Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC[CH:3]([C:6]1[S:7][CH:8]=[C:9]([C:11]([O:13]CC)=[O:12])[N:10]=1)[CH2:4][CH3:5].[C:16](N)(=O)CCCC>>[CH2:3]([C:6]1[S:7][CH:8]=[C:9]([C:11]([OH:13])=[O:12])[N:10]=1)[CH2:4][CH2:5][CH3:16]
Reactant: CCOC(=O)c1csc(C(CC)CC)n1
Reactant: CCCCC(N)=O
Product: CCCCc1nc(C(=O)O)cs1

Procedure:
Prepared by the method of Carboxylic Acid 3, from step b using pentanamide (10 g) in place of 2-ethylbutanamide in step b. Yield 4.6 g.
Reaction SMILES: CC1(C)[O:6][C@H:5]([CH2:7][N:8]2[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:38])[C@@H:15]([N:20]3[CH2:24][C:23]([O:25][C:26]4[C:31]([F:32])=[CH:30][CH:29]=[C:28]([O:33][CH2:34][CH3:35])[C:27]=4[F:36])=[CH:22][C:21]3=[O:37])[CH2:16][CH:17]([CH3:19])[CH3:18])=[N:9]2)[CH2:4][O:3]1.Cl>O1CCCC1.C(OCC)(=O)C>[OH:6][C@@H:5]([CH2:4][OH:3])[CH2:7][N:8]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:38])[C@@H:15]([N:20]2[CH2:24][C:23]([O:25][C:26]3[C:31]([F:32])=[CH:30][CH:29]=[C:28]([O:33][CH2:34][CH3:35])[C:27]=3[F:36])=[CH:22][C:21]2=[O:37])[CH2:16][CH:17]([CH3:18])[CH3:19])=[N:9]1
Reactant: CCOc1ccc(F)c(OC2=CC(=O)N([C@@H](CC(C)C)C(=O)Nc3ccn(C[C@@H]4COC(C)(C)O4)n3)C2)c1F
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOc1ccc(F)c(OC2=CC(=O)N([C@@H](CC(C)C)C(=O)Nc3ccn(C[C@@H](O)CO)n3)C2)c1F
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 73.7 %

Procedure:
A solution of (S)-2-[4-(3-ethoxy-2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-yl]-amide (prepared in Example 116, 1.140 g, 2.08 mmol) in tetrahydrofuran (100 mL) was treated with 2N aqueous hydrochloric acid (150 mL). The reaction mixture was stirred for 2.5 h at room temperature. The reaction mixture was diluted with ethyl acetate, washed with saturated sodium bicarbonate, a saturated sodium chloride solution and dried over magnesium sulfate. The mixture was filtered and evaporated and the residue purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 40 g, 30% to 100% (9:1 dichloromethane:methanol)/hexanes) which afforded (S)-2-[4-(3-ethoxy-2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid [1-((R)-2,3-dihydroxy-propyl)-1H-pyrazol-3-yl]-amide (0.780 g, 74%) as a white solid: HR-ES-MS m/z calculated for C24H30F2N4O6, [M+H]+ 509.2206 observed 509.2206; 1H NMR (300 MHz, DMSO-d6) δ ppm 0.90 (d, J=6.6 Hz, 3H), 0.93 (d, J=6.6 Hz, 3H), 1.35 (t, J=6.8 Hz, 3H), 1.38-1.50 (m, 1H), 1.50-1.67 (m, 1H), 1.68-1.85 (m, 1H), 3.20-3.33 (m, 2H), 3.71-3.94 (m, 2H), 4.04-4.20 (m, 3H), 4.26 (d, J=18.7 Hz, 1H), 4.63 (d, J=18.7 Hz, 1H), 4.71 (t, J=5.3 Hz, 1H), 4.87 (dd, J=10.3, 4.5 Hz, 1H), 4.94 (d, J=4.8 Hz, 1H), 5.05 (s, 1H), 6.41 (s, 1H), 7.09-7.35 (m, 2H), 7.53 (s, 1H), 10.79 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]3[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=3)[NH2:23])[CH2:14][CH2:13]2)[N:3]=1.[C:27]1(=O)[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[C:29](=[O:36])[O:28]1>>[CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N:12]2[CH2:13][CH2:14][N:15]([CH2:18][CH2:19][C:20]3[CH:21]=[C:22]([N:23]4[C:27](=[O:28])[C:31]5[C:30](=[CH:35][CH:34]=[CH:33][CH:32]=5)[C:29]4=[O:36])[CH:24]=[CH:25][CH:26]=3)[CH2:16][CH2:17]2)[N:3]=1
Reactant: Cc1ccc2c(N3CCN(CCc4cccc(N)c4)CC3)cccc2n1
Reactant: O=C1OC(=O)c2ccccc21
Product: Cc1ccc2c(N3CCN(CCc4cccc(N5C(=O)c6ccccc6C5=O)c4)CC3)cccc2n1

Procedure:
Prepared from 3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6) and 2-benzofuran-1,3-dione according to Method I.
