Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:4]([C:6]1[C:7]2[N:8]=[CH:9][CH:10]=[N:11][C:12]=2[C:13]([C:16]2[C:21]([F:22])=[C:20]([O:23][CH3:24])[CH:19]=[C:18]([O:25][CH3:26])[C:17]=2[Cl:27])=[CH:14][CH:15]=1)=[O:5])C.[N:28]1([CH2:33][C:34]2[CH:35]=[CH:36][C:37]([NH2:40])=[N:38][CH:39]=2)[CH:32]=[CH:31][N:30]=[CH:29]1.C[Al](C)C.C([O-])(O)=O.[Na+]>C(Cl)Cl.CO.C(Cl)Cl>[N:28]1([CH2:33][C:34]2[CH:35]=[CH:36][C:37]([NH:40][C:4]([C:6]3[C:7]4[N:8]=[CH:9][CH:10]=[N:11][C:12]=4[C:13]([C:16]4[C:21]([F:22])=[C:20]([O:23][CH3:24])[CH:19]=[C:18]([O:25][CH3:26])[C:17]=4[Cl:27])=[CH:14][CH:15]=3)=[O:5])=[N:38][CH:39]=2)[CH:32]=[CH:31][N:30]=[CH:29]1
Reactant: CCOC(=O)c1ccc(-c2c(F)c(OC)cc(OC)c2Cl)c2nccnc12
Reactant: Nc1ccc(Cn2ccnc2)cn1
Agent: C[Al](C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COc1cc(OC)c(Cl)c(-c2ccc(C(=O)Nc3ccc(Cn4ccnc4)cn3)c3nccnc23)c1F
Temperature: 80 °C
Reaction time: 3 h

Procedure:
The title compound was prepared in analogy to the procedure described in Example 115 but using 8-(2-chloro-6-fluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid ethyl ester (Step 144.1), 5-imidazol-1-ylmethyl-pyridin-2-ylamine (Step 120.1), 2 equiv of trimethyl aluminum, stirring the reaction mixture for 3 h at 80° C. and pouring it onto a saturated aqueous solution of NaHCO3 and DCM. The title compound: ESI-MS: 519.0 [M+H]+; tR=3.86 min (System 1); TLC: Rf=0.40 (DCM/MeOH, 9:1).
Reaction SMILES: [CH3:1][C:2]([CH3:14])([CH3:13])[C:3]([NH:5][C:6]1[N:7]=[N:8][C:9]([CH3:12])=[CH:10][CH:11]=1)=[O:4].[CH:15]([Mg]Br)([CH3:17])[CH3:16].[NH4+].[Cl-]>C1COCC1.C(Cl)Cl>[CH3:16][CH:15]([C:11]1[CH:10]=[C:9]([CH3:12])[N:8]=[N:7][C:6]=1[NH:5][C:3](=[O:4])[C:2]([CH3:14])([CH3:13])[CH3:1])[CH3:17]
Reactant: CC(C)[Mg]Br
Reactant: Cc1ccc(NC(=O)C(C)(C)C)nn1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1cc(C(C)C)c(NC(=O)C(C)(C)C)nn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 28.3 %

Procedure:
A solution of 2,2-dimethyl-N-(6-methyl-pyridazin-3-yl)-propionamide (4.00 g, 20.73 mmol) in THF (50 mL) is stirred at 0° C. 2.0 M iPrMgBr (46.6 mL, 93.26 mmol) is then added dropwise. The reaction is stirred at 0° C. for 30 min, then it is refluxed for 2 h. It is cooled to rt, poured into ice-H2O; sat. NH4Cl is added and extracted with EtOAc; dried with Na2SO4, filtered and concentrated. The crude material is dissolved in CH2Cl2 (100 mL), treated with 12 (5.8 g, 22.80 mmol) and stirred at rt for 2 h. The reaction is diluted with CH2Cl2 (100 mL), washed with 5% Na2SO3 (3×100 mL); dried with Na2SO4, filtered and concentrated. Purification of the crude material gives the title compound (1.38 g, 5.87 mmol, 28%). ES-MS (m/z): calcd for C13H21N3O (M+H)+: 236.3. found: 236.1.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@H:13]([NH:20][C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:22])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=O)=O)=CC=1.[C-:31]#[N:32].[K+].C1OCCOCCOCCOCCOCCOC1.[I-].[K+]>CN(C=O)C>[CH2:24]([O:23][C:21]([NH:20][C@H:13]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[CH2:12][C:31]#[N:32])=[O:22])[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: [C-]#N
Reactant: Cc1ccc(S(=O)(=O)OC[C@H](NC(=O)OCc2ccccc2)c2ccccc2)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#CC[C@H](NC(=O)OCc1ccccc1)c1ccccc1
Temperature: 50 °C
Reaction time: 20 h

