Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:15]=[C:14](F)[C:11]([C:12]#[N:13])=[C:10]([NH:17][CH2:18][CH2:19][CH2:20][C:21]3[C:22]([CH3:27])=[N:23][NH:24][C:25]=3[CH3:26])[CH:9]=2)[CH:5]=[CH:4][N:3]=1.O.[NH2:29][NH2:30]>CCO>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([NH:17][CH2:18][CH2:19][CH2:20][C:21]3[C:25]([CH3:26])=[N:24][NH:23][C:22]=3[CH3:27])[C:11]3[C:12]([NH2:13])=[N:29][NH:30][C:14]=3[CH:15]=2)[CH:5]=[CH:4][N:3]=1
Reactant: NN
Reactant: Cc1n[nH]c(C)c1CCCNc1cc(-c2ccnc(N)n2)cc(F)c1C#N
Solvent: O
Solvent: CCO
Product: Cc1n[nH]c(C)c1CCCNc1cc(-c2ccnc(N)n2)cc2[nH]nc(N)c12
Temperature: 90 °C
Yield: 32 %

Procedure:
To a solution of 4-(2-amino-4-pyrimidinyl)-2-{[3-(3,5-dimethyl-1H-pyrazol-4-yl)propyl]amino}-6-fluorobenzonitrile (22 mg, 0.037 mmol) in EtOH (2 mL) was added hydrazine monohydrate (1 mL). The resulting solution was stirred at 90° C. until the starting material was consumed as judged by LCMS (˜12 hours). The reaction mixture was concentrated, and the resulting yellow solid was dissolved in EtOH and precipitated with hexanes. The filtrate was decanted to afford the title compound (5 mg, 32%) as a light yellow solid. LC-MS (ES) m/z=378 [M+H]+. 1H NMR (400 MHz, CD3OD): δ 1.91-1.98 (m, 2H), 2.16-2.23 (s, 6H), 2.59 (t, J=7.2 Hz, 2H), 3.24-3.31 (m, 2H), 6.60 (s, 1H), 7.04 (d, J=5.3 Hz, 1H), 7.23 (s, 1H), 8.27 (d, J=5.30 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([P:8](=[O:11])([CH3:10])[CH3:9])=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:18]=[C:17](Cl)[N:16]=[CH:15][N:14]=1>CN(C)C=O.C(N(C(C)C)CC)(C)C>[Cl:12][C:13]1[N:14]=[CH:15][N:16]=[C:17]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([P:8]([CH3:9])([CH3:10])=[O:11])=[CH:6][CH:7]=2)[CH:18]=1
Reactant: CP(C)(=O)c1ccc(N)cc1
Reactant: Clc1cc(Cl)ncn1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CP(C)(=O)c1ccc(Nc2cc(Cl)ncn2)cc1
Temperature: 25 °C

Procedure:
A suspension of 4-amino-dimethylphenylphosphine oxide (2.2 mmol) in 15 mL of N,N-Dimethylformamide and 3.6 mL of Diisopropylethylamine, is stirred at room temperature until a clear solution is obtained. 4,6-Dichloropyrimidine (2.6 mmol) is added in four portions over 5 minutes. The reaction mixture is stirred at high temperature until formation of the desired compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[C:7]2[O:11][CH:10]=[CH:9][C:8]=2[CH:12]=1)([O-:3])=[O:2].Cl[CH2:20][C:21]([N:23]([CH2:26][CH3:27])[CH2:24][CH3:25])=[O:22].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:24]([N:23]([CH2:26][CH3:27])[C:21](=[O:22])[CH2:20][N:16]1[CH2:15][CH2:14][N:13]([C:6]2[C:7]3[O:11][CH:10]=[CH:9][C:8]=3[CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[CH2:18][CH2:17]1)[CH3:25]
Reactant: CCN(CC)C(=O)CCl
Reactant: O=[N+]([O-])c1cc(N2CCNCC2)c2occc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN(CC)C(=O)CN1CCN(c2cc([N+](=O)[O-])cc3ccoc23)CC1
Temperature: 225 °C
Yield: 53.8 %