Reaction SMILES: [CH2:1]([N:4]1[CH:8]([CH2:9][CH2:10][CH3:11])[CH2:7][O:6][S@:5]1=[O:12])[CH2:2][CH3:3].I([O-])(=O)(=O)=[O:14].[Na+]>C(OCC)(=O)C.O.[Ru](Cl)(Cl)Cl>[CH2:1]([N:4]1[C@H:8]([CH2:9][CH2:10][CH3:11])[CH2:7][O:6][S:5]1(=[O:14])=[O:12])[CH2:2][CH3:3]
Reactant: CCCC1CO[S@@](=O)N1CCC
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: Cl[Ru](Cl)Cl
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CCC[C@@H]1COS(=O)(=O)N1CCC
Temperature: 3 °C
Yield: 93 %

Procedure:
Ruthenium trichloride hydrate (10 mg) was added to a solution of (R)-3,4-dipropyl-1,2,3-oxathiazolidine 2-oxide (11.09 g) in ethyl acetate (58 mL) under stirring at 3° C. A cold saturated aqueous sodium periodate solution (200 mL) was added to the solution. The resulting suspension was stirred under ice-cooling for 10 minutes and then further stirred at room temperature for 1 hour. The suspension was filtered, and the insoluble matter was washed twice with ethyl acetate (15 mL). The filtrate and the washings were combined. The organic layer was separated, washed with a saturated aqueous sodium hydrogen carbonate solution (15 mL), dried over anhydrous sodium sulfate and then concentrated under reduced pressure. Tetrahydrofuran (13.5 mL) was added to the residue, and the mixture was concentrated under reduced pressure. The concentration was repeated three times. (R)-3,4-Dipropyl-1,2,3-oxathiazolidine 2,2-dioxide (11.22 g, 93% yield) was obtained as a brown oil.
Reaction SMILES: [F:1][C:2]([F:41])([F:40])[C:3]1[CH:4]=[C:5]([CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1)[CH2:6][N:7]([C:27]1[N:28]=[N:29][N:30]([CH3:32])[N:31]=1)[C@H:8]1[CH2:14][CH2:13][CH2:12][N:11](C(Cl)=O)[C:10]2[CH:18]=[C:19]([C:23]([F:26])([F:25])[F:24])[C:20]([CH3:22])=[CH:21][C:9]1=2.C(OC(=O)[NH:48]CCO)(C)(C)C.CN(C1C=CC=CN=1)C.[H-].[Na+].[C:64]([O:67][CH2:68][CH3:69])(=[O:66])C>CN(C)C=O.O.ClCCl>[NH2:48][CH2:69][CH2:68][O:67][C:64]([N:11]1[CH2:12][CH2:13][CH2:14][C@H:8]([N:7]([CH2:6][C:5]2[CH:4]=[C:3]([C:2]([F:41])([F:40])[F:1])[CH:35]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:33]=2)[C:27]2[N:28]=[N:29][N:30]([CH3:32])[N:31]=2)[C:9]2[CH:21]=[C:20]([CH3:22])[C:19]([C:23]([F:26])([F:25])[F:24])=[CH:18][C:10]1=2)=[O:66]
Reactant: CCOC(C)=O
Reactant: CC(C)(C)OC(=O)NCCO
Reactant: Cc1cc2c(cc1C(F)(F)F)N(C(=O)Cl)CCC[C@@H]2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1
Agent: CN(C)c1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc2c(cc1C(F)(F)F)N(C(=O)OCCN)CCC[C@@H]2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (S)-5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepine-1-carbonyl chloride (0.08 mmol) in dimethylformamide (3 mL), add (2-Hydroxy-ethyl)-carbamic acid tert-butyl ester (0.24 mmol) and dimethylaminopyridine (0.08 mmol). Next, add sodium hydride (0.24 mmol) and stir at room temperature for 0.5 h. Quench the reaction with water (15 mL) and dilute with ethyl acetate (10 mL). Separate the organic phase and wash the aqueous with ethyl acetate (2×10 mL). Dry the combined organics over sodium sulfate, filter, and