Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]1[CH:19]=[CH:18][C:14]([C:15](Cl)=[O:16])=[CH:13][C:12]=1[N+:20]([O-:22])=[O:21].C(OC(=O)C)(=[O:25])C>C(Cl)Cl>[F:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:25])=[O:16])=[CH:13][C:12]=1[N+:20]([O-:22])=[O:21]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(Cl)c1ccc(F)c([N+](=O)[O-])c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(O)c1ccc(F)c([N+](=O)[O-])c1
Reaction time: 3 h
Yield: 0.2 %

Procedure:
On a solid phase synthesizer (Advanced Chemtech ACT 90), Wang resin (Nova Biochem, loading: 1.2 mmol/g, 20 mmol, 16.7 g) was washed twice with DCM (100 mL), twice with i-PrOH (100 mL) and was dried overnight under high vacuum over P2O5. The following day, the resin was washed with anhydrous DCM (2×100 mL) and was suspended in anhydrous DCM (100 mL). To the suspension was added DIEA (30 mmol, 5.2 mL) followed by a solution of 4-fluoro-3-nitrobenzoyl chloride (22 mmol, 4.48 g) dissolved in 10 ml of anhydrous DCM. The slurry was shaken for 3 h, the solution was drained and the resin was washed twice with 100 mL-portions of anhydrous DCM. The resin was then suspended in anhydrous DCM (100 mL) and was treated with DIEA (30 mmol, 5.2 mL) followed by acetic anhydride (24 mmol, 2.3 mL). After shaking for 2 h, the solution was drained and the resin was washed successively with DCM (2×100 mL), i-PrOH (2×100 mL), DCM (2×100 mL) and finally with i-PrOH (3×100 mL). The resin was dried overnight under high vacuum. To calculate the level of incorporation, the resin (45.9 mg) was treated with a 1:1 mixture of TFA/1,2-dichloroethane (1.5 mL) for 1 h. The resin was filtered and was washed twice with 1,2-dichloroethane (1.5 mL). The filtrates were combined and concentrated under vacuum. The residue was lyophilized from MeCN/H2O to give 4-fluoro-3-nitro benzoic acid as a yellow solid (6.3 mg, 0.033 mmol). Based on recovered compound, the loading was calculated to be 0.74 mmol/g.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[CH3:11][N:12]=[C:13]=[O:14]>C(Cl)(Cl)Cl>[CH3:11][NH:12][C:13]([NH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1)=[O:14]
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: CN=C=O
Solvent: ClC(Cl)Cl
Product: CNC(=O)Nc1ccc(C(=O)O)cc1
Reaction time: 72 h
Yield: 5.3 %

Procedure:
A mixture of 3.0 g (0.22 mol) of 4-aminobenzoic acid (Aldrich) in 100 mL of chloroform was treated with 10 g (0.175 mol) of methylisocyanate (Aldrich), and the mixture was stirred at ambient temperatures for three days. The mixture was concentrated and the residue was triturated with diethyl ether/petroleum ether. The solid was collected by filtration, air-dried, and then slurried with 100 mL of water. The solid was collected by vacuum filtration and the cake was sucked dry. The cake was then recrystallized from acetonitrile/water to yield 1.8 g (43%) of the title compound as a fluffy white solid, mp>400° C. (lit1 mp>300° C.).
Reaction SMILES: [CH2:1]([N:5]([CH2:10][CH2:11][CH2:12][CH3:13])[C:6](=[O:9])[CH2:7]Cl)[CH2:2][CH2:3][CH3:4].[CH2:14]([PH:18](=[O:23])[CH2:19][CH2:20][CH2:21][CH3:22])[CH2:15][CH2:16][CH3:17]>>[CH2:14]([P:18](=[O:23])([CH2:19][CH2:20][CH2:21][CH3:22])[CH2:7][C:6](=[O:9])[N:5]([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:1][CH2:2][CH2:3][CH3:4])[CH2:15][CH2:16][CH3:17]
Reactant: CCCCN(CCCC)C(=O)CCl
Reactant: CCCC[PH](=O)CCCC
Product: CCCCN(CCCC)C(=O)CP(=O)(CCCC)CCCC
Yield: 104.1 %

