Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:6][CH2:7][C:8]2[N:12]3[CH:13]=[C:14]([O:17][C@H:18]4[C:27]5[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=5)[C@@H:21]([NH2:28])[CH2:20][CH2:19]4)[CH:15]=[CH:16][C:11]3=[N:10][N:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.ClC(Cl)(Cl)C[O:32][C:33](=O)[NH:34][C:35]1[N:36]([C:44]2[CH:49]=[CH:48][C:47]([CH3:50])=[CH:46][CH:45]=2)[N:37]=[C:38]([C:40]([CH3:43])([CH3:42])[CH3:41])[CH:39]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[C:40]([C:38]1[CH:39]=[C:35]([NH:34][C:33]([NH:28][C@@H:21]2[C:22]3[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=3)[C@H:18]([O:17][C:14]3[CH:15]=[CH:16][C:11]4[N:12]([C:8]([CH2:7][CH2:6][N:1]5[CH2:5][CH2:4][CH2:3][CH2:2]5)=[N:9][N:10]=4)[CH:13]=3)[CH2:19][CH2:20]2)=[O:32])[N:36]([C:44]2[CH:49]=[CH:48][C:47]([CH3:50])=[CH:46][CH:45]=2)[N:37]=1)([CH3:43])([CH3:41])[CH3:42]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)cc1
Reactant: N[C@H]1CC[C@@H](Oc2ccc3nnc(CCN4CCCC4)n3c2)c2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(CCN5CCCC5)n4c3)c3ccccc32)cc1
Temperature: 60 °C
Yield: 17 %

Procedure:
Intermediate 1c (270 mg, 0.74 mmol) was dissolved in 1,4-dioxane (6 mL) and (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-carbamic acid 2,2,2-trichloro-ethyl ester (Synthetic Communications, 2009, 39, 3999-4009, which is incorporated herein by reference in its entirety; 329 mg, 0.81 mmol) and DIPEA (257 μL, 1.48 mmol) were added. The reaction was heated to 60° C. for 18 h. After cooling, the mixture was partitioned between EtOAc (50 mL) and water (50 mL), and then extracted into EtOAc (3×). The combined organic extracts were washed with brine, dried (MgSO4) and evaporated in vacuo. The residue was purified by FCC, using 0-10% [2M NH3 in MeOH] in DCM, then further purified by HPLC (C18 X-select column, 10-98% MeCN in H2O, 0.1% formic acid) to give the title compound (78.0 mg, 0.12 mmol, 17%). LCMS (Method 5): Rt 3.67 mins, m/z 633 [MH+]. 1H NMR (400 MHz, d4-MeOD): 1.30 (9H, s), 1.90-2.06 (6H, m), 2.07-2.18 (1H, m), 2.22-2.30 (1H, m), 2.39 (3H, s), 3.08-3.16 (4H, m), 3.42-3.50 (4H, m), 4.87-4.92 (1H, dd, J 9.0, 5.6), 5.43-5.47 (1H, t, J 4.2), 6.33 (1H, s), 7.20-7.36 (10H, m), 7.62-7.66 (1H, d, J 9.7), 8.07-8.09 (1H, d, J 1.6), 8.45 (0.6H, s).
Reaction SMILES: Cl.[O:2]1[C:10]2[CH2:9][CH2:8][NH:7][CH2:6][C:5]=2[CH:4]=[CH:3]1.C(N(CC)CC)C.Cl[S:19]([C:22]1[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=1)(=[O:21])=[O:20]>ClCCl>[O:2]1[C:10]2[CH2:9][CH2:8][N:7]([S:19]([C:22]3[CH:23]=[CH:24][C:25]([C:26]([OH:28])=[O:27])=[CH:29][CH:30]=3)(=[O:21])=[O:20])[CH2:6][C:5]=2[CH:4]=[CH:3]1
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: c1cc2c(o1)CCNC2
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(O)c1ccc(S(=O)(=O)N2CCc3occc3C2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2.900 g (18.169 mmol) of 4,5,6,7-tetrahydrofuro[3,2-c]pyridine hydrochloride and 12.7 ml (90.8 mmol) of triethylamine in 100 ml of dichloromethane, 4.81 g (21.8 mmol) of 4-chlorosulfonylbenzoic acid was added under ice-cooling, followed by overnight stirring at room temperature. After the solvent was distilled off under reduced pressure, 1 N hydrochloric acid was added; the resulting precipitate was filtered, washed with 1 N hydrochloric acid and dried to yield the desired product.
Reaction SMILES: [NH2:1][C@H:2]([CH2:12][O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].C(N(CC)CC)C.Cl[C:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[N:32]=[CH:31][C:30]=1[N+:39]([O-:41])=[O:40].O>C(Cl)Cl.C(OCC)(=O)C.C(Cl)Cl>[Si:14]([O:13][CH2:12][C@@H:2]([NH:1][C:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[N:32]=[CH:31][C:30]=1[N+:39]([O-:41])=[O:40])[CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:9])([CH3:10])[CH3:8])([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:15])[CH3:16]
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Reactant: CC(C)(C)OC(=O)NC[C@H](N)CO[Si](C)(C)C(C)(C)C
Solvent: ClCCl
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC[C@@H](CO[Si](C)(C)C(C)(C)C)Nc1c([N+](=O)[O-])cnc2ccccc12
Reaction time: 8 h
Yield: 89.9 %