remove solvent under vacuum. Dissolve the crude 5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxylic acid 2-tert-butoxycarbonylamino-ethyl ester intermediate in dichloromethane (5 mL) and add trifluoroacetic acid (2 mL). After stirring for 1 h, quench the reaction with concentrated sodium carbonate (5 mL). Dilute the reaction with dichloromethane (10 mL) and water (10 mL). Separate the organic phase and wash the aqueous with dichloromethane (2×10 mL). Dry the combined organics over sodium sulfate, filter, and remove the solvent under vacuum. Chromatograph the product over silica gel, eluting with methanol/dichloromethane (0-5%), to afford the title compound as a colorless foam. MS (ES+): 640 (M+H).
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[C:10]2=[CH:11][C:12]3[NH:13][C:14]4[C:19]([C:20]=3[CH:21]=[C:9]2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:18][C:17]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[CH:16][CH:15]=4.[H-].[Na+].Cl[C:32]1[N:37]=[C:36]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[N:35]=[C:34]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[N:33]=1>CN(C)C=O>[C:44]1([C:34]2[N:35]=[C:36]([C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)[N:37]=[C:32]([N:13]3[C:12]4[CH:11]=[C:10]5[C:2]([CH3:28])([CH3:1])[C:3]6[C:8]([C:9]5=[CH:21][C:20]=4[C:19]4[C:14]3=[CH:15][CH:16]=[C:17]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:18]=4)=[CH:7][CH:6]=[CH:5][CH:4]=6)[N:33]=2)[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: CC1(C)c2ccccc2-c2cc3c(cc21)[nH]c1ccc(-c2ccccc2)cc13
Reactant: Clc1nc(-c2ccccc2)nc(-c2ccccc2)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)c2ccccc2-c2cc3c4cc(-c5ccccc5)ccc4n(-c4nc(-c5ccccc5)nc(-c5ccccc5)n4)c3cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
10 g (27.7 mmol) of 12,12-dimethyl-7-phenyl-10,12-dihydro-10-azaindeno-[2,1-b]fluorene are dissolved in 275 ml of dimethylformamide under a protective-gas atmosphere, and 1.45 g of NaH, 60% in mineral oil (36 mmol), are added. After 1 h at room temperature, a solution of 2-chloro-4,6-diphenyl-1,3,5-triazine (8.2 g, 30.5 mmol) in 75 ml of dimethylformamide is added dropwise. The reaction mixture is then stirred at room temperature for 12 h. After this time, the reaction mixture is poured onto ice and extracted three times with dichloromethane. The combined organic phases are dried over Na2SO4 and evaporated. The residue is extracted with hot toluene. The yield is 14.7 g (24.9 mmol, 90%).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([O:15][C:16]2[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][C:17]=2[C:18](O)=[O:19])(=[O:14])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].O.[OH:27][N:28]1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.NO>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([O:15][C:16]2[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][C:17]=2[C:18]([NH:28][OH:27])=[O:19])(=[O:14])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCOc1ccc(S(=O)(=O)Oc2c(C)cccc2C(=O)O)cc1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NO
