Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.C([Li])CCC.[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18](OCC)=[O:19]>O1CCCC1.CCCCCC.[Cl-].[NH4+]>[NH:4]1[CH:3]=[C:2]([C:18]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][N:12]=2)=[O:19])[CH:6]=[N:5]1
Reactant: Ic1cn[nH]c1
Reactant: CCOC(=O)c1ccccn1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C(c1cn[nH]c1)c1ccccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 10.1 %

Procedure:
To a solution of 4-iodopyrazole (1.0 g) in tetrahydrofuran (10 mL), a solution of n-butyllithium in hexane (2.6 M, 4.8 mL) was added dropwise at −10° C. and stirred at room temperature for 1 hour. The reaction mixture was cooled to −10° C. and ethyl picolinate (0.86 g) was added thereto, followed by stirring at room temperature for 1.5 hours. The reaction mixture was diluted with saturated aqueous ammonium chloride and extracted with diethyl ether. The organic layer was washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by NH-type silica gel column chromatography (eluting solvent: hexane:ethyl acetate=1:1 to 1:2) to give the titled compound (0.090 g) as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:12][CH2:13][CH:14]([NH2:16])[CH3:15].[Cl:17][C:18]1[O:22][C:21]([CH:23]=O)=[CH:20][CH:19]=1>>[Cl:17][C:18]1[O:22][C:21]([CH2:23][NH:16][CH:14]([CH3:15])[CH2:13][O:12][C:3]2[CH:4]=[CH:5][C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:2]=2[Cl:1])=[CH:20][CH:19]=1
Reactant: CC(N)COc1ccc2ccccc2c1Cl
Reactant: O=Cc1ccc(Cl)o1
Product: CC(COc1ccc2ccccc2c1Cl)NCc1ccc(Cl)o1
Yield: 61 %

Procedure:
Prepared from 1-[(1-chloronaphthalen-2-yl)oxy]propan-2-amine and 5-chlorofuran-2-carbaldehyde in 61% yield as a whitish oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[O:11][CH3:12].[CH2:13]([N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)[CH3:14]>O>[CH2:13]([N:15]1[CH2:20][CH2:19][N:18]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=2[O:11][CH3:12])[CH2:17][CH2:16]1)[CH3:14]
Reactant: CCN1CCNCC1
Reactant: COc1cc([N+](=O)[O-])ccc1Br
Solvent: O
Product: CCN1CCN(c2ccc([N+](=O)[O-])cc2OC)CC1

Procedure:
2-Bromo-5-nitroanisole (4.7 g, 20 mmol) and N-ethyl-piperazin (10.3 ml) is stirred for 13 h at 110° C. under N2-atmosphere. Water (80 ml) is added and the mixture extracted twice with CH2Cl2 (2×80 ml). The organic phases are washed with water and brine, dried (Na2SO4) and concentrated. Column chromatography (SiO2; CH2Cl2/MeOH 19:1→9:1) gives the title compound: m.p.: 84-85° C.
Reaction SMILES: Cl.[NH2:2][CH:3]([CH2:31][C:32]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=1)[C:4]([N:6]1[CH2:11][CH2:10][N:9]([CH:12]([CH2:17][C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=2)[C:13]([NH:15][CH3:16])=[O:14])[CH2:8][CH:7]1[CH2:28][O:29][CH3:30])=[O:5].[C:39]([N:46]1[CH2:53][CH2:52][CH2:51][C@H:47]1[C:48](O)=[O:49])([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40].ON1C2C=CC=CC=2N=N1.CN1CCOCC1>CN(C=O)C.O.CCOC(C)=O>[C:42]([O:41][C:39]([N:46]1[CH2:53][CH2:52][CH2:51][CH:47]1[C:48](=[O:49])[NH:2][CH:3]([CH2:31][C:32]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=1)[C:4]([N:6]1[CH2:11][CH2:10][N:9]([CH:12]([C:13](=[O:14])[NH:15][CH3:16])[CH2:17][C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=2)[CH2:8][CH:7]1[CH2:28][O:29][CH3:30])=[O:5])=[O:40])([CH3:45])([CH3:44])[CH3:43]
Reactant: CNC(=O)C(Cc1ccc2ccccc2c1)N1CCN(C(=O)C(N)Cc2ccc(F)cc2)C(COC)C1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CN1CCOCC1
Product: CNC(=O)C(Cc1ccc2ccccc2c1)N1CCN(C(=O)C(Cc2ccc(F)cc2)NC(=O)C2CCCN2C(=O)OC(C)(C)C)C(COC)C1
Temperature: 0 °C

