Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([F:11])([F:10])[F:9].C([Li])CCC.[CH:17]([CH:19]=[CH2:20])=[O:18].OS(O)(=O)=O>C1COCC1.CCCCCC>[CH:19]([CH:17]([C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([C:8]([F:9])([F:10])[F:11])[C:2]=1[F:1])[OH:18])=[CH2:20]
Reactant: C=CC=O
Reactant: Fc1ccccc1C(F)(F)F
Agent: O=S(=O)(O)O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C=CC(O)c1cccc(C(F)(F)F)c1F
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
A solution of 360 g (2.194 mol) of 1-fluoro-2-trifluoromethylbenzene in 3.4 l of anhydrous THF is cooled to -70° C. under a nitrogen atmosphere. 1.508 l (2.412 mol) of a 1.6M solution of n-butyllithium in hexane are added dropwise over 70 minutes while maintaining the temperature below -67° C. and then the mixture is stirred for 30 minutes at -70° C. 154 ml (2.305 mol) of acrolein are then added dropwise over 30 min while maintaining the temperature below -60° C. The mixture is then stirred for 30 min at -70° C. The mixture is allowed to return to room temperature and is poured onto a mixture of 3.8 kg of ice and 300 ml of concentrated H2SO4.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]([CH3:13])([CH3:12])[CH2:10][CH2:9][C:8](=[O:14])[NH:7][C:6]=2[CH:15]=1.Cl[C:17]1[N:22]=[C:21]([NH:23][C:24]2[C:29]([S:30]([CH:33]([CH3:35])[CH3:34])(=[O:32])=[O:31])=[CH:28][CH:27]=[CH:26][C:25]=2[F:36])[C:20]([Cl:37])=[CH:19][N:18]=1>>[Cl:37][C:20]1[C:21]([NH:23][C:24]2[C:29]([S:30]([CH:33]([CH3:34])[CH3:35])(=[O:32])=[O:31])=[CH:28][CH:27]=[CH:26][C:25]=2[F:36])=[N:22][C:17]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[C:11]([CH3:12])([CH3:13])[CH2:10][CH2:9][C:8](=[O:14])[NH:7][C:6]=3[CH:15]=2)=[N:18][CH:19]=1
Reactant: CC(C)S(=O)(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Reactant: CC1(C)CCC(=O)Nc2cc(N)ccc21
Product: CC(C)S(=O)(=O)c1cccc(F)c1Nc1nc(Nc2ccc3c(c2)NC(=O)CCC3(C)C)ncc1Cl