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC#CCOc1ccc(S(=O)(=O)Oc2c(C)cccc2C(=O)NO)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.9 %

Procedure:
To a solution of 0.125 g (0.347 mmol) of the product of Step 2 in 4.4 mL of N,N-dimethylformamide (DMF) is added 0.056 g (0.417 mmol) of 1-hydroxybenzotriazole hydrate (HOBT) followed by 0.089 g (0.462 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC). The resulting mixture is stirred for 1 h at room temperature and then 0.095 mL of a 50% aqueous solution of hydroxylamine is added and the reaction mixture is stirred overnight. The reaction mixture is then diluted with ethyl acetate and washed with water and brine. The organics are dried over sodium sulfate, filtered and concentrated in vacuo. The residue is chromatographed on silica gel eluting with a gradient of ethyl acetate-hexanes (1:1 to 2:1) to provide 0.065 g (50%) of 2-[(hydroxyamino)carbonyl]-6-methylphenyl 4-(2-butynyloxy)benzenesulfonate as a white solid. Electrospray Mass Spec: 376.0 (M+H)+
Reaction SMILES: Cl[C:2]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C:9](=[O:10])[O:8][CH2:7]2)=O.S(N)([NH2:17])(=O)=O.O>S1(CCCC1)(=O)=O>[C:2]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C:9](=[O:10])[O:8][CH2:7]2)#[N:17]
Reactant: O=C(Cl)c1ccc2c(c1)COC2=O
Reactant: NS(N)(=O)=O
Solvent: O
Solvent: O=S1(=O)CCCC1
Product: N#Cc1ccc2c(c1)COC2=O
Temperature: 135 °C
Reaction time: 0.08 h

Procedure:
5-Chlorocarbonylphthalid (24.3 g, 0.124 mole) was dissolved in sulfolane (51 g). Sulfamide (13.8 g 0.144 mole) was added and the temperature was raised to 135° C. for 3 hours. At about 90° C., gas evolution took place. The mixture was allowed to cool and water (100 g) was added. The temperature was held at 85-90° C. for 5 min and then the solution was cooled to 60° C. The crystals were filtered off and washed with water (60 g) and acetic acid (30 g). Then the title compound was dried in vacuo. Yield: 19 g, 96%. Purity: 98.2% (hplc, peak area).
Reaction SMILES: C[N:2](C)[CH:3]=[O:4].[N+:6]([C:9]1[CH:17]=[C:16]2[C:12]([CH2:13][CH2:14][CH:15]2C(O)=O)=[CH:11][CH:10]=1)([O-:8])=[O:7].S(Cl)(Cl)=O.C1(C)C=CC=CC=1>ClCCl>[N+:6]([C:9]1[CH:17]=[C:16]2[C:12]([CH2:13][CH2:14][CH:15]2[C:3]([NH2:2])=[O:4])=[CH:11][CH:10]=1)([O-:8])=[O:7]
Reactant: O=C(O)C1CCc2ccc([N+](=O)[O-])cc21
Reactant: CN(C)C=O
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: NC(=O)C1CCc2ccc([N+](=O)[O-])cc21
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Dimethylformamide (DMF, 1 ml) was added to a solution of 6-nitro-1-indancarboxylic acid, 1a (13 g) and thionylchloride (18 ml) in dichloromethane (125 ml). The mixture was heated to reflux for 4 hours. Toluene was added and volatile material was evaporated in vacua. The thus obtained carboxylic acid chloride was dissolved in dichloromethane (100 ml) and added dropwise to a solution of 4-(4-fluoro phenyl)piperidine (19.5 g) and triethylamine (7 ml) in dichloromethane (100 ml) at 0-5° C. The mixture was stirred at room