Procedure:
tert-Butyl (2S)-2-amino-3-{[tert-butyl(dimethyl)silyl]oxy}propylcarbamate (3.43 g, 11.3 mmol) was dissolved in 110 mL of dry CH2Cl2. Triethylamine (3.14 mL, 22.6 mmol) and 4-chloro-3-nitroquinoline (2.35 g, 11.3 mmol) were then added and the reaction was stirred under N2 overnight. The reaction mixture was then treated with 100 mL of H2O and 100 mL of CH2Cl2. The layers were separated and the organic portion was washed successively with H2O and brine. The organic portion was dried over Na2SO4, filtered and concentrated under reduced pressure to give yellow solid. Chromatography (SiO2, 0-20% ethyl acetate/CH2Cl2) gave tert-butyl (2S)-3-{[tert-butyl(dimethyl)silyl]oxy}-2-[(3-nitroquinolin-4-yl)amino]propylcarbamate (4.84 g) as a yellow solid.
Reaction SMILES: [CH3:1]/[C:2](/[CH2:9][CH2:10]/[CH:11]=[C:12](/[CH3:19])\[CH2:13][CH2:14][CH:15]=[C:16]([CH3:18])[CH3:17])=[CH:3]\[C:4](OCC)=[O:5].[H-].C([Al+]CC(C)C)C(C)C>C1(C)C=CC=CC=1>[CH3:1]/[C:2](/[CH2:9][CH2:10]/[CH:11]=[C:12](/[CH3:19])\[CH2:13][CH2:14][CH:15]=[C:16]([CH3:18])[CH3:17])=[CH:3]\[CH2:4][OH:5]
Reactant: CCOC(=O)/C=C(\C)CC/C=C(/C)CCC=C(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: CC(C)=CCC/C(C)=C\CC/C(C)=C/CO
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 1 g (0.0038 mol) of ethyl (2E,6Z)-3,7,11-trimethyl-2,6,10-dodecatrienoate in 8 ml of toluene is treated dropwise at -5° to -10° with 9.45 ml of a solution of diisobutylaluminium hydride in toluene (1.2 mol/l, i.e. 3.0 mol equivalents). The solution is stirred at the same temperature for 1 hour under argon. The reaction mixture is poured into an ice-water mixture and extracted with ether. After drying and removing the solvent the residue is chromatographed on silica gel with ether-hexane 1:1. There is obtained (2E,6Z)-3,7,11-trimethyl-2,6,10-dodecatrien-1-ol which has the following bands in the IR spectrum: 3323 cm-1, 1668 cm-1, 1446 cm-1, 1377 cm-1, 1001 cm-1.
Reaction SMILES: [I:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].I[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>CN(C=O)C>[I:1][C:2]1[CH:8]=[CH:7][C:5]([N:6]([CH2:7][CH2:8][CH2:2][CH2:3][CH2:4][CH3:5])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:4][CH:3]=1
Reactant: CCCCCCI
Reactant: Nc1ccc(I)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCN(CCCCCC)c1ccc(I)cc1
Temperature: 100 °C
Reaction time: 2.5 h