Procedure:
2-{4-[2-Amino-3-(4-fluorophenyl)-propionyl]-3-methoxymethyl-piperazin-1-yl}-N-methyl-3-naphthalen-2-yl-propionamide HCl, 66, (0.36 g, 0.55 mmol) and BOC-L-Proline (0.13 g, 0.6 mmol) 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.2 g, 1.1 mmol) and 1-hydroxybenzotriazole (0.1 g, 0.7 mmol) are dissolved in anhydrous DMF (1.5 mL). The reaction mixture is cooled to 0° C., then N-methylmorpholine (0.5 mL, 4.1 mmol) is added. The reaction mixture is placed in a refrigerator overnight. EtOAc (25 mL) and water (75 mL) are added, and the organic layer is separated. The aqueous layer is extracted with EtOAc (3×30 mL). All organic layers are combined and washed with water (2×50 mL), and dried over Na2SO4. The solvent is removed in vacuo to afford 0.39 g of the desired product.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:17]=[CH:16][C:7](/[CH:8]=[C:9]2/[C:10](=[O:15])[NH:11][C:12](=[O:14])[S:13]/2)=[CH:6][CH:5]=1)[CH3:2].[C:18]([O:22][C:23]([NH:25][C@@H:26]([CH2:31]O)[C:27]([O:29][CH3:30])=[O:28])=[O:24])([CH3:21])([CH3:20])[CH3:19].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.C(OCC)(=O)C>[C:18]([O:22][C:23]([NH:25][C@@H:26]([CH2:31][N:11]1[C:10](=[O:15])/[C:9](=[CH:8]/[C:7]2[CH:16]=[CH:17][C:4]([O:3][CH2:1][CH3:2])=[CH:5][CH:6]=2)/[S:13][C:12]1=[O:14])[C:27]([O:29][CH3:30])=[O:28])=[O:24])([CH3:21])([CH3:20])[CH3:19]
Reactant: CCOc1ccc(/C=C2\SC(=O)NC2=O)cc1
Reactant: COC(=O)[C@H](CO)NC(=O)OC(C)(C)C
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOc1ccc(/C=C2\SC(=O)N(C[C@H](NC(=O)OC(C)(C)C)C(=O)OC)C2=O)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 99.8 %

Procedure:
Compound 2 (285 mg, 1.15 mmol), (S)-methyl 2-((tert-butoxycarbonyl)amino)-3-hydroxypropanoate (251 mg, 1.15 mmol) and triphenylphosphine (452 mg, 1.72 mmol) were dissolved in 11 mL of anhydrous THF, and stirred at room temperature for 5 min. DIAD (338 μL, 1.72 mmol) was added to the reaction mixture and then stirred overnight at 45° C. The reaction mixture was diluted with ethyl acetate and washed with sat'd NH4Cl aqueous solution. The organic layer was collected, dried over anhydrous Na2SO4, filtered, concentrated and purified by silica column chromatography (30% ethyl acetate in hexanes) to afford compound 21d (99.5%, 517 mg) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]1=[CH:15][C:16](=[O:20])[NH:17][C:18](=[O:19])[N:8]1[CH2:7][CH2:6]2.[H-].[Na+].[CH3:23]I>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]1=[CH:15][C:16](=[O:20])[N:17]([CH3:23])[C:18](=[O:19])[N:8]1[CH2:7][CH2:6]2
Reactant: CI
Reactant: COc1cc2c(cc1OC)-c1cc(=O)[nH]c(=O)n1CC2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc2c(cc1OC)-c1cc(=O)n(C)c(=O)n1CC2
Temperature: 25 °C