Procedure:
8-{5-Chloro-4-[2-fluoro-6-(propane-2-sulfonyl)-phenylamino]-pyrimidin-2-ylamino}-5,5-dimethyl-1,3,4,5-tetrahydro-1-benzazepin-2-one was prepared from 8-Amino-5,5-dimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one and (2,5-Dichloro-pyrimidin-4-yl)-[2-fluoro-6-(propane-2-sulfonyl)-phenyl]-amine in an analogous manner to Example 1251d. (120° C., 60 minutes). Title compound isolated as an off-white solid (68 mg, 48%). LCMS 534.13 (M+H), HPLC purity 98%, 1H-NMR (CDCl3, 400 MHz) δ: 8.17 (d, J=8.6 Hz, 1H), 8.17 (s, 1H), 7.86 (d, J=7.6 Hz, 1H), 7.58-7.54 (m, 2H), 7.24 (d, J=8.7 Hz, 1H), 6.96 (s, 1H), 6.89 (d, J=7.4 Hz, 1H), 6.76 (s, 1H), 3.10-3.02 (m, 1H), 2.38 (dd, J=6.7 Hz, 2H), 2.08 (dd, J=7.0 Hz, 2H), 1.38 (s, 6H), 1.23 (d, J=6.8 Hz, 6H).
Reaction SMILES: C([NH:9][C:10]([NH:12][CH:13]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[S:11])(=O)C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].C1COCC1>CO.O>[CH:13]1([NH:12][C:10]([NH2:9])=[S:11])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: O=C(NC(=S)NC1CCCCCCC1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: NC(=S)NC1CCCCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1-benzoyl-3-cyclooctylthiourea (14.3 g, 49.1 mmol) and potassium carbonate (34.6 g, 250 mmol) in methanol (200 mL), water (100 mL), and THF (100 mL) was stirred at ambient temperature overnight. The low boiling solvents were removed in vacuo, and the residue was partitioned between EtOAc and water. The organic portion was washed with brine, and concentrated in vacuo. The title compound was obtained as a white solid after flash column chromatography (0 to 100% of ethyl acetate in hexanes). MS m/z: 187.1 (M+H)+.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)C.[CH:12]1([C:15]2[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=2[O:23][CH3:24])[C:18]#[N:19])[CH2:14][CH2:13]1>O1CCCC1>[CH:12]1([C:15]2[CH:16]=[C:17]([CH2:18][NH2:19])[CH:20]=[CH:21][C:22]=2[O:23][CH3:24])[CH2:14][CH2:13]1
Reactant: COc1ccc(C#N)cc1C1CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1ccc(CN)cc1C1CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Lithium aluminum hydride in diethyl ether (17.3 ml, 1.0 M, 17.3 mmol, 3.0 eq) was carefully added over twenty minutes to a solution of 3-cyclopropyl-4-methoxybenzonitrile (8-2, 1.0 g, 5.77 mmol, 1.0 eq) in tetrahydrofuran (28.9 ml) at 0° C. under nitrogen atmosphere. The resulting dark orange mixture was allowed to stir at 0° C. for 30 min, then carefully quenched in the following order: water (1.0 ml), 15% NaOH aqueous (1.0 ml) and water (3.0 ml). The resulting emulsion was stirred at room temperature for 30 min. Several spatula amounts of magnesium sulfate was added to the mixture to remove any water. The entire mixture was filtered through a pad of sodium sulfate, washing with ethyl acetate. The collected filtrate was concentrated to give the product (8-3) as a yellow oil. ESI+MS [M-16]+ C11H15NO: 161.1 found, 161.2 required.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]#[N:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C(O)(=[O:16])C>Cl>[C:12]([C:11]1[C:2](=[O:16])[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2)#[N:13]
Reactant: N#Cc1cc2ccccc2nc1Cl
Reactant: CC(=O)O
Agent: Cl
Product: N#Cc1cc2ccccc2[nH]c1=O

Procedure:
Alternatively, the acetanilide can be heated with dimethylformamide, phosphoryl chloride and hydroxylamine hydrochloride to give a 2-chloro-3-cyanoquinoline. This process is a particularly convenient method for obtaining the chlorocyanoquinoline directly from an acetanilide. The indicated chloro-cyano-compound can then be hydrolyzed either under acidic or basic conditions to give the corresponding desired 3-cyano-2(1H)-quinolinone. Specifically, if the 2-chloro-3-cyanoquinoline is boiled in acetic acid for 1 hour or refluxed in 4N hydrochloric acid for 10-15 minutes, the corresponding 3-cyano-2(1H)-quinolinone is obtained.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:7][C:6](=[O:8])[CH2:5][C:4](=[O:9])[O:3]1.N1C=CC=CC=1.[CH:17]1([C:20](Cl)=[O:21])[CH2:19][CH2:18]1>ClCCl>[CH:17]1([C:20]([CH:5]2[C:6](=[O:8])[O:7][C:2]([CH3:10])([CH3:1])[O:3][C:4]2=[O:9])=[O:21])[CH2:19][CH2:18]1
Reactant: O=C(Cl)C1CC1
Reactant: CC1(C)OC(=O)CC(=O)O1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC1(C)OC(=O)C(C(=O)C2CC2)C(=O)O1
Temperature: 0 °C
Yield: 82.2 %