Procedure:
The reaction was conducted as described in example I with the substitution of 22.6 g (0.11 mole) of N,N-di(n-butyl)chloroacetamide and 18.0 g (0.10 mole) of di(n-butyl)phosphine oxide as starting materials. After a reaction period of 5 hours, workup yielded 34.5 g of an amber oil which was 84% pure by GLC. Flash distillation in a Kugelrohr apparatus (10-3 mm Hg) produced a colorless oil which was 91% pure by GLC. Analytical data for this product is summarized in Table I.
Reaction SMILES: [Si](O[C@@H]1[C@@]2(C)C(=CC=C3[C@@H]2CC[C@@]2(C)[C@H]3CC=C2[C@@H](O)C)C[C@@H](O[Si](C(C)(C)C)(C)C)C1)(C(C)(C)C)(C)C.CC(C)([O-])C.[K+].C1OCCOC2C(=CC=CC=2)OCCOCCOC2C(=CC=CC=2)OC1.O1[C@@H](C(C)C)C1.[Si]([O:84][C@@H:85]1[C@@:110]2([CH3:111])[C:89](=[CH:90][CH:91]=[C:92]3[C@@H:109]2[CH2:108][CH2:107][C@@:106]2([CH3:112])[C@H:93]3[CH2:94][CH:95]=[C:96]2[C@@H:97]([O:99][CH2:100][C@@H:101]([OH:105])[CH:102]([CH3:104])[CH3:103])[CH3:98])[CH2:88][C@@H:87]([O:113][Si](C(C)(C)C)(C)C)[CH2:86]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1(C)C=CC=CC=1.C(OCC)C.O1CCCC1.C(OCC)(=O)C>[OH:84][C@@H:85]1[C@@:110]2([CH3:111])[C:89](=[CH:90][CH:91]=[C:92]3[C@@H:109]2[CH2:108][CH2:107][C@@:106]2([CH3:112])[C@H:93]3[CH2:94][CH:95]=[C:96]2[C@@H:97]([O:99][CH2:100][C@@H:101]([OH:105])[CH:102]([CH3:104])[CH3:103])[CH3:98])[CH2:88][C@@H:87]([OH:113])[CH2:86]1
Reactant: CC(C)[C@H](O)CO[C@@H](C)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Agent: CC(C)(C)[O-]
Agent: CC(C)[C@H]1CO1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CC(C)[C@H](O)CO[C@@H](C)C1=CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Temperature: 106 °C
Reaction time: 1 h
Yield: 47.3 %

Procedure:
To a solution of 1α,3β-bis(tert-butyldimethylsilyloxy)-20(S)-hydroxypregna-5,7,16-triene (97.9 mg, 0.175 mmol), potassium t-butoxide (230 mg, 2.05 mmol) and dibenzo-18-crown-6(45.0 mg, 0.125 mmol) in toluene (6 ml) was added (S)-(+)-1,2-epoxy-3-methylbutane (0.18 ml, 1.72 mmol) at room temperature and the mixed solution was stirred at 106° C. for one hour. The reaction solution was diluted with diethyl ether and washed with brine, and then the organic layer was dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was separated by preparative thin layer chromatography (0.5 mm×4, hexane dichloromethane:ethyl acetate=45:5:2, developed three times) to give a fraction containing 1α,3β-bis(tert-butyldimethylsilyloxy)-20(S)-{2(S)-hydroxy-3-methyl-butyloxy}pregna-5,7,16-triene (67.5 mg). An aliquot of 52.6 mg was dissolved in tetrahydrofuran (1.5 ml) and stirred with 1M tetra-n-butylammonium fluoride solution in tetrahydrofuran (0.5 ml) under the condition of an outer temperature of 71° C. for 10 hours. After completion of the reaction, the reaction solution was diluted with ethyl acetate and washed with IN hydrochloric acid, saturated aqueous sodium bicarbonate solution and brine successively, and the organic layer was dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was purified by preparative thin layer chromatography (0.25 mm×2, dichloromethane:ethanol=15:1, developed twice) to give the title compound as a colorless oil (20.6 mg, 36%).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH2:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([N:29]=[CH:30]OCC)(=[O:28])=[O:27])=[CH:22][CH:21]=1>C(O)C>[Br:19][C:20]1[CH:21]=[CH:22][C:23]([S:26]([NH:29][CH:30]=[N:15][CH2:14][CH2:13][CH2:12][O:11][C:10]2[CH:16]=[CH:17][CH:18]=[C:8]([CH2:7][N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[CH:9]=2)(=[O:28])=[O:27])=[CH:24][CH:25]=1
Reactant: NCCCOc1cccc(CN2CCCCC2)c1
Reactant: CCOC=NS(=O)(=O)c1ccc(Br)cc1
Solvent: CCO
Product: O=S(=O)(NC=NCCCOc1cccc(CN2CCCCC2)c1)c1ccc(Br)cc1
Reaction time: 1 h
Yield: 67.2 %