Procedure:
A mixture of 9,10-dimethoxy-3,4,6,7-tetrahydro-2H-pyrimido(6,1-a)isoquinolin-2,4-dione (4.11 g), oil-free sodium hydride (0.75 g) and dimethylformamide (100 ml) is heated for 15 minutes to 100° C. and then cooled to room temperature. Methyl iodide (10 ml) is added and the reaction mixture is heated for 12 hours to 100° C. The solvent is removed under reduced pressure and the residue treated with cold water. The solid matter is filtered off and recrystallized from ethyl acetate/methylene chloride. Yield 4.0 g, melting point 260°-262° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11](O)=[O:12])=[CH:7][C:6]=1[NH:14][C:15](=[O:36])[CH2:16][CH:17]([C:23]1[CH:28]=[CH:27][C:26]([C:29](=[O:33])[CH2:30][CH2:31][CH3:32])=[CH:25][C:24]=1[O:34][CH3:35])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])([CH3:4])([CH3:3])[CH3:2].[NH3:37].CCCCCC.C(OCC)(=O)C>C(#N)C>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:12])[NH2:37])=[CH:7][C:6]=1[NH:14][C:15](=[O:36])[CH2:16][CH:17]([C:23]1[CH:28]=[CH:27][C:26]([C:29](=[O:33])[CH2:30][CH2:31][CH3:32])=[CH:25][C:24]=1[O:34][CH3:35])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCCC(CC(=O)Nc1cc(C(=O)O)ccc1C(C)(C)C)c1ccc(C(=O)CCC)cc1OC
Reactant: N
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CC#N
Product: CCCCCC(CC(=O)Nc1cc(C(N)=O)ccc1C(C)(C)C)c1ccc(C(=O)CCC)cc1OC
Reaction time: 0.58 h
Yield: 96.5 %

Procedure:
210 mg (1.30 mmol) of N,N'-carbonyldiimidazole were added to a suspension of 530 mg (1.07 mmol) of N-(2-t-butyl-5-carboxyphenyl)-3-(4-butyryl-2-methoxyphenyl)octanamide prepared as described in Preparation 64C), in 10 ml of acetonitrile, and the resulting mixture was stirred for 35 minutes, after which 1.0 ml (15 mmol) of concentrated aqueous ammonia were added. The reaction mixture was stirred for 20 minutes, after which it was freed from the organic solvent by distillation under reduced pressure. The concentrate was extracted with ethyl acetate. The extract was washed with 2N aqueous hydrochloric acid, with water, with a saturated aqueous solution of sodium hydrogencarbonate and with a saturated aqueous solution of sodium chloride, in that order, after which it was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography through 50 g of silica gel using a gradient elution method, with mixtures of hexane and ethyl acetate ranging from 1:9 to 0:9 by volume as the eluent, to give 511 mg (yield 97%) of the title compound as a foam-like substance.
Reaction SMILES: [C:1]([N:5]1[C:9](=[O:10])[C:8]([NH:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[C:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[S:6]1(=[O:25])=[O:24])([CH3:4])([CH3:3])[CH3:2].[C:26](O)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>C1COCC1>[C:26]([N:15]1[CH2:16][CH2:17][CH:12]([NH:11][C:8]2[C:9](=[O:10])[N:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[S:6](=[O:25])(=[O:24])[C:7]=2[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:13][CH2:14]1)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C(O)c1ccccc1
Reactant: CC(C)(C)N1C(=O)C(NC2CCNCC2)=C(c2ccccc2)S1(=O)=O
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: C1CCOC1
Product: CC(C)(C)N1C(=O)C(NC2CCN(C(=O)c3ccccc3)CC2)=C(c2ccccc2)S1(=O)=O
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 70.4 %

Procedure:
A mixture of 2-tert-butyl-5-phenyl-4-(piperidin-4-ylamino)isothiazol-3(2H)-one 1,1-dioxide (Example 75) (0.150 mg, 0.413 mmol), benzoic acid (0.055 g, 0.454 mmol), EDC (0.087 g, 0.454 mmol), HOBt (0.061 g, 0.454 mmol) and TEA (0.120 ml, 0.825 mmol) in THF (3 ml) was stirred at rt for 3.5 h. The reaction mixture was evaporated and the residue was purified by silica gel column chromatography (Horizons Biotage) using 50% EtOAc in petroleum ether 40-60° C. as eluent to give the title compound (0.136 g, 71%) as a solid. 1H NMR (500 MHz CDCl3): δ 7.54-7.50 (m, 2H), 7.50-7.42 (m, 5H), 7.42-7.35 (m, 2H), 7.32-7.29 (m, 1H), 5.21 (d, 1H), 4.48 (bs, 1H), 3.56 (bs, 1H), 3.24-3.12 (m, 1H), 2.58-2.44 (m, 2H), 1.90-1.64 (bs, 2H), 1.74 (s, 9H), 1.48-1.16 (bs, 2H); 13C NMR (125 MHz CDCl3): δ 170.6, 159.7, 135.7, 133.9, 131.8, 130.2, 130.0, 128.9, 128.7, 126.9, 125.2, 107.7, 61.9, 50.4, 27.8; Mass Spectrum: M+H+ 468.
Reaction SMILES: [NH:1]([C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])[C@H:2]([C:7]([NH:9][CH2:10][C:11]([O:13]C(C)(C)C)=[O:12])=[O:8])[CH2:3][C:4](=[O:6])[NH2:5].FC(F)(F)C(O)=O>CCOCC>[NH:1]([C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])[C@H:2]([C:7]([NH:9][CH2:10][C:11]([OH:13])=[O:12])=[O:8])[CH2:3][C:4](=[O:6])[NH2:5]
Reactant: CC(C)(C)OC(=O)CNC(=O)[C@H](CC(N)=O)NC(=O)OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Product: NC(=O)C[C@H](NC(=O)OCc1ccccc1)C(=O)NCC(=O)O
Yield: 78 %