Procedure:
A mixture of 2,2-dimethyl-1,3-dioxan-4,6-dione (20.0 g) and pyridine (22.0 g) in dichloromethane (200 ml) was stirred and cooled to 0° C. in an ice bath. A solution of cyclopropylcarbonyl chloride (16.0 g) in dichloromethane (50 ml) was added dropwise with stirring in an atmosphere of nitrogen whilst maintaining the temperature below 3° C. by external cooling. The mixture was stirred at 0° C. for 1 hour and at ambient temperature for 2 hours. The resultant orange suspension was washed with hydrochloric acid (2M, 2×50 ml), water (2×50 ml), dried (anhydrous sodium sulphate) and filtered. The filtrate was evaporated to dryness. The residue was dissolved in ether (150 ml) and the solution was treated with decolourizing charcoal and filtered. The filtrate was evaporated to dryness to give 5-cyclopropylcarbonyl-2,2-dimethyl-1,3-dioxan-4,6-dione (24.2 g) as a yellow solid mp 44°-46° C.
Reaction SMILES: C([O:3][C:4](=[O:22])[CH2:5][CH:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[F:21])=[CH:10][CH:9]=1)[CH3:7])C.Cl>C(O)(=O)C>[F:21][C:15]1[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:14]=1[C:11]1[CH:12]=[CH:13][C:8]([CH:6]([CH3:7])[CH2:5][C:4]([OH:22])=[O:3])=[CH:9][CH:10]=1
Reactant: CCOC(=O)CC(C)c1ccc(-c2ccc(F)cc2F)cc1
Agent: Cl
Solvent: CC(=O)O
Product: CC(CC(=O)O)c1ccc(-c2ccc(F)cc2F)cc1

Procedure:
3.04 g. of 3-(2',4'-difluoro-4-biphenylyl)butyric acid ethyl ester is a mixture of 25 ml. of acetic acid and 25 ml. of 25% hydrochloric acid are heated under reflux for 90 minutes. The customary work up gives 3-(2',4'-difluoro-4-biphenylyl)butyric acid, m.p. 109°-110°.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:15][C:16]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:17]=1[C:26]#[C:27][C:28](O)=[O:29]>ClCCl.CO>[ClH:15].[N:1]1([CH2:7][C:8]2[CH:9]=[CH:10][C:11]([NH:14][C:28](=[O:29])[C:27]#[C:26][C:17]3[CH:18]=[CH:19][C:20]([C:22]([F:24])([F:23])[F:25])=[CH:21][C:16]=3[Cl:15])=[CH:12][CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)C#Cc1ccc(C(F)(F)F)cc1Cl
Reactant: Nc1ccc(CN2CCCCC2)cc1
Solvent: ClCCl
Solvent: CO
Product: Cl
Product: O=C(C#Cc1ccc(C(F)(F)F)cc1Cl)Nc1ccc(CN2CCCCC2)cc1

Procedure:
Prepared analogously to Example 2.3.f. from 4-piperidin-1-ylmethylphenylamine and (2-chloro-4-trifluoromethylphenyl)propynoic acid. Yield: 170 mg (40% of theory); C22H20ClF3N2O (M=420.86); melting point: 193° C.-195° C.; calc.: molecular ion peak (M−H)−: 419/421(Cl); found: molecular ion peak (M−H)−: 419/421 (Cl); Rf value: 0.5 (silica gel, dichloromethane/methanol (9:1)).
Reaction SMILES: [CH3:1][C:2]([CH3:26])([CH2:24][OH:25])[CH2:3][NH:4][C:5](=[O:23])[CH2:6][CH2:7][CH2:8][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][CH3:22].C(N([CH2:32][CH3:33])CC)C.C([C:38]1[CH:39]=[C:40]([CH2:49][CH2:50][C:51](Cl)=[O:52])C=[C:42]([C:45]([CH3:48])(C)C)[C:43]=1O)(C)(C)C>C1(C)C=CC=CC=1>[C:51]([O:25][CH2:24][C:2]([CH3:1])([CH3:26])[CH2:3][NH:4][C:5](=[O:23])[CH2:6][CH2:7][CH2:8][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][CH3:22])(=[O:52])[CH2:50][CH2:49][CH2:40][CH2:39][CH2:38][CH2:43][CH2:42][CH2:45][CH2:48][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:32][CH3:33]
Reactant: CCN(CC)CC
Reactant: CC(C)(C)c1cc(CCC(=O)Cl)cc(C(C)(C)C)c1O
Reactant: CCCCCCCCCCCCCCCCCC(=O)NCC(C)(C)CO
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCCC(=O)NCC(C)(C)COC(=O)CCCCCCCCCCCCCCCCC