Procedure:
60.5 g of (R)-2-benzyloxycarbonylamino-2-phenylethyl 4-methylphenylsulfonate (142.2 mmol) were dissolved in 675 ml of DMF. 13.9 g of potassium cyanide (213.3 mmol), 5.64 g of 18-crown-6 (21.33 mmol) and 520 mg of potassium iodide (3.13 mmol) were added and the mixture was stirred at 50° C. for 20 hours. The reaction solution was poured into 500 ml of ice water and then stirred at 0° C. for 5 hours. The precipitate was filtered off with suction and dissolved in ethyl acetate. The organic phase was washed three times with water, dried over magnesium sulfate and concentrated in vacuo. The residue was triturated with diethyl ether, filtered off with suction, washed with diethyl ether and dried over phosphorus pentoxide. Yield: 25.3 g (63.5%).
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([I:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.Cl[C:21]1[N:22]([CH3:33])[C:23](=[O:32])[C:24]([CH3:31])=[CH:25][C:26]=1[C:27]([O:29][CH3:30])=[O:28]>C1COCC1>[F:1][C:2]1[CH:8]=[C:7]([I:9])[CH:6]=[CH:5][C:3]=1[NH:4][C:21]1[N:22]([CH3:33])[C:23](=[O:32])[C:24]([CH3:31])=[CH:25][C:26]=1[C:27]([O:29][CH3:30])=[O:28]
Reactant: COC(=O)c1cc(C)c(=O)n(C)c1Cl
Reactant: Nc1ccc(I)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)c1cc(C)c(=O)n(C)c1Nc1ccc(I)cc1F
Temperature: -78 °C
Reaction time: 2 h
Yield: 79.3 %

Procedure:
An oven dried three-necked flask was charged with 2-fluoro-4-iodoaniline (2.08 g, 8.79 mmol) and dry THF (40 mL). The mixture was cooled at −78° C. and LiHMDS (17.79 mL, 1.0 M, THF) was added dropwise. The reaction was stirred an additional hour at this temperature and methyl 2-chloro-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylate (1.89 g, 8.79 mmol) previously dissolved in dry THF (30 mL) was added. The mixture was slowly warmed to room temperature and stirred an additional 2 hours and quenched with 2N aq. HCl. The resulting mixture was further diluted with EtOAc and the organic layer was washed with brine, dried (Na2SO4) and concentrated under reduced pressure. The brown residue was purified by flash chromatography (Biotage system) using a gradient of EtOAc (0-25%) in hexane to afford the title product (2.9 g, 79%).
Reaction SMILES: [Br:1][C:2]([F:8])([F:7])[CH2:3][CH2:4][CH2:5][OH:6].C(N(CC)CC)C.[CH3:16][S:17](Cl)(=[O:19])=[O:18].Cl>C(OCC)C>[CH3:16][S:17]([O:6][CH2:5][CH2:4][CH2:3][C:2]([Br:1])([F:8])[F:7])(=[O:19])=[O:18]
Reactant: CS(=O)(=O)Cl
Reactant: OCCCC(F)(F)Br
Agent: Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCCC(F)(F)Br
Temperature: 0 °C

Procedure:
A stirred solution of 4-bromo4,4-difluorobutanol (0.57 g) in dry diethylether (5 cm3) was cooled to 0° C. Maintaining this temperature, triethylamine (1.7 cm3) was added. After ten minutes methanesulfonyl chloride (0.3 cm3) was added and the mixture stirred for a further hour at 0° C. The reaction mixture was poured into 2M hydrochloric acid (2 cm3) and diethylether (20 cm3). The organic phase was separated, washed with saturated brine, then passed through a plug of silica gel eluting with further diethylether. The diethylether fractions were evaporated under reduced pressure to give a light yellow oil (0.705 g). 1H NMR: δ 2.04-2.18(2H,m); 2.46-2.64(2H,m); 3.04(3H,s); 4.32(2H,t).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=2)[CH:7]=1.[C:15]1([C:21]#[CH:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[C:11]([C:9]1[CH:10]=[C:5]2[CH:4]=[CH:3][C:2]([C:22]#[C:21][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:7][N:6]2[N:8]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)c1cc2ccc(Br)cn2n1
Reactant: C#Cc1ccccc1
Product: CC(C)(C)c1cc2ccc(C#Cc3ccccc3)cn2n1