Procedure:
9.13 g. (26 mmoles) of Z-Asn-Gly-OtBu are dissolved in 90 ml. of trifluoroacetic acid, and after 0.5 hours of standing 450 ml. of dry ether are added to the solution. The separated white precipitate is filtered off, washed with ether and crystallized from 35 ml. of water. 6.56 g. (78 %) of Z-Asn-Gly-OH are obtained. M.p.: 170°-172° C, Rf4 = 0.45.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:14])[CH2:9][CH2:10][C:11](=O)[CH3:12].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH3:12][C:11]1[O:14][C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Br:1])=[CH:9][CH:10]=1
Reactant: CC(=O)CCC(=O)c1ccccc1Br
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: Cc1ccc(-c2ccccc2Br)o1
Yield: 70 %

Procedure:
A solution of 18 g of 1-(2-bromophenyl)-1,4-pentanedione and 1 g of p-toluenesulfonic acid in 200 ml of anhydrous benzene is heated under reflux over molecular sieves for 12 h. The resulting solution is washed 3 times with brine, dried over Na2SO4 and evaporated to dryness under reduced pressure. The residue is purified by FC (eluent hexane:acetate 95:5) and 12.2 of a light yellow oil are obtained g (70% yield). 1H NMR (CDCl3), δ: 2.38 (d, 3 H), 6.12 (m, 1 H), 7.1-7.4 (m, 3 H), 7.63 (dd, 1 H), 7.79 (dd, 1 H).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[C:10]([C:12]#[N:13])[CH:9]=[CH:8][N:7]=2)[N:3]=[CH:2]1.[CH2:14](Br)[CH:15]1[O:19][CH2:18][CH2:17][CH2:16]1>>[O:19]1[CH2:18][CH2:17][CH2:16][CH:15]1[CH2:14][N:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[C:10]([C:12]#[N:13])[CH:9]=[CH:8][N:7]=2)[N:3]=[CH:2]1
Reactant: N#Cc1ccnc(-c2c[nH]cn2)c1
Reactant: BrCC1CCCO1
Product: N#Cc1ccnc(-c2cn(CC3CCCO3)cn2)c1

Procedure:
The title compound was prepared from 2-(1H-imidazol-4-yl)pyridine-4-carbonitrile and tetrahydrofurfuryl bromide according to the procedure for the preparation of Example 43, part A (heating to 120°). [M+H] Calc'd for C14H14N4O, 255. Found, 255.
Reaction SMILES: [Cl-].[CH3:2][O:3][C:4]([NH:6][C@@H:7]([CH:40]([CH3:42])[CH3:41])[C:8]([N:10]1[CH2:14][CH2:13][CH2:12][C@H:11]1[C:15]1[NH:19][C:18]2[CH:20]=[CH:21][C:22]([C:24]3[CH:29]=[CH:28][C:27]([C:30]4[NH+:31]=[C:32]([C@@H:35]5[CH2:39][CH2:38][CH2:37][NH2+:36]5)[NH:33][CH:34]=4)=[CH:26][CH:25]=3)=[CH:23][C:17]=2[N:16]=1)=[O:9])=[O:5].[Cl-].[CH3:44][O:45][C:46]([NH:48][C@@H:49]([CH:53]([CH3:55])[CH3:54])[C:50](O)=[O:51])=[O:47].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[CH3:2][O:3][C:4]([NH:6][C@@H:7]([CH:40]([CH3:42])[CH3:41])[C:8]([N:10]1[CH2:14][CH2:13][CH2:12][C@H:11]1[C:15]1[NH:19][C:18]2[CH:20]=[CH:21][C:22]([C:24]3[CH:25]=[CH:26][C:27]([C:30]4[N:31]=[C:32]([C@@H:35]5[CH2:39][CH2:38][CH2:37][N:36]5[C:50]([C@@H:49]([NH:48][C:46](=[O:47])[O:45][CH3:44])[CH:53]([CH3:55])[CH3:54])=[O:51])[NH:33][CH:34]=4)=[CH:28][CH:29]=3)=[CH:23][C:17]=2[N:16]=1)=[O:9])=[O:5]
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc2cc(-c3ccc(-c4c[nH]c([C@@H]5CCC[NH2+]5)[nH+]4)cc3)ccc2[nH]1)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc(-c2ccc(-c3ccc4[nH]c([C@@H]5CCCN5C(=O)[C@@H](NC(=O)OC)C(C)C)nc4c3)cc2)c[nH]1)C(C)C
Temperature: 2 °C
Yield: 40 %