Procedure:
In a 1-liter three-neck, round-bottom flask equipped with a thermometer, stirrer, dropping funnel and condenser were placed 36.9 g of N-(2,2-dimethyl-3-hydroxypropyl)-stearamide, 25 ml of triethylamine and 250 ml of toluene. To this stirred mixture was added 29.6 g of 3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionyl chloride. The mixture was filtered, stripped, and the residue was dissolved in hot methanol. The 2,2-dimethyl-3-stearamidopropyl stearate, melting at 60°-62° C. was isolated. The methanol solution was stripped, and the residue was dissolved in acetonitrile. The title compound was isolated; it melted at 44° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2.[H-].[Na+].CN(C)[S:15](Cl)(=[O:17])=[O:16].[CH2:20]1[CH2:24]OC[CH2:21]1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:15]([CH:20]([CH3:24])[CH3:21])(=[O:17])=[O:16])[N:6]=[CH:5]2
Reactant: CN(C)S(=O)(=O)Cl
Reactant: C1CCOC1
Reactant: Brc1ccc2[nH]ncc2c1
Agent: [H-]
Agent: [Na+]
Product: CC(C)S(=O)(=O)n1ncc2cc(Br)ccc21
Reaction time: 8 h

Procedure:
To a solution of 5-bromo-1H-indazole (2 g, 10.2 mmol) in THF (100 mL) was added sodium hydride (0.61 g, 15.2 mmol) at 0° C. for 1 hour. Dimethylsulfamoyl chloride was then added dropwise, and then the reaction mixture was allowed to reach room temperature overnight. The reaction mixture was then quenched by the addition of a saturated aqueous solution of sodium bicarbonate (100 mL), and the mixture was diluted with ethyl acetate (250 mL). The layers were separated, and the aqueous layer was extracted twice with ethyl acetate (2×250 mL). The organic layers were combined, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude concentrate was purified on silica gel eluting with hexanes and ethyl acetate to afford the title compound.
Reaction SMILES: Cl[C:2](Cl)(Cl)[CH:3]([OH:5])O.Cl.[NH2:9][OH:10].S([O-])([O-])(=O)=O.[Na+].[Na+].[N+:18]([C:21]1[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=1[NH2:23])([O-:20])=[O:19]>O.Cl>[OH:10][N:9]=[CH:2][C:3]([NH:23][C:22]1[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=1[N+:18]([O-:20])=[O:19])=[O:5]
Reactant: OC(O)C(Cl)(Cl)Cl
Reactant: Nc1ccccc1[N+](=O)[O-]
Reactant: NO
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C(C=NO)Nc1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.7 %

Procedure:
A solution of chloral hydrate (29 g, 175 mmol), hydroxylamine hydrochloride (69.4 g, 1000 mmol) and anhydrous sodium sulphate (21 g, 149 mmol) in water (800 mL) was heated to 65° C. To this a suspension, 2-nitroaniline (20 g, 150 mmol) in 2 molar aqueous HCl (20 mL) was added. This mixture was stirred overnight at the same temperature, then cooled to room temperature. The precipitated product was collected by filtration, washed with water dried in a vacuum oven to give 25 g of the required product as a yellow coloured solid (83%).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C([Cl:8])=O.C(OC([N:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]1[CH2:24][CH2:25][CH2:26][C:27]([O:29][CH3:30])=[O:28])=O)(C)(C)C.CCN(CC)CC>C(Cl)Cl>[ClH:8].[NH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]1[CH2:24][CH2:25][CH2:26][C:27]([O:29][CH3:30])=[O:28]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COC(=O)CCCC1CCCCN1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: COC(=O)CCCC1CCCCN1
Product: Cl
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 98.1 %