temperature for another 1.5 hours. Water was added, the organic phase separated, washed with brine, dried (anh. MgSO4), filtered, and dichloromethane evaporated in vacuo leaving the crude 6-nitroindan-1-carboxamide derivative as an oil (35 g). Purification by column chromatography on silica gel (eluted with a 1:1 mixture of ethyl acetate and heptane) yielded 12 g of the pure carboxamide as an oil. All of this oil was dissolved in refluxing 90% ethanol (350 ml). Fe-powder (10 g) and concentrated aqueous HCl (1 ml) were added successively in small portions during 10 minutes. The resulting mixture was refluxed for another 2.5 hours. Inorganic salts were filtered off while still hot and ethanol evaporated in vacua. Diluted aqueous NH4OH was added until pH>9. Extraction with ethyl acetate (2×200 ml) and working-up as above of the organic phase afforded 8 g of the 6-aminoindan-1-carboxamide derivative. Mp: 144-145° C. To a suspension of LiAIH4 (2.7 g) in dry tetrahydrofuran (THF, 125 ml) was added dropwise a solution of all of the carboxamide in THF (125 ml). The mixture was gently refluxed for 2 hours. After cooling to 10° C. water (10 ml) and a 15% aqueous NaOH solution were cautiously added to destroy excess LiAIH4. Inorganic salts were filtered off and washed extensively with THF. The combined THF solutions were evaporated leaving 6.5 g of the title compound 2a as an oil. The hydrochloride salt crystallized from 2-propanol. Mp: 198-201° C. 1H NMR (DMSO-d6): δ 1.85-2.40 (m, 6H); 2.60-2.90 (m, 3 H); 3.00-3.15 (m, 3 H); 3.35 (broad s, 3 H); 3.45-3.60 (m, 2 H); 3.65-3.75 (m, 1 H); 6.45 (d, 1 H); 6.50 (s, 1 H); 6.95 (d, 1 H); 7.15 (t, 2 H); 7.25-7.35 (m, 2 H).
Reaction SMILES: N1C=CC=CC=1.[OH:7][CH:8]([C:10]1[C:20]2=[C:21]3[C:16](=[CH:17][CH:18]=[CH:19]2)[CH2:15][CH2:14][CH2:13][N:12]3[N:11]=1)[CH3:9]>C(Cl)Cl.[O-2].[O-2].[O-2].[Cr+6]>[C:8]([C:10]1[C:20]2=[C:21]3[C:16](=[CH:17][CH:18]=[CH:19]2)[CH2:15][CH2:14][CH2:13][N:12]3[N:11]=1)(=[O:7])[CH3:9]
Reactant: CC(O)c1nn2c3c(cccc13)CCC2
Agent: [Cr+6]
Agent: [O-2]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)c1nn2c3c(cccc13)CCC2
Reaction time: 0.5 h
Yield: 87.4 %

Procedure:
19.7 g (0.25 mol) of pyridine were dissolved in 335 ml of methylene chloride. 15.2 (152 mmol) of chromium trioxide were added in portions under an atmosphere of nitrogen at temperatures below 35° C., and the mixture was stirred for 30 minutes. 4.0 g (0.02 mol) of 2-(1-hydroxyethyl)-7,8-dihydro-6H-pyrazolo[4,5,1-ij]quinoline (obtained by reaction of 2-formyl-7,8-dihydro-6H-pyrazolo[4,5,1-ij]quinoline with 2.5 equivalent of methylmagnesium bromide), dissolved in 40 ml of methylene chloride were then added. The mixture was stirred for a few minutes, decanted and evaporated in vacuum. The residue was chromatographed over silicagel using methylene chloride/ethyl acetate (3/1) as a eluent. 