Procedure:
The title compound, a white solid, MS: m/e=275.4 (M+H+), can be prepared in accordance with the general method of example 1 from 6-bromo-2-tert-butyl-pyrazolo[1,5-a]pyridine (example 41, step 3) and phenylacetylene.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:12][NH2:13]>>[CH3:12][NH:13][S:8]([C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)(=[O:10])=[O:9]
Reactant: CN
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Product: CNS(=O)(=O)c1ccc(Br)cc1

Procedure:
Entry 54: 4-Bromobenzenesulfonyl chloride was reacted with methylamine according to Method A15, Step 1 to afford N-methyl-4-bromobenzenesulfonamide. N-Methyl-4-bromobenzenesulfonamide was coupled with phenol according to Method A15, Step 2 to afford 4-(4-(N-methylsulfamoyl)phenoxy)benzene. 4-(4-(N-Methylsulfamoyl)phenoxy)benzene was converted into 4-(4-(N-methylsulfamoyl)phenoxy)-1-nitrobenzene according to Method A15, Step 3. 4-(4-(N-Methylsulfamoyl)phenoxy)-1-nitrobenzene was reduced to 4-(4-N-methylsulfamoyl)phenyloxy)aniline according to Method A15, Step 4. According to Method C1a, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(3-N-methylsulfamoyl)phenyloxy)aniline to afford the urea.
Reaction SMILES: [C:1]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C(Cl)=O.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([O:25]C)=[CH:21][CH:20]=1.[Al+3].[Cl-].[Cl-].[Cl-]>ClCCl.CN(C=O)C>[OH:25][C:22]1[CH:23]=[CH:24][C:19]([O:18][CH3:17])=[CH:20][C:21]=1[C:8](=[O:10])[CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)Cc1ccccc1
Reactant: COc1ccc(OC)cc1
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(O)c(C(=O)Cc2ccccc2)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 49 %

Procedure:
Phenylacetic acid (7.39 g, 54.28 mmoles) was dissolved in 50 ml dichloromethane. To this mixture, oxalylchloride (4.74 ml, 54.28 mmoles) and DMF (3 drops) were added at 0° C. and stirred for 30 min. The solvent was evaporated and dissolved in 30 ml dichloromethane. To this mixture, 4-methoxyanisole (10 g, 53.47 mmoles) was added and cooled to 0° C. At 0° C. AlCl3 (9.63 g, 72.37 mmoles) was added and the reaction mixture was warmed to RT and stirred for 12 h. The reaction mixture was quenched by the addition of 2N HCl and extracted with ethyl acetate, dried over sodium sulphate and concentrated. The crude product was purified by column chromatography with ethyl acetate: petroleum ether to afford the title compound as yellow liquid (4.3 g, 49% yield. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): δ 11.30(s,1H), 7.42(d, J=3.0 Hz, 1H), 7.33-7.21(m, 5H), 7.17(dd, J=9.0,3.1 Hz, 1H), 6.92(d, J=9.0 Hz, 1H), 4.43(s, 2H), 3.74(s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=[C:10]2[CH:20]([NH:22][C:23]2[N:31]=[CH:30][N:29]=[C:28]3[C:24]=2[N:25]=[CH:26][NH:27]3)[CH3:21])[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:32]C1N=C2C(NC=N2)=C(Br)N=1.BrC1N=CN=C2C=1NC=N2.BrC1C2C(NC(C3N(C4C=CC=C(F)C=4)C(=O)C4C(=CC=CC=4C)N=3)C)=NC=NC=2NC=1>>[NH2:32][C:30]1[N:29]=[C:28]2[C:24]([N:25]=[CH:26][NH:27]2)=[C:23]([NH:22][CH:20]([C:10]2[N:9]([C:4]3[CH:3]=[C:2]([F:1])[CH:7]=[C:6]([F:8])[CH:5]=3)[C:18](=[O:19])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)[CH3:21])[N:31]=1
Reactant: CC(Nc1ncnc2[nH]cnc12)c1nc2ccccc2c(=O)n1-c1cc(F)cc(F)c1
Reactant: Nc1nc(Br)c2[nH]cnc2n1
Agent: Brc1ncnc2nc[nH]c12
Agent: Cc1cccc2nc(C(C)Nc3ncnc4[nH]cc(Br)c34)n(-c3cccc(F)c3)c(=O)c12
Product: CC(Nc1nc(N)nc2[nH]cnc12)c1nc2ccccc2c(=O)n1-c1cc(F)cc(F)c1

