ=1.05-2.10 (27H), 2.23 (d, 2H), 3.41 (m, 4H), 3.69 (s, 3H), 4.82 (s, 1H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:10]([OH:12])=O)[NH:8][N:9]=1)([CH3:4])([CH3:3])[CH3:2].C1CCC(N=C=NC2CCCCC2)CC1.[Cl:28][C:29]1[CH:30]=[C:31]([C:36]2[O:40][C:39]([CH2:41][CH:42]([NH2:44])[CH3:43])=[CH:38][CH:37]=2)[CH:32]=[CH:33][C:34]=1[Cl:35]>C(Cl)Cl.CN(C=O)C.C(Cl)Cl>[C:1]([C:5]1[CH:6]=[C:7]([C:10]([NH:44][CH:42]([CH3:43])[CH2:41][C:39]2[O:40][C:36]([C:31]3[CH:32]=[CH:33][C:34]([Cl:35])=[C:29]([Cl:28])[CH:30]=3)=[CH:37][CH:38]=2)=[O:12])[NH:8][N:9]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1cc(C(=O)O)[nH]n1
Reactant: CC(N)Cc1ccc(-c2ccc(Cl)c(Cl)c2)o1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(Cc1ccc(-c2ccc(Cl)c(Cl)c2)o1)NC(=O)c1cc(C(C)(C)C)n[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 15.1 %

Procedure:
5-Tert-butyl-2H-pyrazole-3-carboxylic acid (94 mg; 0.55 mmol) was dissolved in DCM:DMF (4:1, 5 ml). DCC (172 mg; 0.83 mmol) was added. 1-(5-(3,4-dichlorophenyl)furan-2-yl)propan-2-amine (149 mg; 0.55 mmol) was dissolved in 2 ml of DCM and TEA (77 μl, 0.55 mmol) and the resulting solution was added to the reaction mixture. The reaction mixture was stirred overnight at RT. Then DCM (50 ml) was added and organic phase was washed with water (2×30 ml). The organic phase was dried over Na2SO4, evaporated and purified by chromatography (CombiFlash, 1st column silica, eluent: 7.5-100% EtOAc/heptane; 2nd column silica, eluent: 0-5% MeOH/DCM) to give 35 mg (15%) of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ 1.19 (d, 3H), 1.27 (s, 9H), 2.88 (dd, 1H), 2.98 (dd, 1H), 4.33 (quintet, 1H), 6.29 (d, 1H), 6.33 (s, 1H), 7.00 (d, 1H), 7.60 (m, 2H), 7.83 (d, 1H), 7.89 (d, 1H), 12.84 (s, 1H).
Reaction SMILES: C([Li])(CC)C.[F:6][C:7]([F:22])([F:21])[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16](=[O:20])[O:17][CH2:18][CH3:19].[I:23]I>C1CCCCC1.C1COCC1>[I:23][C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([O:8][C:7]([F:21])([F:22])[F:6])[C:10]=1[NH:15][C:16](=[O:20])[O:17][CH2:18][CH3:19]
Reactant: II
Reactant: CCOC(=O)Nc1ccccc1OC(F)(F)F
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: CCOC(=O)Nc1c(I)cccc1OC(F)(F)F
Reaction time: 1 h
Yield: 73 %

Procedure:
A 1.4 M solution of sec-butyllithium in cyclohexane (3.0 mL) was added drop-wise to a solution of ethyl N-[2-(trifluoromethoxy)phenyl]carbamate (0.5000 g, 0.002006 mol) in THF (9 mL) at −70° C. After stirring for 1 hour a solution of iodine (0.51 g, 0.002 mol) in THF (1.0 mL) was added drop-wise at −70° C. Stirring was continued for another 1 hour then the mixture was quenched with saturated ammonium chloride solution. Water (50 mL) was added and the mixture extracted with diethyl ether (3×40 mL). The combined organic phases was washed with 40% sodium meta-bisulfite solution, water and brine, then dried over Na2SO4 and the solvent removed in vacuo to give the desired product in a 73% yield. 1H NMR (400 MHz, CDCl3): δ 1.29-1.36 (m, 3H), 4.21-4.28 (m, 2H), 6.21 (br, 1H), 7.05 (t, J=8.0 Hz, 1H), 7.30 (m, 1H) and 7.80 (dd, J=6.8, 1.2 Hz, 1H). MS (ES+): m/z 375.78 [MH+].