Procedure:
To a solution of 6.2 g of 3-[3-(1-piperidinylmethyl) phenoxy]-1-propanamine (prepared according to British Pat. No. 2,023,133) in 20 ml of absolute ethanol, 7.3 g of ethyl N-p-bromobenzenesulphonyl-formimidate dissolved in 20 ml of absolute ethanol are dropwise added at room temperature. The mixture is kept under stirring for 1 hour and the ethanol is removed by distillation under reduced pressure. The resulting residue is purified by dissolving in 60 ml of ethyl acetate and 25 ml of water, then acidulated with 3N hydrochloric acid up to pH2. The organic phase is case aside and the aqueous phase is basified in the presence of 20 ml of sodium acetate with 1N sodium hydroxide up to pH8. The organic phase is washed with water, dried over magnesium sulphate and evaporated till dryness. The resulting residue is chromatographied by 60 silicagel column with chloroform-methanol (8:2) as eluent. 8.3 g of N-p-bromobenzene-sulphonyl-N'-[3-[3-(1-piperidinylmethyl)phenoxy]propyl] formamidine are obtained.
Reaction SMILES: [Br:1]Br.[C:3]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][NH:13][C:14](=[O:16])[CH3:15])[N:7]=1)(=[O:5])[CH3:4].Cl.C(OC(C)C)(C)C>O1CCOCC1>[C:14]([NH:13][CH2:12][C:8]1[CH:9]=[CH:10][CH:11]=[C:6]([C:3](=[O:5])[CH2:4][Br:1])[N:7]=1)(=[O:16])[CH3:15]
Reactant: CC(=O)NCc1cccc(C(C)=O)n1
Reactant: BrBr
Agent: Cl
Solvent: CC(C)OC(C)C
Solvent: C1COCCO1
Product: CC(=O)NCc1cccc(C(=O)CBr)n1

Procedure:
Bromine (9.9 ml) was added dropwise to a mixture of 2-acetyl-6-(acetylaminomethyl)pyridine (37.0 g) in dioxane (740 ml) and 4N-dioxanic hydrogen chloride (48.1 ml) at ambient temperature with stirring. After the mixture was stirred at 50° C. for 3 hours. To the mixture was added a diisopropyl ether (600 ml) and the mixture was stirred under ice-cooling for 30 minutes. The isolated precipitate was collected by filtration. The precipitate was added to water and the mixture was adjusted to pH 8 with 20% aqueous potassium carbonate. The aqueous mixture was extracted with a mixture of ethyl acetate and tetrahydrofuran. The extract was dried over magnesium sulfate and evaporated in vacuo to give 2-(acetylaminomethyl)-6-bromoacetylpyridine (50.3 g) as an oil.
Reaction SMILES: [ClH:1].Cl.[NH2:3][CH2:4][C:5]([C:7]1[N:8]=[CH:9][NH:10][C:11]=1[NH2:12])=[O:6].[CH:13](OCC)(OCC)OCC>C(O)C>[ClH:1].[N:8]1[C:7]2[C:5](=[O:6])[CH2:4][NH:3][CH:13]=[N:12][C:11]=2[NH:10][CH:9]=1
Reactant: CCOC(OCC)OCC
Reactant: NCC(=O)c1nc[nH]c1N
Agent: Cl
Solvent: CCO
Product: O=C1CNC=Nc2[nH]cnc21