Procedure:
Compound 99 was prepared using the general procedure described above with respect to compound 95, but 2-amino-6-bromopurine was substituted for 6-bromopurine in step D. ESI-MS m/z 435 (MH+). Compound 96 is shown below.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.Cl[C:17]1[C:18]2[C:25]([C:26]3[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=3)[C:29]#[N:30])=[CH:24][NH:23][C:19]=2[N:20]=[CH:21][N:22]=1>C(O)CCC>[N:1]1([C:17]2[C:18]3[C:25]([C:26]4[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=4)[C:29]#[N:30])=[CH:24][NH:23][C:19]=3[N:20]=[CH:21][N:22]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: N#Cc1cccc(-c2c[nH]c3ncnc(Cl)c23)c1
Reactant: C1COCCN1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: N#Cc1cccc(-c2c[nH]c3ncnc(N4CCOCC4)c23)c1

Procedure:
Morpholine (871 mg, 10 mmol) and N,N-diisopropylethylamine (2.6 g, 20 mmol) were added to a solution of 3-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)benzonitrile (C14) (2.5 g, 9.8 mmol) in n-butanol (100 mL), and the reaction mixture was heated at reflux for 3 hours. Solvents were removed in vacuo and the residue was purified using chromatography on silica gel (Eluent: 1:1 ethyl acetate/petroleum ether). Subsequent recrystallization from ethyl acetate and tert-butyl methyl ether afforded the product as a white solid. Yield: 770 mg, 2.52 mmol, 26%. LCMS m/z 306.0 [M+H+]. 1H NMR (400 MHz, DMSO-d6) δ 12.34 (br s, 1H), 8.41 (s, 1H), 7.99-8.02 (m, 1H), 7.89 (br d, J=8 Hz, 1H), 7.76 (br d, J=7.5 Hz, 1H), 7.71 (s, 1H), 7.68 (dd, J=7.8, 7.8 Hz, 1H), 3.44-3.50 (m, 4H), 3.11-3.17 (m, 4H).
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[N:12]=[C:11]([Cl:14])[NH:10][C:9]=2[C:8](=[O:15])[N:7]([CH2:16][CH2:17][CH2:18][CH2:19][C:20]2ON=[C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:21]=2)[C:6]1=[O:31])[CH2:2][CH2:3][CH3:4].C(N1C2N=C(Cl)N(CC=C)C=2C(=O)NC1=O)CCC.C1(CC2C=C(CCCO)[O:60][N:59]=2)C=CC=CC=1>>[CH2:1]([N:5]1[C:13]2[N:12]=[C:11]([Cl:14])[NH:10][C:9]=2[C:8](=[O:15])[N:7]([CH2:16][CH2:17][CH2:18][C:19]2[O:60][N:59]=[C:21]([CH2:22][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:20]=2)[C:6]1=[O:31])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1c(=O)n(CCCCc2cc(-c3ccccc3)no2)c(=O)c2[nH]c(Cl)nc21
Reactant: OCCCc1cc(Cc2ccccc2)no1
Agent: C=CCn1c(Cl)nc2c1c(=O)[nH]c(=O)n2CCCC
Product: CCCCn1c(=O)n(CCCc2cc(Cc3ccccc3)no2)c(=O)c2[nH]c(Cl)nc21