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][OH:12])=[CH:2]1.[C:13]([O:19][CH3:20])(=[O:18])[CH2:14][C:15]([CH3:17])=O.B(F)(F)F.CCOCC>C1C=CC=CC=1>[CH3:20][O:19][C:13](=[O:18])[CH2:14][C:15]1([CH3:17])[C:2]2[CH2:1][C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[C:3]=2[CH2:10][CH2:11][O:12]1
Reactant: COC(=O)CC(C)=O
Reactant: OCCC1=CCc2ccccc21
Agent: FB(F)F
Solvent: c1ccccc1
Solvent: CCOCC
Product: COC(=O)CC1(C)OCCC2=C1Cc1ccccc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of indene-3-ethanol (8 g) and methyl acetoacetate (6 g) in 250 ml of dry benzene containing hydrated alkali-aluminum silicate (Molecular Sieves No. 4, about 2 g) is added 1 ml of boron trifluoride-etherate and the mixture stirred at room temperature for 4 hr. An additional 1 ml of boron trifluoride-etherate is added, the reaction mixture is stirred at ambient temperature overnight and then heated at reflux for 1 hr. The hydrated alkali-aluminum silicate is collected and the filtrate washed with 10% solution of sodium bicarbonate and water. After drying over magnesium sulfate the benzene is removed under reduced pressure affording 1-methyl-1,3,4,9-tetrahydroindeno[2,1-c]pyran-1-acetic acid methyl ester, νmaxfilm 1724 cm-1.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:37](O)=[O:38])=[N:11][C:12]([N:19]([CH3:36])[S:20]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])(=[O:22])=[O:21])=[C:13]2[C:18]=1[N:17]=[CH:16][CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.[NH2:74][CH2:75][C:76]1[CH:86]=[CH:85][C:84]([F:87])=[CH:83][C:77]=1[C:78]([O:80][CH2:81][CH3:82])=[O:79]>ClCCl>[CH2:1]([O:8][C:9]1[C:10]([C:37]([NH:74][CH2:75][C:76]2[CH:86]=[CH:85][C:84]([F:87])=[CH:83][C:77]=2[C:78]([O:80][CH2:81][CH3:82])=[O:79])=[O:38])=[N:11][C:12]([N:19]([CH3:36])[S:20]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][NH:28][C:29]([O:31][C:32]([CH3:33])([CH3:34])[CH3:35])=[O:30])(=[O:21])=[O:22])=[C:13]2[C:18]=1[N:17]=[CH:16][CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc(F)ccc1CN
Reactant: CN(c1nc(C(=O)O)c(OCc2ccccc2)c2ncccc12)S(=O)(=O)CCCCCNC(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)c1cc(F)ccc1CNC(=O)c1nc(N(C)S(=O)(=O)CCCCCNC(=O)OC(C)(C)C)c2cccnc2c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 71 %

Procedure:
To a solution of 8-(benzyloxy)-5-(5-(tert-butoxycarbonylamino)-N-methylpentylsulfonamido)-1,6-naphthyridine-7-carboxylic acid (Example 2.4; 3.82 mmol) in dichloro methane (38 ml) were added HBTU (4.58 mmol) and DIPEA (15.8 mmol). The mixture was stirred for 5 min at rt. Ethyl 2-(aminomethyl)-5-fluorobenzoate hydrochloride (Example 4; 4.58 mmol) was added portionwise at rt. The mixture was stirred overnight at rt. The product was extracted with CH2Cl2, dried over MgSO4 and concentrated. The crude product was purified by SiO2 column chromatography (AcOEt:Hex, 1:1) to afford the target compound in 71% yield.