Procedure:
4-Iodoaniline (15.05 g, 6.87×10−2 mol), K2CO3 (19.00 g, 0.137 mol), 1-iodohexane (32.0 ml, 0.217 mol) and dry DMF (170 ml) were added to a 500-ml two-neck round-bottom flask. Ar was bubbled into the reaction mixture for 10 min. The reaction mixture was stirred at 90° C. for 16 h and at 100° C. for 2.5 h under Ar. After cooling, the reaction mixture was filtered to remove inorganic solids. Solvents were removed in vacuo, and water was added to the reaction mixture. The organic layers were extracted with CHCl3, washed with aq. NaHCO3 and water, and dried over Na2SO4. The residue was chromatographed on silica gel 4:1 hexane:CHCl3 as the eluent. Yield=20.47 g (77% based on 15.05 g of 4-iodoaniline). 1H NMR (250 MHz, CDCl3): δ 7.41 (d, 2H, J=8.8 Hz, Ph), 6.40 (d, 2H, J=9.1 Hz, Ph), 3.20 (t, 4H, J=7.6 Hz, —NCH2—), 1.43-1.61 (m, 4H, —NCH2CH2—), 1.18-1.37 (m, 12H, —CH2—), 0.89 (t, 6H, J=6.5 Hz, —CH3). CI MS m/z: 388.149 ((M+H)+) (calcd 388.150).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH2:22][CH2:23][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[CH:24]1([CH2:23][CH2:22][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[O:15][CH2:14][CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: CC(C)(C)OC(=O)N1CCC(COc2ccccc2CCC2CCCCC2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1ccc(OCC2CCNCC2)c(CCC2CCCCC2)c1
Reaction time: 0.5 h
Yield: 105.2 %

Procedure:
1.138 g of 1-(tert-butoxycarbonyl)-4-[[(2-cyclohexylethyl)phenoxy]methyl]piperidine was dissolved in 3 ml of dichloromethane, 3 ml of trifluoroacetic acid was added thereto, and the mixture was left at room temperature for one hour 30 minutes. An aqueous sodium carbonate was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated, and to the residue was added n-hexane, to give 899 mg of the title compound as a white powder.
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O.[CH2:32]([N:39]1[C:44]([CH3:45])=[CH:43][C:42]([OH:46])=[C:41]([Br:47])[C:40]1=[O:48])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.[F:49][C:50]1[CH:57]=[C:56]([F:58])[CH:55]=[CH:54][C:51]=1[CH2:52]O>CN(C=O)C>[CH2:32]([N:39]1[C:44]([CH3:45])=[CH:43][C:42]([O:46][CH2:52][C:51]2[CH:54]=[CH:55][C:56]([F:58])=[CH:57][C:50]=2[F:49])=[C:41]([Br:47])[C:40]1=[O:48])[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: Cc1cc(O)c(Br)c(=O)n1Cc1ccccc1
Reactant: OCc1ccc(F)cc1F
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)n1Cc1ccccc1
Temperature: -10 °C
Reaction time: 0.33 h

