Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([NH:6]C(=O)C(C)(C)C)=[C:4]([O:15][CH3:16])[CH:3]=1.[Li]C(CC)C.[F:22][C:23]([F:30])([F:29])[C:24](OCC)=[O:25].Cl.C([O-])([O-])=O.[K+].[K+]>C1COCC1.C1CCCCC1.COCCOC>[NH2:6][C:5]1[C:4]([O:15][CH3:16])=[CH:3][C:2]([Cl:1])=[CH:14][C:13]=1[C:24](=[O:25])[C:23]([F:30])([F:29])[F:22]
Reactant: CCOC(=O)C(F)(F)F
Reactant: COc1cc(Cl)ccc1NC(=O)C(C)(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCCCC1
Solvent: C1CCOC1
Solvent: COCCOC
Product: COc1cc(Cl)cc(C(=O)C(F)(F)F)c1N
Temperature: 0 °C
Reaction time: 1.2 h
Yield: 61.1 %

Procedure:
To a stirred, cooled (−20° C.) solution of 12.1 g (50 mmol) of 4′-chloro-2′-methoxy-2,2-dimethylpropionanilide in 150 mL of THF was added 87 mL (115 mmol) of 1.3 M s-BuLi in cyclohexane over 15 min. The dark solution was warmed to 0° C. and stirred for 1.2 h. The solution was re-cooled to −20° C. and treated with 14.3 mL (120 mmol) of ethyl trifluoroacetate over 5 min. The reaction was warmed to 0° C., stirred 15 min., and quenched with saturated aqueous NaHCO3. The mixture was extracted with hexanes and then with ether, and the combined organic extracts were washed sequentially with 0.5 N HCl, water, and brine. The solution was dried (MgSO4) and concentrated under reduced pressure to give a dark oil. The crude amide was dissolved in 20 mL of 1,2-dimethoxyethane and treated with 100 mL of 6 N aqueous HCl. The mixture was stirred at reflux for 2 h, cooled to 0° C., and brought to pH 9 with K2CO3. The mixture was extracted twice with ether, and the combined organic extracts were washed with brine, dried (MgSO4), and concentrated under reduced pressure to give an oily solid. This crude product was recrystallized from hexanes and a minimal ammount of ethyl acetate to give 7.75 g (61%) of 2′-amino-5′-chloro-3′-methoxy-2,2,2-trifluoroacetophenone as yellow needles, mp 124.5-125.5° C. 1H NMR (300 MHz, CDCl3) δ7.32-7.35(m, 1H); 6.87(br. s, 2H); 6.84(d, 1H, J=1.8 Hz); 3.92(s, 3H). High resolution mass spec: calculated for C9H8NO2ClF3(M+H)+: 254.0196, found: 254.0194. Analysis calculated for C9H7NO2ClF3: C, 42.62; H, 2.78; N, 5.52; Cl, 13.98. Found: C, 42.52; H, 3.04; N, 5.40; Cl, 13.74.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C1COCC1.[CH3:12][C@@H:13]1[N:18]([CH3:19])[C@@H:17]([CH3:20])[CH2:16][NH:15][C:14]1=O>>[CH3:19][N:18]1[C@@H:13]([CH3:12])[CH2:14][NH:15][CH2:16][C@@H:17]1[CH3:20]
Reactant: C[C@H]1CNC(=O)[C@H](C)N1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@H]1CNC[C@H](C)N1C
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 146.9 %

Procedure:
1M LAH in THF (3 mL, 3 mmol) was added dropwise to (3S,5S)-3,4,5-trimethyl-2-piperazinone (123 mg, 0.86 mmol). The reaction was allowed to warm to room temperature, then stirred at room temperature for 40 min and at reflux for an additional 5 h. After cooling to room temperature, the reaction was quenched by the sequential addition of H2O (0.114 mL), 15% NaOH (0.114 mL), and H2O (0.342 mL). The mixture was stirred for 0.5 h, and the solids were filtered off and washed with excess THF. To the combined filtrates was added 1.8 mL 1N HCl, followed by concentration under reduced pressure to provide the hydrochloride salt of (2S,6S)-1,2,6-trimethylpiperazine (162 mg, 93%). LCMS: (M+H)+: 129.1.
Reaction SMILES: [CH:1]1[C:13]2[C:12](=O)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[C:4](C(Cl)=O)=[CH:3][CH:2]=1.[OH:18]CCOC1C=CC(S(C2C=CC(OCCO)=CC=2)(=O)=O)=CC=1.C(N(CC)CC)C>O1CCCC1>[C:1]1(=[O:18])[C:13]2[C:5]([C:6]3[C:11]([CH:12]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)=[CH:4][CH:3]=[CH:2]1
Reactant: O=C(Cl)c1cccc2c1-c1ccccc1C2=O
Reactant: O=S(=O)(c1ccc(OCCO)cc1)c1ccc(OCCO)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C1C=CC=C2C1=Cc1ccccc12
Reaction time: 0.5 h