Procedure:
A mixture of 1-(5-nitro-1-benzofuran-7-yl)piperazine (0.4 g, 1.6 mmol; Intermediate 21) and 2-chloro-N,N-diethylacetamide (0.48 g, 3.2 mmol) in the presence of K2CO3 (0.45 g, 3.2 mmol) in DMF was heated at 225° C. for 5 min using controlled microwave energy. The solvent was evaporated and the residue triturated with MeCN to give 0.31 g (54%) of the title compound as a yellow solid. HPLC purity 80%, RT=1.63 min (System A; 10-97% MeCN over 3 min). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.02 (t, J=7.0 Hz, 3H) 1.14 (t, J=7.0 Hz, 3H) 2.58-2.77 (m, 4H) 3.14-3.50 (m, 10H) 7.14 (d, J=2.3 Hz, 1H) 7.53 (d, J=2.3 Hz, 1H) 8.18 (dd, J=12.5, 2.3 Hz, 2H).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[CH2:13][CH2:14][C:15](=[O:18])[NH:16][N:17]=2)=[CH:4][CH:3]=1.O[C:20]1C=CC=C[C:21]=1[C:22](CCC(O)=O)=[O:23].N1CCCCC1.[OH-].[Na+]>ClCCl>[O:23]1[CH2:22][CH:21]1[CH2:20][O:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[CH2:13][CH2:14][C:15](=[O:18])[NH:16][N:17]=2)=[CH:4][CH:3]=1
Reactant: O=C1CCC(c2ccc(O)c3ccccc23)=NN1
Reactant: O=C(O)CCC(=O)c1ccccc1O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCNCC1
Solvent: ClCCl
Product: O=C1CCC(c2ccc(OCC3CO3)c3ccccc23)=NN1
Yield: 71.7 %

Procedure:
A mixture of 6-(4-hydroxy-1-naphthyl)-4,5-dihydro-3(2H)-pyridazinone (0.5 g, 0.002 mole), epichlorohydrin (2g, 0.02 mole), and piperidine (0.02 g) was heated on a steam bath for 1.5 hours. Evaporation under reduced pressure gave an oil which was dissolved in dichloromethane and shaken with dilute sodium hydroxide (5 ml). The organic phase was washed with water, dried and evaporated to an oil which with ethanol-ether gave crystalline 6[4-(2,3-epoxy-propoxy)-1-naphthyl]-4,5-dihydro-3(2H)-pyridazinone (0.425 g, 69%, m.p. 151°-155° C). Crystallisation from ethanol gave the pure epoxide, m.p. 153.5°-155.5° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][N:17]([C:20]4[N:25]=[CH:24][N:23]=[C:22]([C:26]([OH:28])=O)[CH:21]=4)[CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:29]=1.[F:30][C:31]1[CH:39]=[C:38]2[C:34]([CH2:35][CH2:36][NH:37]2)=[CH:33][CH:32]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[F:30][C:31]1[CH:39]=[C:38]2[C:34]([CH2:35][CH2:36][N:37]2[C:26]([C:22]2[N:23]=[CH:24][N:25]=[C:20]([N:17]3[CH2:18][CH2:19][CH:14]([N:10]4[CH2:9][CH2:8][C:7]5[CH:29]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=5[NH:12][C:11]4=[O:13])[CH2:15][CH2:16]3)[CH:21]=2)=[O:28])=[CH:33][CH:32]=1
Reactant: Fc1ccc2c(c1)NCC2
Reactant: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)O)ncn3)CC1)C(=O)N2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)N4CCc5ccc(F)cc54)ncn3)CC1)C(=O)N2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
100 mg (0.25 mmol) 6-[4-(7-methoxy-2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-yl]-pyrimidine-4-carboxylic acid and 35 mg (0.26 mmol) 6-fluoro-2,3-dihydro-1H-indole in 0.10 mL (0.71 mmol) TEA and 1.5 mL DMF were combined with 90 mg (0.28 mmol) TBTU and stirred for 1 h at RT. Then the reaction mixture was purified by preparative HPLC-MS. The product-containing fractions were combined and freeze-dried.
Reaction SMILES: C([N:3]([CH2:6][CH3:7])CC)C.CS(Cl)(=O)=O.[F:13][C:14]1[CH:15]=[CH:16][C:17]([O:22][CH2:23][O:24][CH3:25])=[C:18](CO)[CH:19]=1.[Cl-].[Na+]>ClCCl>[F:13][C:14]1[CH:15]=[CH:16][C:17]([O:22][CH2:23][O:24][CH3:25])=[C:18]([CH2:7][C:6]#[N:3])[CH:19]=1
Reactant: CCN(CC)CC
Reactant: COCOc1ccc(F)cc1CO
Agent: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Product: COCOc1ccc(F)cc1CC#N