Reaction SMILES: I[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[Cl-].[Li+].C([Mg]Cl)(C)C.[F:20][C:21]([F:27])([F:26])[CH2:22][CH2:23][CH:24]=[O:25]>O1CCCC1>[F:20][C:21]([F:27])([F:26])[CH2:22][CH2:23][CH:24]([C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1)[OH:25]
Reactant: CCOC(=O)c1ccc(I)cc1
Reactant: O=CCCC(F)(F)F
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(C(O)CCC(F)(F)F)cc1
Temperature: -40 °C
Reaction time: 0.25 h

Procedure:
To a solution of the ethyl 4-iodobenzoate (1.21 ml, 7.24 mmol) in tetrahydrofuran (12 ml) at −40° C. was added isopropylmagnesium chloride lithium chloride complex (6.13 ml, 7.97 mmol, 1.3 M in tetrahydrofuran) dropwise. The mixture was stirred for approximately 1 hour whereupon 4,4,4-trifluorobutanal (0.761 ml, 0.724 mmol) was added dropwise. The mixture was stirred at −40° C. for 15 minutes and slowly warmed to ambient temperature over 12 hours. The reaction was quenched with aqueous 1.0 M hydrochloric acid, and the aqueous layer was extracted with ethyl acetate (3×). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give ethyl(+/−)-4-(4,4,4-trifluoro-1-hydroxybutyl)benzoate, which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:19]([F:20])=[CH:18][CH:17]=[C:16]([F:21])[C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][C:7]2[N:11]=[CH:12][C:13](I)=[CH:14][C:6]1=2.[CH3:22][N:23]1[CH2:28][CH2:27][N:26]([C:29]2[CH:34]=[CH:33][C:32](B3OC(C)(C)C(C)(C)O3)=[CH:31][N:30]=2)[CH2:25][CH2:24]1>>[Cl:1][C:2]1[C:19]([F:20])=[CH:18][CH:17]=[C:16]([F:21])[C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][C:7]2[N:11]=[CH:12][C:13]([C:32]3[CH:31]=[N:30][C:29]([N:26]4[CH2:25][CH2:24][N:23]([CH3:22])[CH2:28][CH2:27]4)=[CH:34][CH:33]=3)=[CH:14][C:6]1=2
Reactant: CN1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Reactant: Fc1ccc(F)c(CN2CCNc3ncc(I)cc32)c1Cl
Product: CN1CCN(c2ccc(-c3cnc4c(c3)N(Cc3c(F)ccc(F)c3Cl)CCN4)cn2)CC1
Yield: 16 %

Procedure:
1-(2-Chloro-3,6-difluorobenzyl)-7-iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine (88 mg) was coupled to 1-Methyl-4-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)pyridin-2-yl]piperazine as in General Procedure 4B to give the title compound as a light brown solid (16% yield). M.p.=219° C., LCMS: m/z=471.12 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 2.36 (3H, s), 2.54 (4H, t, J=5.1 Hz), 3.27 (2H, t, J=4.8 Hz), 3.51 (2H, t, J=4.7 Hz), 3.59 (4H, t, J=5.1 Hz), 4.50 (2H, d, J=1.0 Hz), 5.01 (1H, bs), 6.70 (1H, d, J=8.8 Hz), 7.03 (2H, m), 7.11 (1H, m), 7.61 (1H, dd, J=8.8, 2.5 Hz), 7.64 (1H, d, J=1.8 Hz), 8.35 (1H, d, J=2.3 Hz).