Procedure:
A 10.0 g quantity of 9-fluorenone-4-carbonyl chloride (0.04 mole, obtained from Aldrich Chemicals Co, Milwaukee, Wis. 53201, USA) and 100 ml of tetrahydrofuran (obtained from Aldrich) were added to a 250 ml, 3-neck round bottom flask equipped with a reflux condenser and a mechanical stirrer. The solution was stirred for about ½ hour, then 6.97 g of bis[4-(2-hydroxyethoxy) phenyl]sulfone (0.02 mole, obtained from Aldrich) in 50 ml of tetrahydrofuran were added, followed by the addition of 4.17 g of triethylamine (0.04 mole, obtained from Aldrich). The solution was refluxed for 6 hours, filtered hot to remove triethylamine hydrochloride salt byproduct, and the filtrate was evaporated to dryness to obtain the crude product. The crude product was recrystallized from tetrahydrofuran with activated charcoal. The product was dried at 60° C. in a vacuum oven for 6 hours to yield a fifth dimeric fluorenone derivative, which was a yellow solid (9.3 g, 60% yield). A 1H-NMR (300 MHz) spectrum in CDCl3 yielded chemical shifts (ppm) of: 4.35–4.43 (t, 4H); 4.72–4.81 (t, 4H); 6.95–7.05 (m, 4H); 7.27–7.38 (m, 4H); 7.40–7.52 (dd, 2H); 7.66–7.74 (dd, 2H); 7.79–7.94 (m, 8H); 8.25–8.33 (d, 2H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1)#[CH:2].ClC1C=C(C=CC=1)C(OO)=[O:14].[OH-].[Ca+2].[OH-]>C(Cl)Cl>[C:1]([C:3]1[CH:4]=[N+:5]([O-:14])[CH:6]=[CH:7][CH:8]=1)#[CH:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C#Cc1cccnc1
Agent: [Ca+2]
Agent: [OH-]
Solvent: ClCCl
Product: C#Cc1ccc[n+]([O-])c1
Reaction time: 2 h

Procedure:
To a solution of 3-ethynylpyridine in methylene chloride (5 mL/mmol) at room temperature was added m-chloroperoxybenzoic acid (m-CPBA, 70% purity, 1.2 eq) and the resulting mixture was stirred for 2 hours. A further amount of m-CPBA was added (0.25 eq) and stirring was continued for 1 hour. Calcium hydroxide was added (2 eq) and after 15 minutes the mixture was filtered through celite and the filtrate was evaporated. The solid residue was stirred in ether for 3 hours and filtered to afford the 3-ethynylpyridine N-oxide compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:9])[CH2:4][C:5]([O:7][CH3:8])=[O:6].C[O-].[Na+].[CH3:13][O:14][C:15](=[O:22])/[CH:16]=[C:17](/[O:20][CH3:21])\[CH2:18]Cl>CN(C=O)C>[CH3:13][O:14][C:15](=[O:22])/[CH:16]=[C:17](/[O:20][CH3:21])\[CH2:18][CH:4]([C:5]([O:7][CH3:8])=[O:6])[C:3]([O:2][CH3:1])=[O:9]
Reactant: COC(=O)CC(=O)OC
Reactant: COC(=O)/C=C(\CCl)OC
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)/C=C(\CC(C(=O)OC)C(=O)OC)OC
Temperature: 20 °C
Reaction time: 2 h