Procedure:
Triethylamine (5.95 ml) and methanesulfonyl chloride (2.42 ml) were added to a dichloromethane (60 ml) solution of the compound 324-2 (5.23 g), while the solution was stirred under cooling on ice. The obtained mixture was stirred at room temperature for 1 hour. A saturated sodium chloride aqueous solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The obtained organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The obtained residue was dissolved in dimethyl sulfoxide (30 ml). Sodium cyanide (2.09 g) and sodium iodide (851 mg) were added to the solution, and the obtained mixture was stirred at 90° C. for 3 hours. The temperature of the reaction solution was returned to room temperature. Thereafter, water was added to the reaction solution, and the mixture was extracted with diethyl ether. The obtained organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-heptane:ethyl acetate=1:0 to 4:1), so as to obtain the title compound (4.33 g).
Reaction SMILES: [F:1][C:2]([F:28])([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:3][O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1C(=O)C2C(=CC=CC=2)C1=O.O.NN>C(O)C>[F:1][C:2]([F:28])([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[CH2:3][O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][NH2:11]
Reactant: O=C1c2ccccc2C(=O)N1CCCCCCOCC(F)(F)c1ccccc1
Agent: NN
Solvent: CCO
Solvent: O
Product: NCCCCCCOCC(F)(F)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.4 %

Procedure:
To a solution of Intermediate 8 (6.41 g, 16.5 mmol) in ethanol (50 ml) was added hydrazine monohydrate (12 mL, 247 mmol). The mixture was stirred at room temperature overnight, concentrated, and the residue was triturated with isopropyl alcohol. The resulting solid was filtered and the solvent removed under reduced pressure. The residue was purified by column chromatography with silica gel, eluting with methylene chloride/ethanol/ammonium hydroxide (80:8:1) to give the title compound (2.31 g, 54%) as oil.
Reaction SMILES: [Cl:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[CH:8]=2)[N:5]=[CH:4][C:3]=1[C:14]([OH:16])=O.[C:17](N1C=CN=C1)([N:19]1C=CN=C1)=O.Cl.CN.C(N(CC)CC)C>CN(C=O)C>[Cl:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[CH:8]=2)[N:5]=[CH:4][C:3]=1[C:14]([NH:19][CH3:17])=[O:16]
Reactant: O=C(O)c1cnn(-c2cccc(Cl)c2)c1Cl
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CN
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CNC(=O)c1cnn(-c2cccc(Cl)c2)c1Cl
Temperature: 25 °C
Reaction time: 20 h
Yield: 51.8 %

Procedure:
A solution of 5.7 g of 5-chloro-1-(3-chlorophenyl)-1H-pyrazole-4-carboxylic acid and 5.4 g of carbonyldiimidazole in 150 ml DMF was stirred at room temperature for 20 minutes. Next, 3.0 g of methylamine hydrochloride and 4.4 g of triethylamine were added and the mixture was stirred at room temperature for 20 hours. The mixture was poured into ice water and the precipitated solid was collected by filtration and dried. The solid was recrystallized from toluene to provide 3.1 g of 5-chloro-1-(3-chlorophenyl)-N-methyl-1H-pyrazole-4-carboxamide. Yield 50%. mp=163°-165° C.
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][C:4]([N:7]=[C:8]=[O:9])=[CH:3][CH:2]=1.[C:11](OCC)(=[O:19])[C:12]1[C:13](=[CH:15][CH:16]=[CH:17][CH:18]=1)[NH2:14].C[O-].[Na+]>C1(C)C(C)=CC=CC=1>[C:1]1([CH3:10])[CH:6]=[CH:5][C:4]([N:7]2[C:11](=[O:19])[C:12]3[C:13](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:14][C:8]2=[O:9])=[CH:3][CH:2]=1
Reactant: CCOC(=O)c1ccccc1N
Reactant: Cc1ccc(N=C=O)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Product: Cc1ccc(-n2c(=O)[nH]c3ccccc3c2=O)cc1
Temperature: 90 °C
Reaction time: 2.5 h
Yield: 92.4 %