Procedure:
Prepared analogously to 3-butyl-8-chloro-1-[4-(3-phenyl-5-isoxazolyl)butyl]-3,7-dihydro-1H-purine-2,6-dione (Example 213) using half the molar quantities, starting from 3-butyl-8-chloro-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (50 mg, 0.177 mmol) and 3-[3-(phenylmethyl)-5-isoxazolyl]-1-propanol (38.4 mg, 0.177 mmol). Yield 24.2 mg,
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:9][N:10]([S:16]([C:19]1[CH:24]=[CH:23][C:22]([O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:21][CH:20]=1)(=[O:18])=[O:17])[CH:11]([CH2:14][OH:15])[CH2:12][OH:13].N1C=CN=C1>CN(C)C=O>[Si:1]([O:13][CH2:12][C@@H:11]([CH2:14][OH:15])[N:10]([CH3:9])[S:16]([C:19]1[CH:20]=[CH:21][C:22]([O:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[CH:23][CH:24]=1)(=[O:18])=[O:17])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CN(C(CO)CO)S(=O)(=O)c1ccc(Oc2ccccc2)cc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CN([C@H](CO)CO[Si](C)(C)C(C)(C)C)S(=O)(=O)c1ccc(Oc2ccccc2)cc1
Yield: 39.2 %

Procedure:
A solution of tert-butyldimethylsilyl chloride (3.53 g, 23.43 mmol) in N,N-dimethylformamide (50 ml) was added dropwise to a solution of N-methyl-N-(4-phenoxybenzenesulfonyl)serinol (8.32 g, 24.66 mmol), which is the product of Example 67(2), and imidazole (4.13 g, 61.65 mmol) in N,N-dimethylformamide (200 ml) at room temperature with stirring. The mixture was further stirred for 2 hours. The solvent of the reaction mixture was evaporated under reduced pressure. To the residue, water was added and this was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using hexane/ethyl acetate=2/1 as the eluant to afford the desired compound (4.15 g, yield 38%) as a colorless oil.
Reaction SMILES: [CH2:1]([C@H:8]([NH:39]C(=O)OC(C)(C)C)[C@H:9]([OH:38])[CH2:10][C@H:11]([NH:25][C:26](=[O:37])[C@@H:27]([NH:32][C:33]([O:35][CH3:36])=[O:34])[C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[NH2:39][C@@H:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C@H:9]([OH:38])[CH2:10][C@H:11]([NH:25][C:26]([C@@H:27]([NH:32][C:33](=[O:34])[O:35][CH3:36])[C:28]([CH3:31])([CH3:30])[CH3:29])=[O:37])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:15][CH:14]=1
Reactant: COC(=O)N[C@H](C(=O)N[C@H](Cc1ccc(-c2ccccn2)cc1)C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)N[C@H](C(=O)N[C@H](Cc1ccc(-c2ccccn2)cc1)C[C@@H](O)[C@@H](N)Cc1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution containing the product from Example 107G (0.042 g, 0.066 mmol) in dichloromethane (1 mL) was treated with trifluoroacetic acid (1 mL), stirred at 25° C. for 1 hour, concentrated, and partitioned between ethyl acetate and saturated NaHCO3 solution. The organic phase was washed with brine, dried over MgSO4, filtered and concentrated.
Reaction SMILES: [CH:1]1([N:5]2[CH2:11][CH2:10][CH2:9][N:8]([C:12]([N:14]3[CH2:17][CH:16]([OH:18])[CH2:15]3)=[O:13])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Br[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1>C1COCC1>[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([CH2:22][O:18][CH:16]2[CH2:15][N:14]([C:12]([N:8]3[CH2:9][CH2:10][CH2:11][N:5]([CH:1]4[CH2:4][CH2:3][CH2:2]4)[CH2:6][CH2:7]3)=[O:13])[CH2:17]2)=[CH:24][CH:25]=1
Reactant: Clc1ccc(CBr)cc1
Reactant: O=C(N1CCCN(C2CCC2)CC1)N1CC(O)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(N1CCCN(C2CCC2)CC1)N1CC(OCc2ccc(Cl)cc2)C1
Temperature: 80 °C
Yield: 51.9 %