Procedure:
66 g (0.5 mol) of malonic acid dimethyl ester was placed in 250 ml of N,N'-dimethylformamide. 27.8 g (0.5 mol) of sodium methylate was added at 20°C.; 10 minutes later 41.6 g (0.25 mol) of 4-chloro-3-methoxy-2E-butenoic acid methyl ester was added within 5 minutes. It was stirred for 2 hours at 20° C. Then 10.8 g (0.2 mol) of sodium methylate was added once more. After stirring for 15 hours at 20° C. it was distilled off. After working up according to Example (a) 53.8 g (81 percent) of the title compound, with a purity of 98 percent (GC), was obtained. Data for the title compound was:
Reaction SMILES: [CH3:1][C:2]1[CH:7]([OH:8])[CH2:6][CH2:5][C:4]([CH3:10])([CH3:9])[C:3]=1[CH:11]=[CH:12][C:13](=[O:15])[CH3:14].O.O.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[Na+].[Na+].S(=O)(=O)(O)O>CCOCC>[CH3:1][C:2]1[C:7](=[O:8])[CH2:6][CH2:5][C:4]([CH3:9])([CH3:10])[C:3]=1[CH:11]=[CH:12][C:13](=[O:15])[CH3:14]
Reactant: CC(=O)C=CC1=C(C)C(O)CCC1(C)C
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: CC(=O)C=CC1=C(C)C(=O)CCC1(C)C
Temperature: 5 °C
Yield: 734.3 %

Procedure:
To a solution, pre-cooled to 0° C., of 140 g (0.068 mol) of 4-(2,6,6-trimethyl-3-hydroxy-cyclohex-1-en-1-yl)-but-3-en-2-one in 500 ml of ether are added dropwise over a period of 10 minutes 700 ml of an aqueous solution, cooled to 0° C., of 202.6 g of sodium dichromate dihydrate and 186 g of concentrated sulphuric acid with intensive cooling and good stirring so that a temperature of 5° C. is not exceeded. The mixture is then stirred for a further 5 minutes at 5° C., treated with 500 ml of ether, the ether phase is washed three times with water, three times with soda solution and again three times with water, dried over sodium sulphate and concentrated. Distillation of the resulting 125 g of crude product over a 10 cm Widmer column gave 103 g of more than 94% pure 4-(2,6,6-trimethyl-3-oxo-cyclohex-1-en-1-yl)-but- 3-en-2-one of boiling point 109°-110° C./0.05 mm Hg; melting point 50°-51° C.
Reaction SMILES: [CH:1]1([C:6]([O:8]C)=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:10](#[N:12])[CH3:11].[H-].[Na+]>O1CCCC1>[CH:1]1([C:6](=[O:8])[CH2:11][C:10]#[N:12])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC#N
Reactant: COC(=O)C1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#CCC(=O)C1CCCC1
Yield: 92.6 %

Procedure:
According to the procedure described in Example 133A Step 1 methyl cyclopentanecarboxylate (4 g, 31.25 mmol), anhydrous acetonitrile (2.55 mL, 48.75 mmol) and sodium hydride, 60% in mineral oil, (1.95 g, 48.75 mmol) in anhydrous tetrahydrofuran (25 mL) were reacted to afford 3-cyclopentyl-3-oxopropanenitrile (3.97 g, 93%) as yellow oil, which was used directly in the next step without further purification. 1H NMR (300 MHz, CDCl3) δ 3.5 (s, 2H), 3.13-3.02 (m, 1H), 1.95-1.62 (m, 8H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH:13]([O:17][CH3:18])[C:14]([OH:16])=[O:15])=[CH:8][C:7]=1[O:19][CH3:20].[F:21][C:22]([F:38])([F:37])[C:23]1[CH:36]=[CH:35][C:26]([O:27][C:28]2[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=2)=[CH:25][CH:24]=1>>[CH3:18][O:17][CH:13]([CH2:12][C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][CH2:2][O:34][C:31]2[CH:32]=[CH:33][C:28]([O:27][C:26]3[CH:35]=[CH:36][C:23]([C:22]([F:21])([F:37])[F:38])=[CH:24][CH:25]=3)=[CH:29][CH:30]=2)=[C:7]([O:19][CH3:20])[CH:8]=1)[C:14]([OH:16])=[O:15]
Reactant: Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Reactant: COc1cc(CC(OC)C(=O)O)ccc1OCCCBr
Product: COc1cc(CC(OC)C(=O)O)ccc1OCCCOc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1