Procedure:
A solution of DMSO (21.24 ml, 299 mmol) in CH2Cl2 (600 ml) was dropwise added to a solution of oxalyl chloride (15.0 ml, 171 mmol) in CH2Cl2 (300 ml) in 30 min while maintaining the internal temperature below −65° C. A solution of 3 (46.7 g, 142 mmol) in CH2Cl2 (300 ml) was added dropwise in 15 min. while maintaining the temperature below −65° C. The reaction mixture was stirred an additional 45 minutes at −78° C., after which Et3N (99.0 ml, 712 mmol) was added. After the reaction mixture was stirred at −78° C. for 45 min, the reaction mixture was allowed to warm to room temperature and stirring was continued for an additional hour. The reaction mixture was washed with H2O and brine, dried (Na2SO4) and concentrated. The residue was dissolved in Et2O, filtered and the filtrate was concentrated and crystallized (Et2O/heptane) to result in 4 (30.9 g, 67%). The mother liquor was concentrated and crystallized (Et2O/heptane) and gave extra 4 (2.27 g, 5%).
Reaction SMILES: CCCCCC.[OH:7][CH:8]1[CH:13]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)[CH2:12][CH2:11][N:10]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:9]1.C(=O)([O-])[O-].[K+].[K+].[CH2:34](Br)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>CN(C)C=O.C(OCC)(=O)C>[CH2:34]([O:20][C:17]1[CH:16]=[CH:15][C:14]([CH:13]2[CH2:12][CH2:11][N:10]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:9][CH:8]2[OH:7])=[CH:19][CH:18]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(O)cc2)C(O)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(OCc3ccccc3)cc2)C(O)C1
Temperature: 80 °C
Reaction time: 15 h
Yield: 47.4 %

Procedure:
In an analogous manner to that described in Example 22(k), by acylating (3RS,4RS)-4-[4-(3-hydroxy-propoxy)-phenyl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate with benzoyl chloride there was obtained tert-butyl (3RS,4RS)-4-[4-(3-benzoyloxy-propoxy)-phenyl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate as a colourless oil; Rf : 0.84 (SiO2, hexane:ethyl acetate=1:1). (d) A mixture of 1.0 g (3.41 mmol) of tert-butyl (3RS,4RS)-3-hydroxy-4-(4-hydroxy-phenyl)-piperidine-1-carboxylate, 471 mg (34.1 mmol, 10 eq.) of potassium carbonate and 607 ml (5.11 mmol, 1.5 eq.) of benzyl bromide in 30 ml of dimethylformamide was stirred at room temperature for 2 hours and at 80° C. for 15 hours. Subsequently, 471 mg (34.1 mmol, 10 eq.) of potassium carbonate and 607 ml (5.11 mmol, 1.5 eq.) of benzyl bromide were again added and the mixture was stirred at 80° C. for a further 6 hours. The reaction mixture, cooled to room temperature, was poured into 300 ml of an ice/water mixture and extracted three times with 250 ml of ethyl acetate. The organic phases were washed once with water and once with saturated sodium chloride solution, dried over magnesium sulphate, evaporated under reduced pressure and dried in a high vacuum. The yellow oil (1.82 g) was separated on silica gel using an eluent gradient of 4:1 to 3:2 of a mixture of hexane and ethyl acetate as the eluent. There were obtained 620 mg (72% of theory) of tert-butyl (3RS,4RS)-4-(4-benzyloxy-phenyl)-3-hydroxy-piperidine-1-carboxylate which, after recrystallization from a mixture of methylene chloride and hexane, gave 361 mg (28% of theory) as a white, crystalline product; MS: 383 (M)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]([OH:17])=O)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[F:51][C:52]1[CH:57]=[CH:56][C:55]([C@H:58]([NH2:60])[CH3:59])=[CH:54][CH:53]=1>C1COCC1>[F:51][C:52]1[CH:57]=[CH:56][C:55]([C@H:58]([NH:60][C:15]([C@H:12]2[CH2:11][CH2:10][C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:14][CH2:13]2)=[O:17])[CH3:59])=[CH:54][CH:53]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](C(=O)O)CC1
Reactant: C[C@@H](N)c1ccc(F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: C[C@@H](NC(=O)[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Trans-4-(tert-Butoxycabonylamino)cyclohexanecarboxylic acid (10.2 g, 42 mmol), HATU (24 g, 63 mmol) and N,N-diisopropylethylamine (22 ml, 126 mmol) were dissolved in THF (350 ml). The reaction mixture was stirred for 30 min at room temperature, then (R)-1-(4-Fluoro-phenyl)-ethylamine 6.3 ml, 46 mmol) was added. The reaction was stirred overnight at room temperature. LCMS indicated that the reaction was complete, and it was concentrated in vacuo. The concentrate was taken up in 1M NaOH (500 ml) and EtOAc (100 ml) and was stirred for 1 hr. The precipitate that formed was collected by filtration and washed with 1M NaOH:EtOAc (4:1) and dried to give the title compound as a white solid (14.8 g, 97%). LCMS [M+H]=365.3
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[N:6][C:7]([C@@H:17]([NH2:19])[CH3:18])=[C:8]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[CH:9]=2)[CH:4]=[CH:3]1.Cl[C:21]1[C:26]([C:27]#[N:28])=[C:25](Cl)[N:24]=[C:23]([S:30][CH3:31])[N:22]=1.CC[N:34](CC)CC>C1COCC1.CCOC(C)=O>[NH2:34][C:21]1[C:26]([C:27]#[N:28])=[C:25]([NH:19][C@H:17]([C:7]2[N:6]=[C:5]3[CH:4]=[CH:3][N:2]([CH3:1])[C:10]3=[CH:9][C:8]=2[N:11]2[CH2:12][CH2:13][O:14][CH2:15][CH2:16]2)[CH3:18])[N:24]=[C:23]([S:30][CH3:31])[N:22]=1
Reactant: CCN(CC)CC
Reactant: C[C@H](N)c1nc2ccn(C)c2cc1N1CCOCC1
Reactant: CSc1nc(Cl)c(C#N)c(Cl)n1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CSc1nc(N)c(C#N)c(N[C@@H](C)c2nc3ccn(C)c3cc2N2CCOCC2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 35.9 %