Procedure:
To a stirred solution of 1-[(4-cyclobutyl-1,4-diazepan-1-yl)carbonyl]azetidin-3-ol (40 mg, 0.158 mmol) in THF (3 mL) was added NaH (13 mg, 0.316 mmol, 60% in mineral oil). The suspension was stirred at RT for 1 h before 1-(bromomethyl)-4-chlorobenzene (65 mg, 0.316 mmol) was added in one portion. The resulting mixture was heated at 80° C. for 1 H, cooled to RT and concentrated at reduced pressure. The crude residue was dissolved in MeOH and filtered through a short pad of silica before purification by preparative HPLC to provide the title compound (31 mg, 40%) as colourless oil.
Reaction SMILES: C[O:2][C:3](=[O:13])[C@H:4]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[NH2:5].[NH2:14][C@@H:15]1[C:20](=[O:21])[O:19][C:17](=[O:18])[CH2:16]1.N[C@H](C(O)=O)CC1C=CC=CC=1.C(N[C@@H]1C(=O)OC(=O)C1)=O>C(O)(=O)C>[NH2:14][C@H:15]([C:20]([NH:5][C@H:4]([C:3]([OH:2])=[O:13])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:21])[CH2:16][C:17](=[O:18])[OH:19]
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Reactant: N[C@H]1CC(=O)OC1=O
Agent: N[C@@H](Cc1ccccc1)C(=O)O
Agent: O=CN[C@H]1CC(=O)OC1=O
Solvent: CC(=O)O
Product: N[C@@H](CC(=O)O)C(=O)N[C@@H](Cc1ccccc1)C(=O)O

Procedure:
In known methods for producing α-AMP, an N-protected-L-aspartic anhydride is reacted with L-phenylalanine methyl ester in an organic solvent, and then the protecting group is eliminated by a conventional method (U.S. Pat. No. 3,786,039); and addition salt of L-aspartic anhydride with a strong acid is directly reacted with L-phenylalanine methyl ester (Japanese Patent Publication No. 14,217/74); or L-phenylalanine is reacted with N-formyl-L-aspartic anhydride in glacial acetic acid, and the formyl group is eliminated from the product to give α-L-aspartyl-L-phenylalanine (hereinafter referred to as α-AP), which is then esterified with methanol (U.S. Pat. No. 3,933,781).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1[C:13]1[C:22]2[C:17](=[CH:18][C:19]([S:23]([N:26](CC3C=CC(OC)=CC=3OC)[C:27]3[S:28][CH:29]=[CH:30][N:31]=3)(=[O:25])=[O:24])=[CH:20][CH:21]=2)[CH:16]=[CH:15][N:14]=1)#[N:2].[C:43](O)(C(F)(F)F)=[O:44]>C(Cl)Cl>[S:28]1[CH:29]=[CH:30][N:31]=[C:27]1[NH:26][S:23]([C:19]1[CH:18]=[C:17]2[C:22](=[CH:21][CH:20]=1)[C:13]([C:4]1[CH:5]=[CH:6][C:7]([C:9]([F:11])([F:12])[F:10])=[CH:8][C:3]=1[C:1](=[NH:2])[O:44][CH3:43])=[N:14][CH:15]=[CH:16]2)(=[O:25])=[O:24]
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(-c4ccc(C(F)(F)F)cc4C#N)nccc3c2)c(OC)c1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=N)c1cc(C(F)(F)F)ccc1-c1nccc2cc(S(=O)(=O)Nc3nccs3)ccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.9 %

Procedure:
1-(2-cyano-4-(trifluoromethyl)phenyl)-N-(2,4-dimethoxybenzyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide (0.011 g, 0.018 mmol) was dissolved in 1 mL of DCM and TFA (0.1 ml, 1.298 mmol) was added. The reaction was stirred for 30 minutes at room temperature. The reaction was concentrated, dissolved in methanol, and passed through an SCX ion exchange column (pre-wetted with methanol). The column was flushed several times with methanol, then the product was liberated by flushing the column several times with 2.0 M ammonia in methanol. The product-containing filtrate was concentrated to afford an orange solid. The material was purified via silica gel column chromatography (12 g silica gel column, gradient elution 0 to 10% MeOH:DCM) to afford methyl 2-(6-(N-(thiazol-2-yl)sulfamoyl)isoquinolin-1-yl)-5-(trifluoromethyl)benzimidate (0.008 g, 0.016 mmol, 9.10% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm=12.90 (br. s., 1H), 8.78 (br. s., 1H), 8.66 (d, J=5.6 Hz, 1H), 8.58 (s, 1H), 8.14 (d, J=5.0 Hz, 1H), 8.06 (br. s., 1H), 7.99 (d, J=7.5 Hz, 1H), 7.89-7.83 (m, 1H), 7.77 (d, J=8.5 Hz, 2H), 7.28 (d, J=4.6 Hz, 1H), 6.87 (d, J=4.6 Hz, 1H), 3.02 (s, 3H). m/z (ESI) 493.2 (M+H)+.
Reaction SMILES: Br[CH:2]([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:3]([OH:5])=[O:4].[Cl-:18].[Ca+2].[Cl-].C(N(CC)CC)C>C(#N)C.[Cl-].C([N+](CC)(CC)CC)C>[Cl:18][CH:2]([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:3]([OH:5])=[O:4]
Reactant: CCCCCCCCCCCCC(Br)C(=O)O
Reactant: [Cl-]
Agent: CC[N+](CC)(CC)CC
Agent: [Ca+2]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCCCCCCCCCCCC(Cl)C(=O)O
Temperature: 80 °C
Reaction time: 3 h
Yield: 75.4 %