Procedure:
The title compound was prepared from 3-[4-(3-Bromo-propoxy)-3-methoxy-phenyl]-2-methoxy-propionic acid (Example 175, Step B) and 4-(4-Trifluoromethyl-phenoxy)-phenol following the Standard Procedure J. MS (ES) for C27H27F3O7 [M+Na]+: 543.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([C:17]1[S:18][C:19]2[CH:25]=[C:24](C(=S)N)[CH:23]=[CH:22][C:20]=2[N:21]=1)([OH:16])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1.C(=O)([O-])O.[Na+].BrC[C:36](=O)[CH3:37].C(OCC)(=O)C>C(O)C.O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([C:17]1[S:18][C:19]2[CH:25]=[C:24]([SH:18]3[CH:37]=[CH:36][N:21]([CH3:20])[CH2:17]3)[CH:23]=[CH:22][C:20]=2[N:21]=1)([OH:16])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1
Reactant: NC(=S)c1ccc2nc(C(O)(Cn3cncn3)c3ccc(F)cc3F)sc2c1
Reactant: CC(=O)CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: CN1C=C[SH](c2ccc3nc(C(O)(Cn4cncn4)c4ccc(F)cc4F)sc3c2)C1

Procedure:
1-(2,4-Difluorophenyl)-1-(6-thiocarbamoylbenzothiazol-2-yl)-2-(1H-1,2,4-triazol-1-yl)ethanol (219 mg) was dissolved in ethanol (2 ml), and sodium hydrogencarbonate (42 mg) and bromoacetone (46 μl) were added to the solution. The resultant mixture was heated at 60° C. for 3 hours. Ethyl acetate and water were added to the liquid reaction mixture to separate liquid layers. An organic layer was washed with saline and then dried, and the solvent was distilled out. The residue was subjected to column chromatography on silica gel (eluting solvent: chloroform:methanol=100:1), thereby obtaining the intended compound (114 mg). Melting point: 213°-215° C.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][P:7](=[O:14])([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:24](Cl)(=[O:27])[CH:25]=[CH2:26]>C1(C)C=CC=CC=1>[C:24]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][P:7](=[O:14])([O:8][CH2:9][CH3:10])[O:11][CH2:12][CH3:13])=[CH:15][CH:16]=1)(=[O:27])[CH:25]=[CH2:26]
Reactant: C=CC(=O)Cl
Reactant: CCOP(=O)(Cc1ccc(N)cc1)OCC
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: C=CC(=O)Nc1ccc(CP(=O)(OCC)OCC)cc1
Temperature: 25 °C
Yield: 90 %

Procedure:
To a solution of diethyl 4-(amino)benzylphosphonate (2.02 g; 8.3 mmoles) and triethylamine (1.02 g; 9 mmoles) in toluene (7 ml) cooled to 0-5° C., is added dropwise a solution of acryloyl chloride (0.91 g of 95% purity; 10 mmoles) in toluene (2 ml) for 30 min. Thereafter, more toluene (5 ml) is poured into the flask and the mixture is stirred at room temperature for two more hours. The reaction is terminated by addition of water (10 ml). The organic phase is extracted with diethyl ether, dried over MgSO4 and stripped of solvent under vacuum to afford a pale-yellow solid (2.22 g; yield 90%).
Reaction SMILES: [OH-].[Na+].CO.[Br:5][C:6]1[N:18]=[C:9]2[CH2:10][CH:11]([C:14]([O:16]C)=[O:15])[CH2:12][CH2:13][N:8]2[N:7]=1>O>[Br:5][C:6]1[N:18]=[C:9]2[CH2:10][CH:11]([C:14]([OH:16])=[O:15])[CH2:12][CH2:13][N:8]2[N:7]=1
Reactant: COC(=O)C1CCn2nc(Br)nc2C1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)C1CCn2nc(Br)nc2C1
Reaction time: 0.5 h
Yield: 82.4 %