Procedure:
A solution of p-tolyl isocyanate (133.2 g, 1.00 mol) in xylene (300 ml) is metered at room temperature into a solution of ethyl anthranilate (165.2 g, 1.00 mol) in xylene (600 ml). After addition is complete, the mixture is stirred at 90° C. for 2.5 hours. 18.0 ml of a 30% strength solution of methanolic sodium methoxide (0.10 mol) are metered in and the mixture is stirred at 90° C. for a further 2 hours, ethanol and methanol being distilled off. After cooling, the product is filtered off with suction and washed with 3×75 ml of xylene. The xylene-moist precipitate is treated with dilute hydrochloric acid and the residual xylene is removed by azeotropic distillation. The product is then filtered off with suction, washed with water and dried. 233.0 g of 3-(4-tolyl)-2,4(1H,3H)-quinazolinedione (yield 92.4% of theory) of melting point 267° C. (lit 265° to 266° C.) are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.C(N(CC)CC)C.[CH2:21]([S:23][CH:24]([CH3:39])[CH2:25][CH:26]1[CH:31]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:30](=[O:37])[CH2:29][C:28](=[O:38])[CH2:27]1)[CH3:22].CC(C)(O)C#N>ClCCl>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([CH:29]2[C:28](=[O:38])[CH2:27][CH:26]([CH2:25][CH:24]([S:23][CH2:21][CH3:22])[CH3:39])[CH:31]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:30]2=[O:37])=[O:7])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1[N+](=O)[O-]
Reactant: CCOC(=O)C1C(=O)CC(=O)CC1CC(C)SCC
Agent: CC(C)(O)C#N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C1C(=O)C(C(=O)c2ccc(Cl)cc2[N+](=O)[O-])C(=O)CC1CC(C)SCC
Temperature: 25 °C
Reaction time: 2 h
Yield: 28.1 %

Procedure:
A solution of 4-chloro-2-nitrobenzoyl chloride (1 g) in dry dichloromethane (5 ml) was added at 0°-10° C. to a stirred solution of triethylamine (0.62 ml) and 5-(2-ethylthiopropyl)-6-carbethoxycyclohexane-1,3-dione (1.3 g) in dry dichloromethane (20 ml) and the mixture stirred at ambient temperature for 2 hours. Triethylamine (1.9 g) and acetone cyanohydrin (0.1 ml) were added successively to the solution and the mixture stirred at ambient temperature for a further 18 hours. The mixture was washed successively with 2N hydrochloric acid (10 ml) and water (2×10 ml) dried over magnesium sulphate and evaporated under reduced pressure to give 2-(4-chloro-2-nitrobenzoyl)-5-(2-ethylthiopropyl)-6-carbethoxycyclohexane-1,3-dione (0.6 g), mp 102°-104° C., as an orange crystalline solid.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:11]2[S:15][C:14]([C:16]([OH:18])=O)=[CH:13][CH:12]=2)=[N:4][O:5][C:6]=1[C:7]([F:10])([F:9])[F:8].[OH:19][CH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>>[OH:19][CH:20]1[CH2:25][CH2:24][N:23]([C:16]([C:14]2[S:15][C:11]([C:3]3[C:2]([CH3:1])=[C:6]([C:7]([F:8])([F:9])[F:10])[O:5][N:4]=3)=[CH:12][CH:13]=2)=[O:18])[CH2:22][CH2:21]1
Reactant: Cc1c(-c2ccc(C(=O)O)s2)noc1C(F)(F)F
Reactant: OC1CCNCC1
Product: Cc1c(-c2ccc(C(=O)N3CCC(O)CC3)s2)noc1C(F)(F)F
Yield: 78 %