3.5 g of the desired product were obtained after evaporation of the desired fractions. Melting point 101°-102° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12](=[N:45][C:46]([O:48][CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)=[O:47])[N:13]1[CH2:18][CH2:17][CH2:16][CH:15]([C:19]([NH:21][C:22]2[C:23]([NH:32][C:33](=[O:44])[C:34]3[CH:39]=[CH:38][C:37]([C:40]([CH3:43])([CH3:42])[CH3:41])=[CH:36][CH:35]=3)=[CH:24][C:25]([C:28]([O:30]C)=[O:29])=[CH:26][CH:27]=2)=[O:20])[CH2:14]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.O1CCOCC1.[OH-].[Na+]>O>[CH2:49]([O:48][C:46]([NH:45][C:12](=[N:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[N:13]1[CH2:18][CH2:17][CH2:16][CH:15]([C:19]([NH:21][C:22]2[C:23]([NH:32][C:33](=[O:44])[C:34]3[CH:35]=[CH:36][C:37]([C:40]([CH3:43])([CH3:42])[CH3:41])=[CH:38][CH:39]=3)=[CH:24][C:25]([C:28]([OH:30])=[O:29])=[CH:26][CH:27]=2)=[O:20])[CH2:14]1)=[O:47])[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1
Reactant: COC(=O)c1ccc(NC(=O)C2CCCN(C(=NC(=O)OCc3ccccc3)NC(=O)OCc3ccccc3)C2)c(NC(=O)c2ccc(C(C)(C)C)cc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Solvent: O
Product: CC(C)(C)c1ccc(C(=O)Nc2cc(C(=O)O)ccc2NC(=O)C2CCCN(C(=NC(=O)OCc3ccccc3)NC(=O)OCc3ccccc3)C2)cc1
Reaction time: 48 h
Yield: 91.3 %

Procedure:
To a solution of N1-[[1-(benzyloxycarbonylamino-(benzyloxycarbonylimino)methyl)piperidin-3-yl]carbonyl]-N2-(4-t-butylbenzoyl)-4-methoxycarbonyl-1,2-benzenediamine (0.7 g, 0.94 mmol), CH3OH (10 mL), dioxane (10 mL), and water (6 mL) was added 1 N NaOH (3.7 mL, 3.7 mmol) The reaction was stirred for 48 h and was concentrated. The residue was partitioned between H2O (100 mL) and Et2O (100 mL). The aqueous layer was extracted with Et2O (100 mL), acidified to pH, 2.5 with 5 N HCl and extracted with EtOAc (3×200 mL). The combined EtOAc layers were washed with water, MgSO4 dried, concentrated and crystallized at 0° C. overnight to give the title compound as a solid (0.63 g, 92%); TLC: Rf=0.38 (1:15:135 acetic acid:methanol:chloroform); NMR (CDCl3) δ1.35 (s,9H), 1.50-2.05 (m, 8H), 3.20-3.40 (m, 1H), 3.60-4.05 (m, 3H), 5.05 (s, 4H), 7.20-7.35 (m, 12H), 7.40-7.50 (m, 2H), 7.55-7.65 (m, 1H), 7.90-8.00 (m, 2H), 8.05-8.15 (m, 1H); MS(FAB): 734 (MH+).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].[CH3:18][N:19]1[CH:23]=[CH:22][N:21]=[C:20]1[CH3:24]>CC#N>[Cl-:1].[CH3:18][N+:19]1[CH:23]=[CH:22][N:21]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[C:20]=1[CH3:24]
Reactant: CCCCCCCCCCCCCCCCCl
Reactant: Cc1nccn1C
Solvent: CC#N
Product: CCCCCCCCCCCCCCCCn1cc[n+](C)c1C
Product: [Cl-]
Temperature: 80 °C
Reaction time: 72 h
Yield: 62 %

Procedure:
To a 2L three-necked round bottom flask equipped with overhead mechanical stirrer were added 1-chlorohexadecane (260 g, 1.00 moles), 1,2 dimethylimidazole (91.0 g, 0.95 moles), and CH3CN (500 mL) and the two-phase reaction mixture was vigorously stirred in an oil bath at 80° C. After 72 h, the reaction mixture was cooled to room temperature and the product was crystallized overnight. The crystallized solid was filtered, thoroughly washed with cold CH3CN, and vacuum dried at 70° C. for 3 days to give 1,2-dimethyl-3-hexadecylimidazolium chloride as a slightly off-white solid, 220 g, 62% yield.