Procedure:
A 2 N sodium hydroxide aqueous solution (6.9 ml) was added to a mixed solution of methanol (20 ml) and water (10 ml) containing the methyl 2-bromo-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-7-carboxylate (2.4 g) obtained in (Example 5.16) <Step 3>. The obtained mixture was stirred for 1 hour 30 minutes. Thereafter, methanol was distilled away under reduced pressure, and the obtained aqueous solution was then washed with ethyl acetate (2 ml). Insoluble substances were removed by filtration. The filtrate was adjusted to pH 1 with concentrated hydrochloric acid, and was then extracted with a mixed solution (50 ml) of 20% isopropanol and methylene chloride five times. The organic layer was dried over anhydrous sodium sulfate, and the solvent was then distilled away under reduced pressure, so as to obtain a crude product (1.87 g) of the title compound in the form of a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[Cl:20])[CH2:5][NH:6][C:7]([NH:9][C:10]1[S:11][CH:12]=[C:13]([CH2:15]I)[N:14]=1)=[O:8].[NH2:21][CH2:22][CH2:23][OH:24]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[Cl:20])[CH2:5][NH:6][C:7]([NH:9][C:10]1[S:11][CH:12]=[C:13]([CH2:15][NH:21][CH2:22][CH2:23][OH:24])[N:14]=1)=[O:8]
Reactant: O=C(NCc1ccc(Cl)c(Cl)c1)Nc1nc(CI)cs1
Reactant: NCCO
Solvent: C1CCOC1
Product: O=C(NCc1ccc(Cl)c(Cl)c1)Nc1nc(CNCCO)cs1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-(3,4-Dichloro-benzyl)-3-(4-iodomethyl-thiazol-2-yl)-urea (Intermediate 6, 0.3 mmol) was taken up in tetrahydrofuran (5 ml) and 2-Amino-ethanol (20 eq.) was added. The reaction was stirred overnight at room temperature. Added a saturated solution of NaSO3 (40 ml). Extracted this with EtOAc twice. The combined organic extracts were dried over Na2SO4, filtered and solvent removed in vacuo to give the title compound a solid.
Reaction SMILES: [CH2:1]([NH2:4])[CH:2]=[CH2:3].C(N(CC)CC)C.[CH2:12]([O:19][C:20](Cl)=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>ClCCl>[CH2:1]([NH:4][C:20](=[O:21])[O:19][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH:2]=[CH2:3]
Reactant: C=CCN
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCNC(=O)OCc1ccccc1
Reaction time: 0.03 h

Procedure:
To a solution of allylamine (58 mmoles, 3.34 g) at 0° C. in dichloromethane (100 mL) was added triethylamine (120 mmoles, 16 mL). The mixture was stirred for two minutes, then benzylchloroformate (58 mmoles, 8.25 mL) added dropwise. The resulting solution was stirred at 0° C. for 2 hours, and at ambient temperature for an additional 90 minutes. A white precipitate formed, which was filtered off. Solvent was removed from the filtrate under reduced pressure, and the residue chromatographed on a silica gel column, eluting with 20% ethyl acetate/hexanes, to give benzyl allylcarbamate, a compound of formula (2), as a clear oil. Yield: 5.0 g.
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:5]([NH:7][C@H:8]([C:24]([NH:26][C@H:27]([C:33]([OH:35])=[O:34])[CH2:28][CH2:29][C:30](=[O:32])[OH:31])=[O:25])[CH2:9][CH2:10][CH2:11][CH2:12][NH:13][S:14]([C:17]1[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=1)(=[O:16])=[O:15])=[O:6])[CH2:3][OH:4]>CO.C(O)(=O)C.[Pd]>[NH2:1][C@H:2]([C:5]([NH:7][C@H:8]([C:24]([NH:26][C@H:27]([C:33]([OH:35])=[O:34])[CH2:28][CH2:29][C:30](=[O:31])[OH:32])=[O:25])[CH2:9][CH2:10][CH2:11][CH2:12][NH:13][S:14]([C:17]1[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=1)(=[O:15])=[O:16])=[O:6])[CH2:3][OH:4]
Reactant: Cc1ccc(S(=O)(=O)NCCCC[C@H](NC(=O)[C@H](CO)NC(=O)OCc2ccccc2)C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc1
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: Cc1ccc(S(=O)(=O)NCCCC[C@H](NC(=O)[C@@H](N)CO)C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc1
Reaction time: 8 h