Procedure:
A mixture of 285 mg. of 2-amino-1-(5-amino-1H-imidazol-4-yl)ethanone dihydrochloride (Example 1), 200 ml. of absolute ethanol and 10 ml. of triethyl orthoformate is stirred and heated at reflux for 1 hour, then cooled and evaporated at reduced pressure. The residue of 6,7-dihydroimidazo[4,5-d][1,3]diazepin-8(3H)-one monohydrochloride, which crystallizes on standing, is collected by filtration, washed with ethanol, then with ether, and dried at reduced pressure; m.p. above 250° C. dec.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([OH:9])=O.S(Cl)(Cl)=O.[NH2:14][C:15]1[CH:16]=[C:17]([CH:30]=[CH:31][CH:32]=1)[C:18]([C:20]1[CH:28]=[C:27]2[C:23]([CH2:24][C:25](=[O:29])[NH:26]2)=[CH:22][CH:21]=1)=[O:19]>C1COCC1>[O:29]=[C:25]1[CH2:24][C:23]2[C:27](=[CH:28][C:20]([C:18]([C:17]3[CH:16]=[C:15]([NH:14][C:7]([C:3]4[S:4][CH:5]=[CH:6][C:2]=4[CH3:1])=[O:9])[CH:32]=[CH:31][CH:30]=3)=[O:19])=[CH:21][CH:22]=2)[NH:26]1
Reactant: Cc1ccsc1C(=O)O
Reactant: Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3)c1
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: Cc1ccsc1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3)c1
Temperature: 79 °C
Reaction time: 3 h
Yield: 71.1 %

Procedure:
A dry flask was charged with 3-Methyl-thiophene-2-carboxylic acid (0.500 g, 3.520 mmol) and thionyl chloride (10 mL) and allowed to stir at 79° C. for 3 h. The thionyl chloride was then removed by concentration in vacuo. The crude acid chloride was cooled to room temperature, and then dissolved in THF (35 mL). 6-(3-Amino-benzoyl)-1,3-dihydro-indol-2-one (as prepared in Example 40, 0.888 g, 3.517 mmol) was added to the THF solution of the acid chloride, and the mixture was allowed to reflux overnight. The reaction mixture was then allowed to cool to room temperature and filtered. The solid residue was washed with 0° C. THF and collected to afford the 3-Methyl-thiophene-2-carboxylic acid [3-(2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide as a solid (0.940 g, 2.50 mmol, 71%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7]2)([O-])=O>[Pd].C(O)C>[NH2:1][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7]2
Reactant: CC(C)(C)OC(=O)N1Cc2ccc([N+](=O)[O-])cc2C1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1Cc2ccc(N)cc2C1
Yield: 99.9 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer was charged with tert-butyl 5-nitroisoindoline-2-carboxylate (650 mg, 2.5 mmol) and C2H5OH (50 mL). This solution was hydrogenated with Pd/C (160 mg) at room temperature for 15 h. It was then filtered and the filtrate was concentrated under reduced pressure to afford 231c as a yellow oil (585 mg, 99%), which was used in the next step without further purification. MS: [M+H]+ 179.
Reaction SMILES: [CH:1]([C:3]1[N:7]([CH3:8])[CH:6]=[N:5][CH:4]=1)=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:21]([SH:25])[CH2:22][CH2:23][SH:24]>C1(C)C=CC=CC=1>[S:24]1[CH2:23][CH2:22][CH2:21][S:25][CH:1]1[C:3]1[N:7]([CH3:8])[CH:6]=[N:5][CH:4]=1
Reactant: Cn1cncc1C=O
Reactant: SCCCS
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: Cn1cncc1C1SCCCS1
Yield: 63.9 %