Procedure:
To a degassed cold solution of DMF (10 mL) and PPh3 (resin, 0.93 g, 2.75 mmol) was added DEAD (0.44 mL, 2.75 mmol). The reaction mixture stirred at −10° C. for 20 minutes under nitrogen. A solution of 1-benzyl-3-bromo-4-hydroxy-6-methylpyridin-2(1H)-one (0.62 g, 2.1 mmol) and 2,4-difluorobenzylalcohol (0.283 mL, 2.5 mmol) in DMF (10 mL) was added to the resin suspension. The reaction mixture stirred at −10° C. for 30 minutes and then allowed to stir at room temperature for 1 hour. The resin was filtered and rinsed with fresh MeOH and the filtrate was concentrated. The residue was dissolved in ethyl acetate and purified by flash column chromatography (ethyl acetate/hexane 1:1 v/v). The appropriate fractions were concentrated. 1H-NMR (CD3OD, 400 MHz) δ 7.62 (m, 1H), 7.31 (m, 3H), 7.1 (d, 2H, J=7.2 Hz), 7.02 (t, 2H, J=8.6 Hz), 6.48 (s, 1H), 5.42 (s, 2H), 5.28 (s, 2H), 2.34 (s, 3H); ES-HRMS m/z 420.0399/422.0380 (M+H calculated for C20H17NO2F2Br requires 420.0405/422.0387).
Reaction SMILES: [Br:1][C:2]1[C:3]2[C:4]3[CH:16]=[N:15][C:14]([C:17]([O:19]CC)=[O:18])=[CH:13][C:5]=3[NH:6][C:7]=2[C:8]([C:11]#[N:12])=[CH:9][CH:10]=1.B1([O-])O[O:23]1.O.O.O.O.[Na+].Cl>C(O)C.O>[Br:1][C:2]1[C:3]2[C:4]3[CH:16]=[N:15][C:14]([C:17]([OH:19])=[O:18])=[CH:13][C:5]=3[NH:6][C:7]=2[C:8]([C:11](=[O:23])[NH2:12])=[CH:9][CH:10]=1
Reactant: CCOC(=O)c1cc2[nH]c3c(C#N)ccc(Br)c3c2cn1
Reactant: [O-]B1OO1
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: NC(=O)c1ccc(Br)c2c1[nH]c1cc(C(=O)O)ncc12
Temperature: 100 °C
Yield: 79.2 %

Procedure:
A suspension of crude ethyl 9-bromo-6-cyano-5H-pyrido[4,3-b]indole-3-carboxylate (0.78 g, 2.266 mmol) and sodium perborate tetrahydrate (1.395 g, 9.07 mmol) in ethanol-water (3:2, 99 mL) was heated at 100° C. for 3 h. The mixture was cooled to room temperature and the ethanol was removed under vacuum to give a suspension. The pH was adjusted to about 5-6 with 1 M aqueous HCl. The precipitate was collected by filtration, washed with water and air-dried to afford the desired product (0.60 g). The filtrate was concentrated under vacuum to provide additional desired product (70 mg, total of 88% yield). LCMS (M+H)+ m/z 334.0, 335.9.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][C:10]2[CH:15]=[C:14]([N+:16]([O-])=O)[CH:13]=[C:12]([CH3:19])[CH:11]=2)=[CH:5][CH:4]=1.C(OC1C=CC(OC2C=CC(C3NC4C=C(Br)C=CC=4N=3)=CC=2[N+]([O-])=O)=CC=1)C1C=CC=CC=1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([S:9][C:10]2[CH:15]=[C:14]([NH2:16])[CH:13]=[C:12]([CH3:19])[CH:11]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(Sc2cc(C)cc([N+](=O)[O-])c2)cc1
Agent: O=[N+]([O-])c1cc(-c2nc3ccc(Br)cc3[nH]2)ccc1Oc1ccc(OCc2ccccc2)cc1
Product: COc1ccc(Sc2cc(C)cc(N)c2)cc1

Procedure:
The product from Example 181A was reduced according to the procedure from Example 147C substituting the product from Example 181A for the product from Example 147B to provide the title compound.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])(=[O:12])=[O:11].C(N(CC)CC)C.[C:25](OC(=O)C)(=[O:27])[CH3:26]>ClCCl>[C:25]([O:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])(=[O:12])=[O:11])(=[O:27])[CH3:26]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1CCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OCCc1ccccc1S(=O)(=O)NC(C)(C)C
Temperature: 25 °C
Reaction time: 22 h