Procedure:
To a cold (0-4° C.) stirred light suspension of 4-(4-(2-((S)-1-((S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-benzo[d]imidazol-5-yl)phenyl)-2-((S)-pyrrolidin-1-ium-2-yl)-1H-imidazol-3-ium chloride (98.09 mg, 0.15 mmol) and (2S)-2-(methoxycarbonylamino)-3-methyl-butanoic acid (28.91 mg, 0.1650 mmol) in DMF (1.5 mL) is sequentially added HATU (85.55 mg, 0.2250 mmol) and DIPEA (116.3 mg, 156.7 μL, 0.9000 mmol). The resulting mixture is slowly warmed up to rt, stirred overnight, then diluted with water (5 mL), extracted with ethyl acetate (3×6 mL). The combined extracts are washed with saturated bicarbonate solution, brine, dried (Na2SO4) and concentrated. Residue purified on 25+M biotage SiO2 cartridge using MeOH-EtOAc (0:100, 15:85) as eluent to afford methyl N-[(1S)-1-[(2S)-2-[4-[4-[2-[(2S)-1-[(2S)-2-(methoxycarbonylamino)-3-methyl-butanoyl]pyrrolidin-2-yl]-1H-benzimidazol-5-yl]phenyl]-1H-imidazol-2-yl]pyrrolidine-1-carbonyl]-2-methyl-propyl]carbamate (45.8 mg, 0.06007 mmol, 37.45%) as white solid. This product is repurified by reverse phase HPLC to give methyl N-[(1S)-1-[(2S)-2-[4-[4-[2-[(2S)-1-[(2S)-2-(methoxycarbonylamino)-3-methyl-butanoyl]pyrrolidin-2-yl]-1H-benzimidazol-5-yl]phenyl]-1H-imidazol-2-yl]pyrrolidine-1-carbonyl]-2-methyl-propyl]carbamate (29.6 mg) as white solid.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH:7]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:8][CH2:9][CH3:10])[N:5]=[C:4]([CH2:17][CH2:18][CH3:19])[C:3]=1[C:20]([NH2:22])=[O:21].[Cl:23][C:24]1[CH:25]=[C:26]([CH2:31][C:32](OC)=O)[CH:27]=[CH:28][C:29]=1[Cl:30].[O-]CC.[Na+].C(=O)([O-])O.[Na+]>ClCCl>[Cl:23][C:24]1[CH:25]=[C:26]([CH:27]=[CH:28][C:29]=1[Cl:30])[CH2:31][C:32]1[NH:22][C:20](=[O:21])[C:3]2[C:4]([CH2:17][CH2:18][CH3:19])=[N:5][N:6]([CH:7]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:8][CH2:9][CH3:10])[C:2]=2[N:1]=1
Reactant: COC(=O)Cc1ccc(Cl)c(Cl)c1
Reactant: CCCCCCC(CCC)n1nc(CCC)c(C(N)=O)c1N
Agent: CC[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCCCCCC(CCC)n1nc(CCC)c2c(=O)[nH]c(Cc3ccc(Cl)c(Cl)c3)nc21
Yield: 55.1 %