Procedure:
(S)-1-(1-Methyl-6-morpholino-1H-pyrrolo[3,2-b]pyridin-5-yl)ethanamine (200 mg, 0.768 mmol) was dissolved in THF (5 mL) along with 4,6-dichloro-2-(methylthio)pyrimidine-5-carbonitrile (169 mg, 0.768 mmol) and Et3N (0.118 mL, 0.845 mmol) to give an orange suspension. The reaction mixture was stirred at room temperature for 2 h, then diluted with EtOAc and washed aq 1M HCl (3×15 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The crude product was then loaded onto an ISCO® silica gel cartridge (12 g) and eluted using an EtOAc/Hexane gradient. The product was collected and concentrated in vacuo to afford the title compound as a white solid (117 mg, 61%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.36-1.50 (m, 3 H), 2.43-2.47 (m, 3 H), 2.72-2.88 (m, 2 H), 2.99-3.15 (m, 2 H), 3.68-3.89 (m, 7 H), 5.89-6.02 (m, 1 H), 6.46-6.58 (m, 1 H), 7.04-7.18 (m, 1 H), 7.21-7.42 (m, 2 H), 7.53-7.65 (m, 1 H), 7.82-7.95 (m, 1 H); ESI-MS m/z [M+H]+ calc'd for C20H24N8OS, 425.5; found 425.5.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([O:9][C:10](N1C=CN=C1)=[O:11])[CH2:2]2.[F:17][C:18]1[CH:19]=[C:20]([CH:24]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[OH:25])[CH:21]=[CH:22][CH:23]=1>>[F:32][C:29]1[CH:28]=[CH:27][C:26]([CH:24]([O:25][C:10](=[O:11])[O:9][C@@H:3]2[CH:4]3[CH2:5][CH2:6][N:1]([CH2:8][CH2:7]3)[CH2:2]2)[C:20]2[CH:21]=[CH:22][CH:23]=[C:18]([F:17])[CH:19]=2)=[CH:31][CH:30]=1
Reactant: O=C(O[C@H]1CN2CCC1CC2)n1ccnc1
Reactant: OC(c1ccc(F)cc1)c1cccc(F)c1
Product: O=C(OC(c1ccc(F)cc1)c1cccc(F)c1)O[C@H]1CN2CCC1CC2