Procedure:
A solution of 29.0 g of the product from Example 1 and 24 ml triethylamine in 290 ml of dichloromethane was cooled to 0° C. and treated with 13 ml acetic anhydride. The reaction mixture was stirred at room temperature for 22 hours. Dichloromethane (200 ml) was added and the organic layer washed with three 50 ml portions of water and one portion of brine. Drying the organic layer over magnesium sulfate followed by concentrating in vacuo gave the crude product. Purification by silica gel chromatography (elution with hexanes-ethyl acetate, 70:30) afforded 19.5 g of pure 2-[2-(acetyloxy)ethyl]-N-(1,1-dimethylethyl)benzenesulfonamide as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:27])=[C:4]([CH:8]=[C:9]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH:26]=[CH:25][CH:24]=[N:23]3)=[CH:18][CH:17]=2)[C:10]=1[C:11]([F:14])([F:13])[F:12])[C:5]([OH:7])=[O:6].[C:28](Cl)(=O)[C:29](Cl)=O.C(N(CC)CC)C>ClCCl.C(O)C>[Cl:1][C:2]1[C:3]([OH:27])=[C:4]([CH:8]=[C:9]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([N:22]3[CH:26]=[CH:25][CH:24]=[N:23]3)=[CH:20][CH:21]=2)[C:10]=1[C:11]([F:14])([F:13])[F:12])[C:5]([O:7][CH2:28][CH3:29])=[O:6]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cc(Cc2ccc(-n3cccn3)cc2)c(C(F)(F)F)c(Cl)c1O
Solvent: ClCCl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cc(Cc2ccc(-n3cccn3)cc2)c(C(F)(F)F)c(Cl)c1O
Temperature: 15 °C
Reaction time: 16 h
Yield: 31.1 %

Procedure:
To a solution of 3-chloro-2-hydroxy-5-[4-(1H-pyrazol-1-yl)benzyl]-4-(trifluoromethyl)benzoic acid (0.60 g) in dichloromethane (20.0 mL) was added oxalyl chloride (0.29 g) under ice-cooling, and the mixture was stirred at 15° C. for 16 hr. The reaction mixture was added to a solution of triethylamine (2.00 mL) in ethanol (40.0 mL), and the mixture was stirred for 1 hr. The mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate. The mixture was washed with 1N hydrochloric acid and saturated aqueous sodium bicarbonate solution, and the organic layer was concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography (ethyl acetate/petroleum ether) to give the title compound (0.20 g).
Reaction SMILES: [NH2:1][C@H:2]([C:11]([OH:13])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[CH3:14][C@H:15]([NH2:30])[C:16]([NH:18][C@H:19]([C:27]([OH:29])=[O:28])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:17].[NH2:31][CH2:32][C:33]([O:35]C)=[O:34].CO.[OH-].[Na+].Cl>O>[NH2:1][C@H:2]([C:11]([OH:13])=[O:12])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1.[CH3:14][C@H:15]([NH2:30])[C:16]([NH:18][C@H:19]([C:27]([OH:29])=[O:28])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:17].[NH2:31][CH2:32][C:33]([OH:35])=[O:34]
Reactant: COC(=O)CN
Agent: C[C@H](N)C(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: Cl
Agent: N[C@@H](Cc1ccc(O)cc1)C(=O)O
Solvent: O
Solvent: CO
Product: NCC(=O)O

Procedure:
Alternatively, 0.10 g peptide ester (16) are suspended in 5 ml H2O and 3 ml methyl alcohol and saponified with 0.32 ml 1 N NaOH for 90 min. at room temperature. 0.32 ml 1 N HCl are added, and the solution concentrated in vacuo. By dilution with 95% ethanol 0.08 g of the title compound (17) is obtained, m.p. 250°-252° C. (dec.); [α]D28 -2.8° (C=1, DMF), RfC =0.56. Amino acid ratios: Gly 1.04; ala 0.94; Tyr 1.00; Phe 1.05.
Reaction SMILES: [C:1]1(=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[NH:3][NH:2]1.[O-]CC.[Na+].[C:17]([O:21]CC)(=[O:20])[CH:18]=[CH2:19].Cl>C(O)C.[OH-].[Na+]>[C:17]([CH2:18][CH2:19][N:3]1[NH:2][C:1](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]1=[O:11])([OH:21])=[O:20]
Reactant: O=c1[nH][nH]c(=O)c2ccccc12
Reactant: C=CC(=O)OCC
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: O=C(O)CCn1[nH]c(=O)c2ccccc2c1=O
Reaction time: 8 h
Yield: 26 %