Reaction SMILES: [NH2:1][CH2:2][C:3]([C@@H:5]1[C@@H:10]([OH:11])[C@H:9]([OH:12])[C@@H:8]([CH2:13][OH:14])[O:7][C@@:6]1([NH2:43])[N:15]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[C:16](=[O:28])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:4].[C:44]([N:54]([CH2:56][C:57](O)=[O:58])[CH3:55])([O:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:45]>ClCCl>[C:44]([N:54]([CH2:56][C:57]([NH:1][CH2:2][C:3]([C@@H:5]1[C@@H:10]([OH:11])[C@H:9]([OH:12])[C@@H:8]([CH2:13][OH:14])[O:7][C@@:6]1([NH2:43])[N:15]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[C:16](=[O:28])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:4])=[O:58])[CH3:55])([O:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:45]
Reactant: CCCCCCCCCCCCCCN(C(=O)CCCCCCCCCCC)[C@]1(N)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1C(=O)CN
Reactant: CN(CC(=O)O)C(=O)OCc1ccccc1
Solvent: ClCCl
Product: CCCCCCCCCCCCCCN(C(=O)CCCCCCCCCCC)[C@]1(N)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1C(=O)CNC(=O)CN(C)C(=O)OCc1ccccc1
Yield: 64 %

Procedure:
from N-(2-glycyl-amino-2-deoxy-β-D-glucopyranosyl)-N-tetradecyl-dodecanamide and N-carbobenzoxy-sarcosine. Yield 64%. [α]D =+18.4° (c=1.02, dichloromethane). m.p. 76-77°.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[O:7][C:6](=[O:8])[N:5]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[CH2:15][N:14]([C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])[CH2:13][CH2:12]3)[CH2:4]1.N1C=CC=CC=1.[C:35](OC(=O)C)(=[O:37])[CH3:36]>C(Cl)Cl>[C:35]([NH:1][CH2:2][C@@H:3]1[O:7][C:6](=[O:8])[N:5]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[CH2:15][N:14]([C:19]([O:21][CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[O:20])[CH2:13][CH2:12]3)[CH2:4]1)(=[O:37])[CH3:36]
Reactant: NC[C@H]1CN(c2ccc3c(c2)CCN(C(=O)OCc2ccccc2)C3)C(=O)O1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)NC[C@H]1CN(c2ccc3c(c2)CCN(C(=O)OCc2ccccc2)C3)C(=O)O1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 93.1 %

Procedure:
A solution of phenylmethyl 6-[(5S)-5-(aminomethyl)-2-oxo-3-oxazolidinyl]-3,4-dihydro-2(1H)-isoquinolinecarboxylate (Step 4, 1.75 g, 4.59 mmol) and pyridine (1.11 mL, 13.77 mmol) in dry CH2Cl2 (23 mL) under N2 is treated with acetic anhydride (0.649 mL, 6.88 mmol), and the mixture is stirred at ambient temperature for 3.5 hrs. The mixture is then washed with H2O (2×15 mL) and brine (10 mL), dried over Na2SO4 and concentrated under reduced pressure. The crude product is chromatographed on a Flash 40S silica gel (40 g, 32-63 μm) cartridge, eluting with a gradient of MeOH/CH2Cl2 (0.5/99.5-2/98), and those fractions with an Rf=0.25 by TLC (MeOH/CHCl3, 5/95) are pooled and concentrated to give 1.81 g (93%) of the title compound as an amorphous, white solid. 1H NMR (400 MHz, CDCl3) δ 7.35 (m, 7H), 7.11 (m, 1H), 6.11 (m, 1H), 5.19 (s, 2H), 4.78 (m, 1H), 4.62 (s, 2H), 4.05 (t, 1H), 3.78 (dd, 1H), 3.70 (m, 3H), 3.60 (m, 1H), 2.86 (m, 2H), 2.02 (s, 3H); MS (ESI+) for C23H25N3O5 m/z 424 (M+H)+; [α]25D=−17° (c 0 77, DMSO).