Procedure:
The desired product was prepared by reacting imidazole-1-carboxylic acid (R)-1-aza-bicyclo[2.2.2]oct-3-yl ester with (3-fluoro-phenyl)-(4-fluoro-phenyl)-methanol.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]2[CH:13]=[C:12]([C:14]([C:21]3[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][CH:22]=3)=[CH:15][CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[N:11](S(C3C=CC=CC=3)(=O)=O)[C:8]2=[N:9][CH:10]=1)=[O:4].Cl>C(O)C.O1CCCC1.[OH-].[Na+].C(OCC)(=O)C>[CH:16]1([CH:15]=[C:14]([C:12]2[NH:11][C:8]3=[N:9][CH:10]=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=[C:7]3[CH:13]=2)[C:21]2[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][CH:22]=2)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: COC(=O)c1cnc2c(c1)cc(C(=CC1CCCC1)c1ccc(S(C)(=O)=O)cc1)n2S(=O)(=O)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1ccc(C(=CC2CCCC2)c2cc3cc(C(=O)O)cnc3[nH]2)cc1
Temperature: 100 °C
Yield: 98 %

Procedure:
A mixture of 1-benzenesulfonyl-2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-vinyl]-1H-pyrrolo[2,3-b]pyridin-5-carboxylic acid methyl ester (950 mg, 1.69 mmol) in ethanol (10 mL), tetrahydrofuran (2 mL) and 10% aqueous sodium hydroxide solution (1.5 mL) was heated at 100° C. for 1 h. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution, diluted with ethyl acetate (150 mL), washed with brine, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-vinyl]-1H-pyrrolo[2,3-b]pyridin-5-carboxylic acid (680 mg, 98%) as a solid which was used without further purification.
Reaction SMILES: [F:1][C:2](F)=[C:3]([CH2:18][CH3:19])[C:4]([C:6]1[C:7]([CH3:17])=[CH:8][C:9]([CH3:16])=[C:10]([CH:15]=1)[C:11]([O:13][CH3:14])=[O:12])=O.O.[NH2:22][NH2:23].FC(F)(F)C(O)=O>C1COCC1.O>[CH2:18]([C:3]1[C:2]([F:1])=[N:22][NH:23][C:4]=1[C:6]1[C:7]([CH3:17])=[CH:8][C:9]([CH3:16])=[C:10]([CH:15]=1)[C:11]([O:13][CH3:14])=[O:12])[CH3:19]
Reactant: NN
Reactant: CCC(C(=O)c1cc(C(=O)OC)c(C)cc1C)=C(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Solvent: O
Product: CCc1c(F)n[nH]c1-c1cc(C(=O)OC)c(C)cc1C
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 52.5 %

Procedure:
Into a 250-mL round-bottom flask, was placed a solution of methyl 5-(2-(difluoromethylene)butanoyl)-2,4-dimethylbenzoate (compound 255.3, 175 mg, 0.62 mmol) in THF (100 mL). At room temperature, hydrazine hydrate (120 μL, 2.48 mmol) was added followed by trifluoroacetic acid (144 μL, 1.88 mmol), then the solution was stirred at 50° C. for 1.5 h. The reaction was cooled to room temperature, carefully diluted with water and the mixture was extracted with ethyl acetate (3×50 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by a silica gel column with ethyl acetate/hexane (1:10) as eluent to obtain the title compound as a yellow oil (90 mg, 53%).
Reaction SMILES: [NH2:1][C@H:2]([C:9]([OH:11])=[O:10])[CH2:3][C:4]1[N:8]=[CH:7][NH:6][CH:5]=1.S1[CH2:17][CH2:16][C:15](=[O:18])NC1=O.[OH-].C[N+:22](C)(C)C.[N+](C1C=C(C=CC=1)C(O)=O)([O-])=O>>[CH:5]1[N:6]=[CH:7][NH:8][C:4]=1[CH2:3][C@H:2]([NH:1][C:15]([CH2:16][CH2:17][NH2:22])=[O:18])[C:9]([OH:11])=[O:10]
Reactant: O=C1CCSC(=O)N1
Reactant: N[C@@H](Cc1c[nH]cn1)C(=O)O
Reactant: C[N+](C)(C)C
Agent: O=C(O)c1cccc([N+](=O)[O-])c1
Agent: [OH-]
Product: NCCC(=O)N[C@@H](Cc1cnc[nH]1)C(=O)O

Procedure:
Following the procedure of Example 1, 1.55 g. (10 mmol) of L-histidine and 2.62 g. (20 mmol) of tetrahydro-1,3-thiazin-2,4-dione are reacted, using 40% aqueous tetramethylammonium hydroxide solution to raise pH and m-nitrobenzoic acid to lower pH, to give L-carnosine in good yield.