Procedure:
4.03 Grams of Z-Ser-Lys(Tos)-Glu-OH was dissolved in a mixture of 60 ml of methanol with 40 ml of 10%-acetic acid and a small amount of palladium black was added and stirred overnight under introducing hydrogen gas. After completion of the reaction, the catalyst was removed by vacuum filtration, and the filtrate was distilled under a reduced pressure, then the residue was poured into water and was lyophilized to obtain the desired product.
Reaction SMILES: [CH:1]1([NH:5][S:6]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[NH:15][CH:14]([C:19]2[CH:24]=[C:23]([F:25])[CH:22]=[C:21](Br)[CH:20]=2)[CH2:13][C:12]3([CH3:28])[CH3:27])(=[O:8])=[O:7])[CH2:4][CH2:3][CH2:2]1.Cl.CN(C)CC(O)=O.[NH:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.[Cu]I>[CH:1]1([NH:5][S:6]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[NH:15][CH:14]([C:19]2[CH:20]=[C:21]([N:37]4[CH2:42][CH2:41][O:40][CH2:39][CH2:38]4)[CH:22]=[C:23]([F:25])[CH:24]=2)[CH2:13][C:12]3([CH3:28])[CH3:27])(=[O:8])=[O:7])[CH2:4][CH2:3][CH2:2]1
Reactant: C1COCCN1
Reactant: CC1(C)CC(c2cc(F)cc(Br)c2)Nc2ccc(S(=O)(=O)NC3CCC3)cc21
Agent: [Cu]I
Agent: CN(C)CC(=O)O
Agent: Cl
Solvent: CS(C)=O
Product: CC1(C)CC(c2cc(F)cc(N3CCOCC3)c2)Nc2ccc(S(=O)(=O)NC3CCC3)cc21
Temperature: 25 °C
Yield: 39.9 %

Procedure:
The mixture solution of 2-(3-bromo-5-fluoro-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-sulfonic acid cyclobutylamide (158.4 mg, 0.34 mmol), copper(I) iodide (20.0 mg, 0.1 mmol), N,N-dimethylglycine hydrochloride (37.5 mg, 0.27 mmol), morpholine (0.78 mL, 9.0 mmol) and potassium carbonate (140.0 mg, 1.0 mmol) in dimethyl sulfoxide (2.0 mL) was stirred at 120° C. for 16 h. Then the reaction mixture was cooled to room temperature and extracted with ethyl acetate (70 mL×2), washed with water (30 mL×3) and saturated aqueous ammonium chloride solution (30 mL×2), dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 2-(3-fluoro-5-morpholin-4-yl-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-sulfonic acid cyclobutylamide (64.3 mg, 40.0%) as a white solid: MS (ESI) M+1=474.2.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH:12]=1)[C:7]([NH2:9])=[O:8])([O-])=O.[H][H]>[Pd].C1COCC1>[NH2:1][C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH:12]=1)[C:7]([NH2:9])=[O:8]
Reactant: CCCCCCCCCCCCCCCCCCOc1cc(C(N)=O)cc([N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCCCOc1cc(N)cc(C(N)=O)c1
Reaction time: 4 h
Yield: 90.5 %

Procedure:
A mixture of 4.75 g of 3-nitro-5-(octadecyloxy)benzamide and 1.0 g of 10% palladium on carbon in 750 ml of THF was shaken in a hydrogen atmosphere at room temperature until uptake ceased after 4 hours. The catalyst was removed by filtration and the filtrate was concentrated at reduced pressure to a solid which was recrystallized from methanol to give 4.0 g (91% yield, mp 139°-143°) of 3-amino-5-(octadecyloxy)benzamide.
Reaction SMILES: [C:1]([C:3]1[C:11]2[S:10][N:9]=[N:8][C:7]=2[CH:6]=[CH:5][CH:4]=1)#[N:2].[H][H]>CO.[Ni]>[NH2:2][CH2:1][C:3]1[C:11]2[S:10][N:9]=[N:8][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: N#Cc1cccc2nnsc12
Reactant: [H][H]
Agent: [Ni]
Solvent: CO
Product: NCc1cccc2nnsc12