Procedure:
2,3-Dihydrophthalazine-1,4-dione(8.1 g; 0.05 mol) was suspended in 100 ml of absolute ethanol containing a catalytic amount of sodium ethoxide. Ethyl acrylate (5.0 g; 0.05 mol) was added to the suspension and the mixture was reacted under reflux for 42 hours. The hot reaction mixture was filtered and the solvent removed in vacuo. The product thus formed was dissolved in sodium hydroxide (0.07 M; 250 ml) and stirred overnight. The solution was acidified by the addition of hydrogen chloride resulting in the formation of a white crystalline solid. The solid was recrystallized from water to produce the product, 2-(2'-carboxyethyl)-2,3-dihydrophthalazine-1,4-dione.
Reaction SMILES: [C:1]([NH2:6])([CH2:4][CH3:5])([CH3:3])[CH3:2].Cl[CH2:8][CH2:9][O:10][CH:11]([OH:13])[CH3:12]>>[C:1]([NH:6][CH2:8][CH2:9][O:10][CH:11]([OH:13])[CH3:12])([CH2:4][CH3:5])([CH3:3])[CH3:2]
Reactant: CC(O)OCCCl
Reactant: CCC(C)(C)N
Product: CCC(C)(C)NCCOC(C)O
Yield: 66.7 %

Procedure:
In the manner described in Example 8, 129.7 g of tertiaryamylamine and 92.2 g of 2-chloroethoxyethanol yielded 86.5 g of tertiaryamylaminoethoxyethanol having a b.p. of 124° C. (10 mm).
Reaction SMILES: [NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8].[H-].[Na+].[C:19](Cl)(=[O:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>C1C=CC=CC=1>[C:19]([N:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])(=[O:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCC(=O)Cl
Reactant: O=C1CC[C@@H](C(=O)OCc2ccccc2)N1
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Product: CCCCCC(=O)N1C(=O)CC[C@H]1C(=O)OCc1ccccc1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
A solution of 17.5 g (80 mmol) of benzyl (L)-pyroglutamate, prepared according to Example II(1), in 150 ml of benzene is added over 1 hour to a suspension of 3.85 g (80 mmol) of sodium hydride in 15 ml of dry benzene. After stirring for 1 hour at ordinary temperature, a solution of 10.9 g (81 mmol) of hexanoyl chloride in 140 ml of benzene is run in. The mixture is heated at 50° C. for 5 hours and then stirred at ordinary temperature for 15 hours, washed with water (2×100 ml), dried and evaporated.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.S(Cl)([Cl:19])=O>O1CCOCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C:14]([Cl:19])=[O:16])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=C(O)C1CCN(c2ccc(F)cc2)CC1
Reactant: O=S(Cl)Cl
Solvent: C1COCCO1
Product: O=C(Cl)C1CCN(c2ccc(F)cc2)CC1
Reaction time: 1 h

Procedure:
1-(4-Fluorophenyl)-4-piperidinecarboxylic acid (0.1 g, 0.45 mmol) was stirred in dioxane (5 mL) and thionyl chloride (0.165 mL, 2.25 mmol) was added drop-wise. After stirring for 1 h the solvent was removed by evaporation, DCM was added to the residue which was then re-concentrated to give 1-(4-fluorophenyl)-4-piperidinecarbonyl chloride which was used directly in step 2.
Reaction SMILES: [Br:1]Br.[OH:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C:10]([C:14]1[O:15][C:16]3[CH:22]=[C:21]([OH:23])[CH:20]=[CH:19][C:17]=3[N:18]=1)=[CH:9][CH:8]=[CH:7]2.O>C(O)(=O)C>[Br:1][C:5]1[C:4]([OH:3])=[CH:13][CH:12]=[C:11]2[C:6]=1[CH:7]=[CH:8][CH:9]=[C:10]2[C:14]1[O:15][C:16]2[CH:22]=[C:21]([OH:23])[CH:20]=[CH:19][C:17]=2[N:18]=1
Reactant: Oc1ccc2c(-c3nc4ccc(O)cc4o3)cccc2c1
Reactant: BrBr
Solvent: O
Solvent: CC(=O)O
Product: Oc1ccc2nc(-c3cccc4c(Br)c(O)ccc34)oc2c1
Reaction time: 2 h