Procedure:
Prepared from 5-(4-Methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-carboxylic acid and 4-hydroxypiperdine by the method described in Example 2 Method B. The reaction mixture was evaporated to a solid, triturated and filtered with the aid of water, then washed with a 1 N aqueous hydrochloric acid solution followed by water. The solid was air dried to afford product as a colorless solid (141 mg, 78%). 1H NMR (CDCl3) 1.58-1.69 (m, 2 H), 1.93-2.00 (m, 2 H), 2.26 (br s, 1 H), 2.37 (s, 3 H), 3.44-3.52 (m, 2 H), 4.00-4.12 (m, 3 H), 7.33 (d, J=4.0, 1 H), 7.46 (d, J=3.5, 1 H). 13C NMR 7.9, 34.4, 42 (br), 66.9, 114.8, 118.7 (q, J=271), 128.0, 129.2, 131.2, 140.1, 155.2 (q, J=40), 158.1, 162.8. 19F NMR −63.1. LC/MS 5.71 min, [M+1]+ 361.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[C:15](=[O:16])[CH:14]=[CH:13][C:12]2[C:17]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[C:18]([C:20]([OH:22])=O)[S:19][C:11]1=2)([O-:3])=[O:2].C(N1C=CN=C1)([N:31]1C=CN=C1)=O.N>CN(C=O)C>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[C:15](=[O:16])[CH:14]=[CH:13][C:12]2[C:17]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[C:18]([C:20]([NH2:31])=[O:22])[S:19][C:11]1=2)([O-:3])=[O:2]
Reactant: O=C(O)c1sc2c(ccc(=O)n2-c2ccccc2[N+](=O)[O-])c1-c1ccccc1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: N
Solvent: CN(C)C=O
Product: NC(=O)c1sc2c(ccc(=O)n2-c2ccccc2[N+](=O)[O-])c1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 40 %