Procedure:
8.3 g (75.4 mmol) of 5-formyl-1-methylimidazole are dissolved in 120 ml of toluene, and 17.1 g (89.9 mmol) of 4-toluenesulfonic acid monohydrate are added. After addition of 8.12 g (75.0 mmol) of 1,3-propanedithiol, the suspension obtained in this way is boiled under reflux with a water trap. It is subsequently washed with 4N sodium hydroxide solution, and the organic phase is dried over sodium sulfate and concentrated in vacuo until crystallization starts. After storage in a refrigerator overnight, 9.6 g (47.9 mmol, 64%) of 5-(1,3-dithian-2-yl)-1-methylimidazole are obtained as a white solid of melting point 111.5°-112.5° C.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]1(=[O:14])[CH2:13][CH2:12][CH2:11][CH2:10]1>>[CH:1](=[C:10]1/[C:9](=[O:14])[CH2:13][CH2:12][CH2:11]/1)\[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCCC1
Reactant: O=Cc1ccccc1
Product: O=C1CCC/C1=C\c1ccccc1

Procedure:
The procedure was similar to that in Example 4 by reacting benzaldehyde with the morpholine enamine of cyclopentanone to give 2-(E)-benzylidene cyclopentanone. The melting point of this intermediate compound was determined to be 67°-69° C. A subsequent Mannich reaction yielded the 2-Dimethylaminomethyl-5-(E)-benzylidene cyclopentanone hydrochloride. The melting point of the product was determined to be 153°-155° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1.C1C=C(Cl)C=C(C(OO)=[O:17])C=1.[OH-].[Ca+2].[OH-]>C(Cl)(Cl)Cl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N+:3]=1[O-:17]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ccc(C)nc1
Agent: [Ca+2]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: Cc1ccc(C)[n+]([O-])c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.7 %

Procedure:
To a solution of 2,5-dimethylpyridine (2.24 g, 21 mmol) in CHCl3(20 mL) was added MCPBA (4.31 g, 25 mmol) in portions over 30 min. The mixture was stirred at room temperature overnight. Calcium hydroxide (4 g, 54 mmol) was added to quench the reaction and the mixture was stirred vigorously for 3 h. The mixture was filtered through a Celite pad. The filtrate was concentrated and dried under vacuum to give 2,5-dimethylpyridine 1-oxide (2.5 g, 97.1% yield) as white solid, which was used without purification. CMS retention time 0.442 min; LCMS MH+ 124.
Reaction SMILES: Cl[C:2]1[S:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[N:3]=1.[NH:14]1[CH:18]=[CH:17][CH:16]=[CH:15]1.[H-].[Na+].O>CS(C)=O>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:4]2[N:3]=[C:2]([N:14]3[CH:18]=[CH:17][CH:16]=[CH:15]3)[S:6][N:5]=2)=[CH:8][CH:9]=1
Reactant: c1cc[nH]c1
Reactant: Clc1ccc(-c2nsc(Cl)n2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: Clc1ccc(-c2nsc(-n3cccc3)n2)cc1
Temperature: 80 °C
Reaction time: 5 h
Yield: 44.7 %