Procedure:
10 mg (0.019 mmol) of 5-amino-3-propyl-1-(4-decyl)-1H-pyrazole-4-carboxamide and 20 mg (0.091 mmol) of methyl 3,4-dichlorophenylacetate are refluxed for 6 hours in 0.3 ml of a 0.5M ethanolic sodium ethoxide solution. After dichloromethane and saturated aqueous sodium hydrogen carbonate solution have been added, the phases are separated. Purification by chromatography gives 5 mg (48%) of a solid, Rf=0.70 (dichloromethane/methanol=15:1).
Reaction SMILES: [F:1][C:2]([F:13])([C:9]([F:12])([F:11])[F:10])[C:3]([F:8])([F:7])[C:4](Cl)=[O:5].[Cl:14][C:15]1[CH:23]=[C:22]2[C:18]([C:19]([NH2:24])=[N:20][NH:21]2)=[CH:17][CH:16]=1>N1C=CC=CC=1>[Cl:14][C:15]1[CH:23]=[C:22]2[C:18]([C:19]([NH:24][C:4](=[O:5])[C:3]([F:8])([F:7])[C:2]([F:13])([F:1])[C:9]([F:12])([F:11])[F:10])=[N:20][NH:21]2)=[CH:17][CH:16]=1
Reactant: Nc1n[nH]c2cc(Cl)ccc12
Reactant: O=C(Cl)C(F)(F)C(F)(F)C(F)(F)F
Solvent: c1ccncc1
Product: O=C(Nc1n[nH]c2cc(Cl)ccc12)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 6 °C
Reaction time: 19 h

Procedure:
0.60 cm3 of heptafluorobutyryl chloride is added to 1 g of 6-chloro-1H-indazole-3-amine in 10 cm3 of pyridine, after cooling the medium to about 6° C., the mixture is then allowed to return to room temperature over 19 hours and is evaporated to dryness under reduced pressure (2 kPa; 45° C.). The residue is taken up in 40 cm3 of ethyl acetate and 20 cm3 of water; the precipitate formed is filtered off on a sinter funnel and then rinsed with 2×10 cm3 of methylene chloride and purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 3.5 cm), eluting with a cyclohexane/ethyl acetate mixture (70/30 by volume). The fractions containing the expected product are combined and evaporated under reduced pressure (2 kPa; 50° C.) to give 0.77 g of N-[6-chloro-1H-indazol-3-yl]-2,2,3,3,4,4,4-heptafluorobutanamide in cottony form.
Reaction SMILES: [I:1][C:2]1[N:11]=[CH:10][C:9]2[CH2:8][CH2:7][C:6]3[C:12]([C:16]([O-:18])=O)=[N:13][N:14]([CH3:15])[C:5]=3[C:4]=2[N:3]=1.[K+].[N:20]1(C([O-])=O)C2C=CC=CC=2N=N1.[NH4+]>CN(C)C=O.O>[I:1][C:2]1[N:11]=[CH:10][C:9]2[CH2:8][CH2:7][C:6]3[C:12]([C:16]([NH2:20])=[O:18])=[N:13][N:14]([CH3:15])[C:5]=3[C:4]=2[N:3]=1
Reactant: Cn1nc(C(=O)[O-])c2c1-c1nc(I)ncc1CC2
Reactant: O=C([O-])n1nnc2ccccc21
Agent: [K+]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1nc(C(N)=O)c2c1-c1nc(I)ncc1CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.1 %

Procedure:
A suspension of potassium 8-iodo-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate (394 mg, 1.0 mmol) in anhydrous dimethylformamide (10 mL) was treated with N-ethyl-N′,N′-diisopropyl carbodiimide hydrochloride (EDCI) (287 mg, 1.5 mmol) and with ammonium 1H-1,2,3-benzotriazol-1-ate (304 mg, 2 mmol). The reaction was stirred at room temperature overnight. The reaction was diluted with water and the resulting precipitate was collected by filtration to afford the title compound (320 mg, 90% yield).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[C:8]1([S:14]([C:17]2[C:18]([S:35][CH3:36])=[N:19][N:20]3[C:25](Cl)=[CH:24][C:23]([CH2:27][N:28]4[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]4)=[N:22][C:21]=23)(=[O:16])=[O:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CN(C=O)C>[C:8]1([S:14]([C:17]2[C:18]([S:35][CH3:36])=[N:19][N:20]3[C:25]([N:5]4[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]4)=[CH:24][C:23]([CH2:27][N:28]4[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]4)=[N:22][C:21]=23)(=[O:16])=[O:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CSc1nn2c(Cl)cc(CN3CCN(C)CC3)nc2c1S(=O)(=O)c1ccccc1
Reactant: CN1CCNCC1
Solvent: CN(C)C=O
Product: CSc1nn2c(N3CCN(C)CC3)cc(CN3CCN(C)CC3)nc2c1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 82.2 %