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[Cl:28][C:29]1[CH:30]=[C:31]([N:35]2[C:39]([C:40]([F:43])([F:42])[F:41])=[C:38]([C:44]([OH:46])=O)[CH:37]=[N:36]2)[CH:32]=[CH:33][CH:34]=1.[F:47][C:48]([F:58])([F:57])[C:49]1[CH:50]=[C:51]([CH:54]=[CH:55][CH:56]=1)[CH2:52][NH2:53].C(N(CC)CC)C>O1CCCC1>[F:47][C:48]([F:57])([F:58])[C:49]1[CH:50]=[C:51]([CH:54]=[CH:55][CH:56]=1)[CH2:52][NH:53][C:44]([C:38]1[CH:37]=[N:36][N:35]([C:31]2[CH:32]=[CH:33][CH:34]=[C:29]([Cl:28])[CH:30]=2)[C:39]=1[C:40]([F:41])([F:42])[F:43])=[O:46]
Reactant: O=C(O)c1cnn(-c2cccc(Cl)c2)c1C(F)(F)F
Reactant: NCc1cccc(C(F)(F)F)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(NCc1cccc(C(F)(F)F)c1)c1cnn(-c2cccc(Cl)c2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Benzotriazole-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP) (0.083 g; 0.189 mmol) was added to a solution of 1-(3-chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid (0.050 g; 0.172 mmol), 3-trifluoromethyl benzylamine (0.030 g; 0.206 mmol) and triethylamine (0.072 mL; 0.516 mmol) in tetrahydrofuran (10 mL). The reaction mixture was stirred at room temperature for 4 h, concentrated and the crude product purified by column chromatography on silica gel to give 1-(3-chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid 3-trifluoromethyl-benzylamide. LCMS m/z=448.8 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([Cl:13])[C:8]=1[F:14])=O.S(Cl)([Cl:22])=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:3]=1[C:4]([Cl:22])=[N:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([Cl:13])[C:8]=1[F:14]
Reactant: O=S(Cl)Cl
Reactant: O=C(Nc1ccnc(Cl)c1F)c1c(Cl)cccc1Cl
Solvent: Cc1ccccc1
Product: Fc1c(N=C(Cl)c2c(Cl)cccc2Cl)ccnc1Cl
Temperature: 25 °C

Procedure:
A mixture of 2,6-dichloro-N-(2-chloro-3-fluoropyridin-4-yl)benzamide (1.12 g, 3.5 mmol) and thionyl chloride (10 mL) was heated under reflux for 18 hours then cooled to ambient temperature. The reaction mixture was diluted with toluene (10 mL) and concentrated under reduced pressure to afford the title compound as a pale brown solid (1.23 g, quant. yield). 1H NMR (400 MHz, CDCl3): δ 8.23 (d, J=5.1 Hz, 1H), 7.45-7.44 (m, 2H), 7.38 (dd, J=9.4, 6.5 Hz, 1H), 6.98 (t, J=5.1 Hz, 1H).
Reaction SMILES: [CH3:1][CH:2]([CH3:16])[CH2:3][CH2:4][N:5]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[C:6]1[C:13](Cl)=[O:14].Cl.[NH2:18][CH2:19][CH2:20][CH2:21][C:22]#[N:23].N1C=CC=CC=1>C1(C)C=CC=CC=1>[C:19]([CH2:20][CH2:21][CH2:22][NH:23][C:13]([C:6]1[N:5]([CH2:4][CH2:3][CH:2]([CH3:16])[CH3:1])[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=1)=[O:14])#[N:18]
Reactant: CC(C)CCn1cc([N+](=O)[O-])cc1C(=O)Cl
Reactant: N#CCCCN
Agent: Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CC(C)CCn1cc([N+](=O)[O-])cc1C(=O)NCCCC#N
Temperature: 50 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
To a mixture of the acid chloride 45 (0.6 g, 2.45 mmol) and 3-aminopropylcyanide hydrochloride (0.31 g, 2.57 mmol) in anhydrous toluene was added 1.5 ml of anhydrous pyridine. The reaction mixture was stirred at 50° C. overnight and then evaporated to dryness. The product was purified by chromatography using toluene-ethyl acetate (2:1) to yield white crystals (0.623 g, 87%). 1H NMR (DMSO-d6) δ 8.46 (t, 1H), 8.17 (d, 1H), 7.39 (d, 1H), 4.37 (t, 2H), 3.27 (quintet, 2H), 2.53 (d, 2H), 1.77 (quintet, 2H), 1.60–1.42 (q and quintet, 3H), 0.87 (d, 6H).