Procedure:
The 5-chloro-1,2,4-thiadiazole compound (102 mg, 0.445 mmol) was dissolved in DMSO (2 mL) and pyrrol (300 mg, 2.22 mmol) added at room temperature. The mixture was heated for 18 h to 55° C. ext. temperature, however no conversion was found (sample tested by 1H-NMR). Sodium hydride (55% wetted with mineral oil, 20 mg, 0.467 mmol) was added and the mixture heated to 80° C. ext. temperature for 5 h. As the conversion was not complete (sample tested by 1H-NMR) the mixture was heated to 100° C. ext. temperature for 6 h. The reaction mixture was poured into water (10 mL) and crude product isolated by filtration. The purification by column chromatograpy (SiO2, 0-10% ethyl acetate inheptanes) afforded 3-(4-chlorophenyl)-5-(1H-pyrrol-1-yl)-1,2,4-thiadiazole (52 mg, 0.199 mmol, 45%), which was 98% pure (HPLC 254 nm). 1H-NMR spectra is in accordance with the chemical structure.
Reaction SMILES: C([O:5][C:6](=[O:42])[C@@H:7]([NH:28][S:29]([C:32]1[CH:37]=[CH:36][C:35]([C:38]([CH3:41])([CH3:40])[CH3:39])=[CH:34][CH:33]=1)(=[O:31])=[O:30])[CH2:8][NH:9][C:10]([C:12]1[S:13][C:14]([CH2:17][CH2:18][C:19](=[O:27])[NH:20][C:21]2[NH:22][CH2:23][CH2:24][CH2:25][N:26]=2)=[CH:15][CH:16]=1)=[O:11])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[C:38]([C:35]1[CH:34]=[CH:33][C:32]([S:29]([NH:28][C@@H:7]([CH2:8][NH:9][C:10]([C:12]2[S:13][C:14]([CH2:17][CH2:18][C:19](=[O:27])[NH:20][C:21]3[NH:22][CH2:23][CH2:24][CH2:25][N:26]=3)=[CH:15][CH:16]=2)=[O:11])[C:6]([OH:42])=[O:5])(=[O:31])=[O:30])=[CH:37][CH:36]=1)([CH3:41])([CH3:39])[CH3:40]
Reactant: CC(C)(C)OC(=O)[C@H](CNC(=O)c1ccc(CCC(=O)NC2=NCCCN2)s1)NS(=O)(=O)c1ccc(C(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)c1ccc(S(=O)(=O)N[C@@H](CNC(=O)c2ccc(CCC(=O)NC3=NCCCN3)s2)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 103.1 %

Procedure:
0.27 g (0.43 mmol) of the compound obtained in step b) were dissolved in dichloromethane (1 ml). Trifluoroacetic acid (1 ml) was added and the reaction mixture was stirred for 2 h at room temperature. After evaporation of the solvents lyophilization gave the title compound (0.25 g, 86%) as a white amorphous solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:21][C:22]2[CH:23]=[N:24][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:26][CH:27]=2)[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][CH:14]([CH2:17][C:18]([OH:20])=O)[CH2:15][N:16]=1)=[CH:8]2.Cl.[CH2:33]([N:35]=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.Cl.CN>O.C(N(CC)CC)C.CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:21][C:22]2[CH:23]=[N:24][C:25]([S:28]([CH3:31])(=[O:29])=[O:30])=[CH:26][CH:27]=2)[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][CH:14]([CH2:17][C:18]([NH:35][CH3:33])=[O:20])[CH2:15][N:16]=1)=[CH:8]2
Reactant: CCN=C=NCCCN(C)C
Reactant: COc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C3=NCC(CC(=O)O)S3)[nH]c12
Agent: CN
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CNC(=O)CC1CN=C(c2cc3cc(Oc4ccc(S(C)(=O)=O)nc4)cc(OC)c3[nH]2)S1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.6 %