Procedure:
0.4 g (4 mmol) of 1-methyl-piperazine was added to a solution of 0.8 g (1.77 mmol) of 3-benzenesulphonyl-7-chloro-5-(4-methyl-piperazin-1-ylmethyl)-2-methylsulphanyl-pyrazolo[1,5-a]pyrimidine in 20 ml of DMF and stirred at RT for 6 hrs. The reaction solution was evaporated and the residue was partitioned between 2N NaOH and CH2Cl2. The aqueous phase was extracted three times with CH2Cl2, and the combined organic phases were dried (MgSO4), filtered and evaporated. Subsequent chromatography (SiO2, CH2Cl2/MeOH/NH4OH 80:10:1) and crystallization from EtOH yielded 0.75 g (82%) of 3-benzenesulphonyl-7-(4-methyl-piperazin-1-yl)-5-(4-methyl-piperazin-1-ylmethyl)-2-methylsulphanyl-pyrazolo[1,5-a]pyrimidine as colorless crystals, m.p. 193-195°.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.C(Cl)(Cl)Cl.[C:21]1([CH:27](O)[CH:28]([NH2:30])[CH3:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>O>[C:21]1([CH2:27][CH:28]([NH:30][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH3:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(N)C(O)c1ccccc1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(Cc1ccccc1)NC(=O)c1ccccc1
Reaction time: 2 h

Procedure:
Benzoyl chloride in an amount of 349 mg (2.48 mmol) and triethylamine in an amount of 1.0 ml (7.3 mmol) were added into 10 ml of chloroform solution of the above-described 1-phenyl-2-aminopropanol in an amount of 465 mg (2.48 mmol). The resulting solution was stirred for 2 hours in ice bath and added with water to discontinue the reaction. After separation of the solution, the chloroform solution was dried with anhydrous magnesium sulfate and distilled out under reduced pressure to obtain 1-phenyl-2-benzoylaminopropane in crude state. The crude product was purified by means of silica gel column chromatography (hexane:ethyl acetate=3:1) to obtain anti-isomer of 1-phenyl-2-benzoylaminopropanol in an amount of 705 mg (2.42 mmol) at a yield of 97%. The optical purity of said anti-isomer was determined by means of high performance liquid chromatography (ethanol:hexane 1:30, flow rate: 1.0 ml/min., chiralcell OJ) and was found to be 95% ee as the purity of the (1S, 2R)-isomer. The optical purity of the syn-isomer was also determined and the purity was found to be 90% ee as the purity of the (1S, 2S)-isomer.
Reaction SMILES: C[O:2][C:3](=[O:18])[CH2:4][CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([OH:17])[CH:14]=[C:15]([CH3:16])[C:7]1=2.[Li+].[OH-].Cl>C1COCC1.O>[OH:11][B:9]1[C:8]2[CH:12]=[C:13]([OH:17])[CH:14]=[C:15]([CH3:16])[C:7]=2[CH:6]([CH2:5][CH2:4][C:3]([OH:18])=[O:2])[O:10]1
Reactant: COC(=O)CCC1OB(O)c2cc(O)cc(C)c21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(O)cc2c1C(CCC(=O)O)OB2O
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.3 %

Procedure:
To a solution of 3-(1,6-dihydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl)propionic acid methyl ester (0.190 g, 0.76 mmol) in THF (4 mL) and H2O (2 mL) was added LiOH (0.146 g, 6.08 mmol) at 0° C. The resulting mixture was stirred at room temperature for 2 hours then cooled to 0° C. and acidified to pH 3 with 6N HCl. The mixture was concentrated and purified by silica gel flash column chromatography to give 3-(1,6-dihydroxy-4-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)propionic acid (0.110 g, 61%). 1H NMR (400 MHz, DMSO-d6) δ 9.20 (s, 1H), 9.00 (s, 1H), 6.88 (s, 1H), 6.66 (s, 1H), 2.30-2.10 (m, 6H), 1.50 (m, 1H). MS (ESI) m/z: 235 [M−1]−. HPLC purity: 99.06% (220 nm), 98.87% (Maxplot).