Procedure:
A mixture of the compound of Example 123 (105 mg, 0.268 mmol) and 1,1′-carbonyldiimidazole (65 mg, 0.40 mmol) in DMF (3 mL) was stirred at r.t. for 45 min. Concentrated ammonia solution (1 mL) was added and the mixture stirred overnight at r.t. Volatiles were removed in vacuo, the residue taken up in DCM, washed 2M HCl(aq), dried (Na2SO4), and concentrated in vacuo. Purification by column chromatography on silica (4% MeOH in DCM) gave the title compound as a yellow solid (42 mg). δH (DMSO-d6) 8.28 (1H, dd, J 1.3, 8.2 Hz), 7.99 (1H, dt, J 1.4, 7.8 Hz), 7.92 (1H, dd, J 1.4, 7.8 Hz), 7.87–7.82 (1H, m), 7.54–7.47 (3H, m), 7.46–7.37 (3H, m), 6.44 (1H, d, J 9.7 Hz), 6.21 (2H, v br). LCMS (ES+) RT 2.997 minutes, 392.0 (M+H)+.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@@H:2]([C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([C:13]([O:15][CH3:16])=[O:14])[CH:5]=1.C(OCC)C.[ClH:39].O1CCOCC1>>[NH2:1][C@@H:2]([C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([C:13]([O:15][CH3:16])=[O:14])[CH:5]=1.[ClH:39]
Reactant: COC(=O)n1cc(C[C@@H](NC(=O)OC(C)(C)C)C(=O)OCc2ccccc2)c2ccccc21
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: COC(=O)n1cc(C[C@@H](N)C(=O)OCc2ccccc2)c2ccccc21
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of Boc-DTrp-OBzl (12.19 g) in dichloromethane (60 ml) were added methyl chloroformate (4.8 ml), pulverized sodium hydroxide (4.1 g) and TBAHS (9.2 g), and the mixture was stirred at room temperature for 4 h. The reaction mixture was washed with water, dried over MgSO4 and evaporated in vacuo. The residue was crystallized from dichloromethane and hexane to give Boc-DTrp(COOMe)-OBzl (12.57 g). Boc-DTrp(COOMe)-OBzl (4.52 g) was dissolved in 4N-hydrogen chloride/1,4-dioxane (50 ml) and the mixture was stirred at room temperature for 45 min. Ethyl ether (50 ml) was added to the mixture to complete the precipitation. The precipitate was collected by filtration and dried in vacuo to give H-DTrp(COOMe)-OBzl·HCl (3.71 g). To a suspension of H-DTrp(COOMe)-OBzl·HCl (1.94 g) in dichloromethane (50 ml) were added NMM (0.55 ml), 2,6-dimethylpiperidinocarbonyl-γMeLeu-OH (1.42 g), HOBT·H2O (0.84 g) and EDCI·HCl (1.05 g) under ice cooling. The mixture was stirred at the same temperature for 2 h and at room temperature over night. The reaction mixture was washed with sat. aq NaHCO3 (50 ml), 10% aq. citric acid (50 ml) and brine (50 ml) successively, dried over MgSO4 and evaporated. The residue was purified by MPLC (Merck, LiChroprep Si 60) with hexane/ethyl acetate=2/1 for elution to give 2,6-dimethylpiperidinocarbonyl-γMeLeu-DTrp(COOMe)-OBzl (1.17 g). A solution of 2,6-dimethylpiperidinocarbonyl-γMeLeu-DTrp(COOMe)-OBzl (1.10 g) in methanol (30 ml) was hydrogenated over 10% Pd/C (50 mg) at an atmospheric pressure of hydrogen for 1.5 h. After removal of the catalyst by filtration, the filtrate was evaporated in vacuo to give the product (0.93 g).
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=[C:7]([C:9]2[NH:10][C:11]3[C:16]([CH:17]=2)=[CH:15][C:14]([C:18]([OH:20])=[O:19])=[CH:13][CH:12]=3)[CH:6]=[CH:5][N:4]=1.[F:21][C:22]1[C:27](O)=[C:26]([F:29])[C:25]([F:30])=[C:24]([F:31])[C:23]=1[F:32].Cl.C(N=C=NCCCN(C)C)C>C1COCC1>[CH3:1][NH:2][C:3]1[N:8]=[C:7]([C:9]2[NH:10][C:11]3[C:16]([CH:17]=2)=[CH:15][C:14]([C:18]([O:20][C:27]2[C:26]([F:29])=[C:25]([F:30])[C:24]([F:31])=[C:23]([F:32])[C:22]=2[F:21])=[O:19])=[CH:13][CH:12]=3)[CH:6]=[CH:5][N:4]=1
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Reactant: CNc1nccc(-c2cc3cc(C(=O)O)ccc3[nH]2)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Product: CNc1nccc(-c2cc3cc(C(=O)Oc4c(F)c(F)c(F)c(F)c4F)ccc3[nH]2)n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 45.5 %

Procedure:
6.38 g (23.78 mmol) of the acid 20 were suspended in 100 ml of THF. 5.25 g (28.54 mmol) of pentafluorophenol and 5.47 g (28.54 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC*HCl) were then added. The mixture was stirred at RT for 15 h, after which the solvent was removed i.v. and the residue was partitioned between 300 ml of a sat. solution of NaHCO3 and 300 ml of ethyl acetate. The solids were filtered off through kieselguhr and the residue was washed twice with in each 100 ml of ethyl acetate. The phases were separated and the aqueous phase was extracted twice with in each case 100 ml of ethyl acetate. The combined organic phases were washed with 200 ml of a sat. solution of NaCl and then dried with MgSO4. After the solvents had been removed i.v., the residue was chromatographed on silica gel using heptane/ethyl acetate 1:1. 4.7 g (46%) of the pentafluorophenyl ester 55 were obtained.
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([C:22]2[CH:27]=[CH:26][C:25]([S:28][CH:29]3[CH2:33][CH2:32][CH2:31][CH2:30]3)=[C:24]([Cl:34])[CH:23]=2)[C:8](N([C@H](C)[C@H](O)C2C=CC=CC=2)C)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.S(=O)(=O)(O)[OH:36]>O1CCOCC1.O>[Cl:34][C:24]1[CH:23]=[C:22]([C@@H:7]([CH2:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[C:8]([OH:9])=[O:36])[CH:27]=[CH:26][C:25]=1[S:28][CH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: C[C@H]([C@H](O)c1ccccc1)N(C)C(=O)[C@H](CC1CCCC1)c1ccc(SC2CCCC2)c(Cl)c1
Reactant: O=S(=O)(O)O
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)[C@H](CC1CCCC1)c1ccc(SC2CCCC2)c(Cl)c1
Temperature: 105 °C