Procedure:
A mixture of [2-(7-methoxy-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indol-2-yl)-4,5-dihydro-1,3-thiazol-5-yl]acetic acid (800 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (500 mg), 1-hydroxybenzotriazole (350 mg) and N,N-dimethylformamide (15 mL) was stirred at room temperature for 30 min. Then triethylamine (440 mg) and methylamine hydrochloride (230 mg) were added to the mixture. The whole was stirred at room temperature for 20-h. Water was added to the mixture and the resultant was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and brine, dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (ethyl acetate:methanol=100:0 to 95:5, volume ratio) to give pale yellow crystals. The crystals were washed with ethyl acetate-hexane to give the title compound (540 mg, 67%) as pale yellow crystals. The crystals were recrystallized from acetone-hexane to give colorless prisms. MS 475 (MH+). mp 201-202° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([OH:9])=O)[N:2]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)C(C)C)C.[Cl:41][C:42]1[CH:47]=[CH:46][C:45]([C:48]2[CH:49]=[C:50]([NH2:61])[CH:51]=[N:52][C:53]=2[O:54][C@@H:55]([CH3:60])[C:56]([F:59])([F:58])[F:57])=[CH:44][CH:43]=1>CN(C=O)C>[Cl:41][C:42]1[CH:43]=[CH:44][C:45]([C:48]2[CH:49]=[C:50]([NH:61][C:7]([C:3]3[N:2]=[N:1][CH:6]=[CH:5][CH:4]=3)=[O:9])[CH:51]=[N:52][C:53]=2[O:54][C@@H:55]([CH3:60])[C:56]([F:57])([F:58])[F:59])=[CH:46][CH:47]=1
Reactant: C[C@H](Oc1ncc(N)cc1-c1ccc(Cl)cc1)C(F)(F)F
Reactant: O=C(O)c1cccnn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Oc1ncc(NC(=O)c2cccnn2)cc1-c1ccc(Cl)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.3 %

Procedure:
Pyridazine-3-carboxylic acid (CAN 2164-61-6; 43.1 mg, 347 μmol) was suspended in DMF (1.0 mL). TBTU (112 mg, 347 μmol), ethyldiisopropylamine (102 mg, 131 μl, 789 μmol,) and 5-(4-chloro-phenyl)-6-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-pyridin-3-ylamine (0.100 g, 316 μmol) were added and the reaction mixture was stirred at room temperature for 1 h. The rection mixture was extracted with ethyl acetate and 1M citric acid solution; the organic phase was dried with MgSO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 10 g, 10% to 50% ethyl acetate in heptane) to give 0.11 g (83%) of the title compound as white solid; MS (EI) 423.1 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:10]([O:12]N1C(=O)CCC1=O)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:28][CH2:29][CH2:30][N:31]([CH2:40][CH2:41][Cl:42])[C:32]1[CH:37]=[CH:36][C:35]([CH3:38])=[C:34]([NH2:39])[CH:33]=1.C(N(CC)CC)C>C(#N)C>[Cl:28][CH2:29][CH2:30][N:31]([CH2:40][CH2:41][Cl:42])[C:32]1[CH:37]=[CH:36][C:35]([CH3:38])=[C:34]([NH:39][C:10](=[O:12])[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:20][C:21]([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:22])[CH:33]=1
Reactant: CC(C)(C)OC(=O)C[C@H](NC(=O)OC(C)(C)C)C(=O)ON1C(=O)CCC1=O
Reactant: Cc1ccc(N(CCCl)CCCl)cc1N
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1ccc(N(CCCl)CCCl)cc1NC(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Adapting a literature known protocol (Levi and Weed, U.S. Pat. No. 3,235,594 (1966)), to a solution of O1-(2,5-Dioxopyrrolidin-1-yl)O4-tert-butyl(2S)-2-(tert-butoxycarbonylamino)-butanedioate (Boc-L-Asp(Osu)-OtBu) (6a) (386 mg, 1.0 mmol) in anhydrous acetonitrile (MeCN) (10 mL) is added N,N-bis(2-chloroethyl)-4-methyl-benzene-1,3-diamine (16b) as a bis hydrochloride salt (320 mg, 1.0 mmol) followed by neat triethylamine (Et3N, TEA) (321 μL, 233 mg, 2.3 mmol). The reaction mixture is stirred for about 12 h at room temperature. The reaction is followed by TLC and/or LC/MS to completion. The volatile solvents are removed under reduced pressure using a rotary evaporator. Aqueous work-up and purification by silica gel column chromatography furnish the target compound (16c).