Reaction SMILES: [Br:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[H-].[Na+].[CH2:11](Br)[C:12]#[CH:13]>C1COCC1>[Br:1][C:2]1[C:7]([O:8][CH2:13][C:12]#[CH:11])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Oc1cccnc1Br
Reactant: C#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C#CCOc1cccnc1Br
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A solution of 2-bromo-3-hydroxypyridine (10 g) in dry THF (100 ml) was treated with 1 equivalent of sodium hydride (80% in oil) (1.72 g) and stirred at room temperature under nitrogen for 0.75 hours. Propargyl bromide (80% in toluene) (19.2 ml) was added and the mixture was heated under reflux for 88 hours. After cooling, the solvent was evaporated under reduced pressure and the residue partitioned between 5% aqueous NaOH and EtOAc. The organic layer was removed, dried (Na2SO4) and concentrated in vacuo to give a pale yellow gum. This was purified by column chromatography on silica using dichloromethane as eluant to give 2-bromo-3-propargyloxypyridine as an off white solid 6 g.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[C:9]([O:10][CH3:11])=[CH:8][C:7]([CH2:12][OH:13])=[CH:6][C:5]=1[O:14][CH3:15].IC.[C:18](OCC)(=O)C>CN(C)C=O>[Br:3][C:4]1[C:9]([O:10][CH3:11])=[CH:8][C:7]([CH2:12][O:13][CH3:18])=[CH:6][C:5]=1[O:14][CH3:15]
Reactant: COc1cc(CO)cc(OC)c1Br
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: COCc1cc(OC)c(Br)c(OC)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Sodium hydride (60% in oil; 24.7 g) was added to a solution of (4-bromo-3,5-dimethoxyphenyl)methanol (118.8 g) in N,N-dimethylformamide (960 mL) while cooling with ice, and after stirring for 10 minutes, iodomethane (41.7 mL) was added dropwise, the temperature was increased to room temperature and stirring was continued for 1 hour. The obtained reaction mixture was poured into ice water (2.5 L), extraction was performed with ethyl acetate, the extract was washed with brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography and the title compound (121.3 g) was obtained as a colorless oil from the n-hexane:ethyl acetate (4:1) fraction.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=O.[N+](C1C=CC=CC=1)([O-])=O.[N:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]2[CH:26]=[C:27]([NH2:39])[C:28]([NH2:38])=[CH:29][C:30]=2[O:31][C:32]2[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=2)[CH:19]=1>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[NH:39][C:27]2[CH:26]=[C:25]([O:24][C:20]3[CH:19]=[N:18][CH:23]=[CH:22][CH:21]=3)[C:30]([O:31][C:32]3[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=3)=[CH:29][C:28]=2[N:38]=1
Reactant: Nc1cc(Oc2cccnc2)c(Oc2cccnc2)cc1N
Reactant: O=Cc1ccccn1
Solvent: O=[N+]([O-])c1ccccc1
Product: c1ccc(-c2nc3cc(Oc4cccnc4)c(Oc4cccnc4)cc3[nH]2)nc1
Reaction time: 2 h

Procedure:
0.01 ml of pyridine-2-carboxaldehyde was added to a nitrobenzene (0.3 ml) solution of 30 mg of 4,5-bis(pyridin-3-yloxy)-benzene-1,2-diamine at 120° C., and the reaction liquid was stirred at the same temperature for 2 hours. The reaction mixture was purified through reversed-phase middle-pressure liquid chromatography [ODS-AS-360-CC (by YMC), mobile phase: water-acetonitrile-0.1% trifluoroacetic acid]. The solvent of the resulting fraction was evaporated away under reduced pressure, and this was purified through partitioning thin-layer chromatography (Kieselgel™ 60F254, Art 5744 (by Merck), chloroform/methanol=20/1) to obtain the entitled compound as a yellow oily substance.