Procedure:
A solution of (R)-3-cyclopentyl-2-(3-chloro-4-cyclopentylsulfanyl-phenyl)-N-((1R,2R)-2-hydroxy-1-methyl-2-phenyl-ethyl)-N-methyl-propionamide (1.5 mmol) in dioxane (5 mL) is treated with a 9 N aqueous sulfuric acid solution (1.5 mL). The resulting solution is then heated at 105° C. for 16 h. The reaction is then cooled and diluted with water (13 mL) and extracted with a chloroform/methanol solution (3:2, 3×20 mL) and then combined the organic extracts and dried over magnesium sulfate, filtered and concentrated. Purification on an AnaLogix Intelliflash system (silica gel column) will afford (R)-2-(3-chloro-4-cyclopentylsulfanyl-phenyl)-3-cyclopentyl-propionic acid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C@H:10]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C@H:11]2[CH2:13][O:12]2)[CH:5]=[C:6]([F:8])[CH:7]=1.[I:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[O:29][CH2:28][CH2:27][CH:26]2[NH2:33]>C(O)(C)C>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([F:8])[CH:7]=1)[CH2:9][C@H:10]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C@H:11]([OH:12])[CH2:13][NH:33][CH:26]1[C:25]2[C:30](=[CH:31][CH:32]=[C:23]([I:22])[CH:24]=2)[O:29][CH2:28][CH2:27]1
Reactant: NC1CCOc2ccc(I)cc21
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H]1CO1
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)CNC1CCOc2ccc(I)cc21
Yield: 84.6 %

Procedure:
An isopropyl alcohol (25 ml) solution of tert-butyl (1S)-2-(3,5-difluorophenyl)-1-[(2S)-oxiran-2-yl]ethylcarbamate (2.2 g, 7.2 mmol) and 6-Iodo-chroman-4-ylamine (3.0 g, 10.9 mmol) was stirred at 75° C. for 0 h. The IPA was removed in vacuo and the resulting residue dissolved in EtOAc (200 ml). The organic layer was washed with 1 N HCl (4×50 ml), followed by NaHCO3 (2×50 ml), and brine (1×50 ml). The organic layer was dried over Na2SO4 and concentrated in vacuo to yield 3.5 g (85%) of the title compound as an off white solid. MS (ESI+) for C24H29F2IN2O4 m/z 574.8 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C@@H:20]([OH:23])[CH2:21][Br:22])=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(C1C=CC(C)=CC=1)([O-])(=O)=O.[NH+]1C=CC=CC=1.[O:41]1[CH:46]=[CH:45][CH2:44][CH2:43][CH2:42]1>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C@@H:20]([O:23][CH:42]2[CH2:43][CH2:44][CH2:45][CH2:46][O:41]2)[CH2:21][Br:22])=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[CH:14]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=c1ccc2c([C@@H](O)CBr)ccc(OCc3ccccc3)c2[nH]1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=c1ccc2c([C@H](CBr)OC3CCCCO3)ccc(OCc3ccccc3)c2[nH]1
Temperature: 22 °C
Reaction time: 18 h

Procedure:
A suspension of 8-(benzyloxy)-5-[(1R)-2-bromo-1-hydroxyethyl]quinolin-2(1H)-one (100 mg) and pyridinium tosylate (14 mg) in dry DCM (2 ml) was treated with 2,3-dihydropyran (61.2 μl) and stirred at 22° C. for 18 h. The reaction mixture was concentrated in vacuo and purified by chromatography (Hexane-EtOAc 2:1, biotage) to give the title compound (77 mg). Rf [EtOAc-Hexane (1:1)] 0.54