Reaction SMILES: N[CH2:2]/[CH:3]=[CH:4]/[CH:5]=[CH2:6].[CH2:7]1[CH2:11][O:10]CC1>>[CH2:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[CH3:2][C:11]([CH3:7])=[O:10]
Reactant: C1CCOC1
Reactant: C=C/C=C/CN
Product: C1CCCCC1
Product: CC(C)=O

Procedure:
Initially introduce 83.2 g (1.0 mol) of (E)-1-amino-2,4-pentadiene (title compound from Example B.2.) in 250 ml of THF, and add 0.1 g of 4-hydroxyanisole. Subsequently, at an internal temperature of 20°-30° C., add 229.2 g (1.05 mol) of di-tert-butyl dicarbonate dissolved in 250 ml of THF dropwise. After addition is complete, stir at room temperature for 20 h. Add 103.0 g (1.05 mol) of maleic anhydride, and heat to reflux for 5 h. Concentrate and take up the residue in 500 ml of methanol, add 30 ml of p-toluenesulphonic acid, and then heat once again to reflux for 5 h. After cooling with ice, and stirring, rapidly add a solution of 20 g of sodium carbonate dissolved in 500 ml of water dropwise, allow the mixture to stand for a further 30 min in an ice bath, and filter off the precipitate with suction, wash it with a little water, and dry it at 50° C. to constant weight.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:30]=[CH:31][CH:32]=1)[CH2:16][O:17][C:18]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[C:19]=1[CH:20]=[O:21].O.O.P([O-])(O)(O)=[O:36].[Na+].Cl([O-])=O.[Na+].ClCCl>CC(=CC)C.C(O)(C)(C)C.O>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:30]=[CH:31][CH:32]=1)[CH2:16][O:17][C:18]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:27])([F:28])[F:29])[C:19]=1[C:20]([OH:36])=[O:21]
Reactant: O=P([O-])(O)O
Reactant: O=Cc1c(OCc2cccc(OCc3ccc4ccccc4n3)c2)cccc1C(F)(F)F
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: ClCCl
Solvent: CC(C)(C)O
Solvent: O
Product: O=C(O)c1c(OCc2cccc(OCc3ccc4ccccc4n3)c2)cccc1C(F)(F)F

Procedure:
A solution of 2-[3-(quinolin-2-ylmethoxy)-benzyloxy]-6-trifluoromethyl-benzaldehyde (46 mg, 0.1 mmol, example 50) in 2-methyl-2-butene (1 mL), t-butanol (2 mL) and water (2 mL) is treated with sodium dihydrogenphosphate dihydrate (153 mg, 1.1 mmol) and sodium chlorite (198 mg, 2.2 mmol). After 45 min. the reaction is partioned between dichloromethane (50 mL) and water (50 mL). The organic layer is dried over magnesium sulfate, filtered and concentrated in vacuo to provide the title compound: m.p. 184–185° C.; 1H NMR (300 MHz, CDCl3) δ 8.28 (d, 1H), 8.12 (d, 1H), 7.82–7.75 (m, 2H), 7.66–7.55 (m, 2H), 7.42 (dd, 1H), 7.30–7.27 (m, 2H), 7.16 (d, 1H), 7.07 (dd, 1H), 6.88 (d, 1H), 6.77 (dd, 1H), 5.44 (s, 2H), 5.07 (s, 2H); MS (ESI) 454 (M+H)+.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][SH:5].[CH3:6][N:7]([CH2:9][C:10]1[N:15]=[C:14]([CH2:16]O)[CH:13]=[CH:12][CH:11]=1)[CH3:8]>Br>[CH3:6][N:7]([CH2:9][C:10]1[N:15]=[C:14]([CH2:16][S:5][CH2:4][CH2:3][NH2:2])[CH:13]=[CH:12][CH:11]=1)[CH3:8]
Reactant: NCCS
Reactant: CN(C)Cc1cccc(CO)n1
Agent: Br
Agent: Cl
Product: CN(C)Cc1cccc(CSCCN)n1
Reaction time: 8 h
Yield: 46.3 %

Procedure:
Cysteamine hydrochloride (3.58 g; 31.5 mmoles) and 6-dimethylaminomethyl-2-hydroxymethylpyridine (5.0 g; 30.1 mmole) [prepared in Step B] were dissolved in 50 ml of 48% hydrobromic acid and the solution heated at reflux temperature for 12 hours and then allowed to stand at ambient temperature for 8 hours. The reaction mixture was evaporated under reduced pressure to half volume, made basic with 40% aqueous NaOH and extracted with several portions of methylene chloride. The combined organic phase was washed with a small amount of water and saturated brine solution then dried and evaporated under reduced pressure to yield 3.14 g of the title compound.