Procedure:
In a hydrogenation vessel, a solution of 14.5 g of 7-cyanobenzo-1,2,3-thiadiazole in 150 ml of methanol is treated with 4.4 g of Raney nickel and with 15 g of liquid nitrogen. Hydrogen is subsequently injected, the vessel is heated, and the mixture is hydrogenated at 60° C. and constant hydrogen pressure of 107Pa until hydrogen is no longer taken up. The mixture is then cooled, the catalyst is removed by filtration, the filtrate is evaporated and chromatographed on silica gel (hexane/ethyl acetate 2:1), resulting in the title compound of m.p. 136°-139° C.).
Reaction SMILES: [C:1](Cl)(=[O:7])/[CH:2]=[CH:3]/[CH:4]=[CH:5]/[CH3:6].[CH2:9]([OH:27])[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][CH2:23][CH2:24][CH2:25][CH3:26]>C1COCC1>[C:1]([O:27][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][CH2:23][CH2:24][CH2:25][CH3:26])(=[O:7])/[CH:2]=[CH:3]/[CH:4]=[CH:5]/[CH3:6]
Reactant: C/C=C/C=C/C(=O)Cl
Reactant: CCCCCCCCCCCCCCCCCCO
Solvent: C1CCOC1
Product: C/C=C/C=C/C(=O)OCCCCCCCCCCCCCCCCCC

Procedure:
A solution of 0.9 g (6.9 mmol) of sorboyl chloride in 6 mL of THF was added slowly with stirring to a mixture of 1.87 g (6.9 mmol) of n-octadecanol in 10 mL of THF at 40° C. The resulting mixture was refluxed for 16 hours. The solvent was evaporated under reduced pressure and the crude product was purified by column chromatography on silica gel using chloroform as eluent. The appropriate fractions were combined and evaporated to dryness in vacuo to give a white solid product: 1.04 g (42%) yield. TLC (CHCl3)Rf=0.75. 1H NMR (300 MHz) δ 0.89 [3H, t, —(CH3)15CH3)],1.25 [30H, br m, —(CH3)15—], 1.62 [2H, t, —OCH2CH2—], 1.86 [3H, d, CH3CH═], 4.14 [2H, t, —OCH2—], 5.79 [1H, d, OCCH═], 6.19 [2H, m, CH3CH═CH—], 7.22 [1H, m, CH3CH═CH—CH═].
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[N:6][C:7]([CH2:11][CH2:12][CH:13]=O)=[CH:8][CH:9]=2)[CH2:4][O:3]1.[OH:15][CH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>>[OH:15][CH:16]1[CH2:21][CH2:20][N:19]([CH2:13][CH2:12][CH2:11][C:7]2[N:6]=[C:5]3[CH2:4][O:3][C:2](=[O:1])[C:10]3=[CH:9][CH:8]=2)[CH2:18][CH2:17]1
Reactant: O=CCCc1ccc2c(n1)COC2=O
Reactant: OC1CCNCC1
Product: O=C1OCc2nc(CCCN3CCC(O)CC3)ccc21

Procedure:
In a process similar to that described in Preparation 8, 3-(5-Oxo-5,7-dihydro-furo[3,4-b]pyridin-2-yl)-propionaldehyde and 4-hydroxypiperidine are reacted to provide the title compound.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH2:6]([O:13][CH2:14][CH:15]1[CH2:24][CH2:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[O:16]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:25]([O-])(=[O:27])C.[Na+]>ClCCl>[CH2:6]([O:13][CH2:14][CH:15]1[CH2:24][CH2:23][C:22]2[C:17](=[CH:18][CH:19]=[C:20]([CH:25]=[O:27])[CH:21]=2)[O:16]1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: c1ccc(COCC2CCc3ccccc3O2)cc1
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1ccc2c(c1)CCC(COCc1ccccc1)O2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53 %

Procedure:
Phosphorous oxychloride (0.863 ml, 9.26 mmol) was added very slowly and under inert atmosphere on N-methylformanilide (1.14 ml, 9.26 mmol) and the mixture was left under stirring at room temperature for 30 minutes. After that 2-(benzyloxymethyl)chromane (1.569 g, 6.18 mmol) was added stirring at 65° C. for 1.5 h. Subsequently the mixture was diluted with dichloromethane (30 ml), added with a 15% sodium acetate solution (20 ml), the phases were separated and the organic phase was washed successively with a 1M hydrochloric acid solution and a sodium chloride saturated solution. After drying and removing the solvent by evaporation under reduced pressure, a residue was obtained which was purified by flash chromatography through a silica gel column. Eluting with hexane:ethyl acetate, 10:1, 0.921 g of the title product were recovered (53% yield).