Procedure:
To 2-bromotetradecanoic acid (2 g) dissolved in acetonitrile (100 mg) were added calcium chloride (7.2 g), tetraethylammonium chloride (2.2 g) and triethylamine (0.84 ml), and the mixture was stirred at 80° C. for 3 hours. After precipitates produced by cooling the reaction mixture was removed by filtration, the filtrate was concentrated and the residue was distributed into ethyl acetate and an aqueous citric solution. The ethyl acetate layer was dried and concentrated to give 2-chloro-tetradecanoic acid (1.29 g). To 2-chlorotetradecanoic acid (1.29 g) dissolved in N, N-dimethylformamide (DMF, 50 ml) were added para-nitrophenol (0.68 g) and N,N'-dicyclohexylcarbodiimide (1.1 g), and the mixture was stirred for 12 hours. After precipitates were removed by filtration, the solvent (DMF) was evaporated and the residue was subjected to chromatography on a silica gel column with eluent systems of n-hexane-ethyl acetate (from 200:1 to 50:1) to give the active ester of 2-chlorote tradecanoic acid (11.12 g). To the active ester (500 mg) dissolved in DMF (30 ml) were added 6-(4'-N-glycyl -spicaminyl-amino)purine hydrochloride (500 mg) and triethylamine (2.0 ml). The mixture was stirred for 12 hours. After the solvent was evaporated, the residue was subjected to chromatography on a silica gel column with eluent systems of chloroform-methanol (from 7:1 to 5:1) to give SPK259 in the yield of 202 mg.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][N:8]=1.[Cl:17][C:18]1[CH:23]=[C:22]([O:24][CH2:25][CH:26]=[C:27]([Cl:29])[Cl:28])[CH:21]=[C:20]([CH3:30])[C:19]=1O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>ClCCl>[Cl:17][C:18]1[CH:23]=[C:22]([O:24][CH2:25][CH:26]=[C:27]([Cl:28])[Cl:29])[CH:21]=[C:20]([CH3:30])[C:19]=1[O:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:14])[F:15])=[CH:9][N:8]=1
Reactant: Cc1cc(OCC=C(Cl)Cl)cc(Cl)c1O
Reactant: OCCCCOc1ccc(C(F)(F)F)cn1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1cc(OCC=C(Cl)Cl)cc(Cl)c1OCCCCOc1ccc(C(F)(F)F)cn1
Temperature: 25 °C
Yield: 93.3 %

Procedure:
To a solution of 0.26 g of 2-(4-hydroxybutyloxy)-5-trifluoromethylpyridine, 0.3 g of 2-chloro-6-methyl-4-(3,3-dichloro-2-propenyloxy)phenol and 0.31 g of triphenylphosphine dissolved in 30 ml of dichloromethane was added dropwise a solution of 0.24 g of diisopropyl azodicarboxylate dissolved in 5 ml of dichloromethane, while stirring at room temperature. After stirring at room temperature for 24 hours, the reaction mixture was concentrated to obtain a residue. The residue was subjected to silica gel chromatography, which afforded 0.50 g of 3-chloro-5-methyl-4-[4-(5-trifluoromethyl-2-pyridyloxy)butyloxy]-1-(3,3-dichloro-2-propenyloxy)benzene (89% yield), nD23.0 1.5275.