Procedure:
Bromine (86 mg, 0.54 mmol) in acetic acid (2 mL) was added dropwise into solution of 2-(6-hydroxy-1-naphthyl)-1,3-benzoxazol-6-ol (0.15 g, 0.54 mmol) and acetic acid (9 mL). The reaction mixture was stirred for 2 h, poured into water and the precipitated solid filtered and dried. The product was recrystallized from acetone/EtOAc to give a yellow solid, m.p. 221-223° C.; MS m/e 354 (M−H)+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:26]([O:29][C:30]([F:33])([F:32])[F:31])=[CH:25][C:4]=1[C:5]([N:7]1[CH2:11][CH2:10][C:9]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([CH2:12][CH2:13]OS(C)(=O)=O)[CH2:8]1)=[O:6].[CH2:34]([O:36][CH2:37][CH2:38][N:39]1[C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=2[N:41]=[C:40]1[NH:48][CH:49]1[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]1)[CH3:35]>>[CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:26]([O:29][C:30]([F:31])([F:33])[F:32])=[CH:25][C:4]=1[C:5]([N:7]1[CH2:11][CH2:10][C:9]([CH2:12][CH2:13][N:52]2[CH2:51][CH2:50][CH:49]([NH:48][C:40]3[N:39]([CH2:38][CH2:37][O:36][CH2:34][CH3:35])[C:43]4[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=4[N:41]=3)[CH2:54][CH2:53]2)([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:8]1)=[O:6]
Reactant: CCOCCn1c(NC2CCNCC2)nc2ccccc21
Reactant: COc1ccc(OC(F)(F)F)cc1C(=O)N1CCC(CCOS(C)(=O)=O)(c2ccccc2)C1
Product: CCOCCn1c(NC2CCN(CCC3(c4ccccc4)CCN(C(=O)c4cc(OC(F)(F)F)ccc4OC)C3)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 1.6 using 1-(2-methoxy-5-trifluoromethoxybenzoyl)-3-phenyl-3-(2-methanesulfonyloxyethyl)pyrrolidine and (1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)(piperidin-4-yl)amine to give the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:16](=[O:32])[N:17]3[C:22](=[C:23]([C:25](O)=[O:26])[CH:24]=2)[C:21]2[N:28]=[CH:29][N:30]([CH3:31])[C:20]=2[CH:19]=[CH:18]3)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=S(Cl)Cl.C(N(CC)CC)C.[CH3:44][O:45][CH2:46][CH2:47][NH:48][CH2:49][CH2:50][O:51][CH3:52]>C1(C)C=CC=CC=1.ClCCl>[CH3:44][O:45][CH2:46][CH2:47][N:48]([CH2:49][CH2:50][O:51][CH3:52])[C:25]([C:23]1[CH:24]=[C:15]([C:12]2[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:14][CH:13]=2)[C:16](=[O:32])[N:17]2[C:22]=1[C:21]1[N:28]=[CH:29][N:30]([CH3:31])[C:20]=1[CH:19]=[CH:18]2)=[O:26]
Reactant: Cn1cnc2c1ccn1c(=O)c(-c3ccc(OCc4ccccc4)cc3)cc(C(=O)O)c21
Reactant: COCCNCCOC
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: COCCN(CCOC)C(=O)c1cc(-c2ccc(OCc3ccccc3)cc2)c(=O)n2ccc3c(ncn3C)c12

Procedure:
From 8-(4-benzyloxy-phenyl)-3-methyl-7-oxo-3,7-dihydro-imidazo[4,5-a]-quinolizine-10-carboxylic acid with SOCl2 in toluene and treatment with triethylamine and bis(2-methoxyethyl)amine in dichloromethane.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1.[CH3:16][O:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20](Cl)=[O:21]>>[CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][N:5]([C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1)[C:20](=[O:21])[C:19]1[CH:23]=[CH:24][CH:25]=[CH:26][C:18]=1[O:17][CH3:16]
Reactant: COc1ccccc1C(=O)Cl
Reactant: CN(C)CCNc1ccc([N+](=O)[O-])cc1
Product: COc1ccccc1C(=O)N(CCN(C)C)c1ccc([N+](=O)[O-])cc1

Procedure:
Prepared from 4-(2-dimethylamino-ethylamino)-nitrobenzene and 2-methoxy-benzoyl chloride