Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][CH2:5][NH2:6].[S:7]([O-:11])([O-:10])(=[O:9])=[S:8].[Na+].[Na+]>O>[NH2:6][CH2:5][CH2:4][CH2:3][SH:8]=[S:7](=[O:9])([OH:11])[OH:10]
Reactant: NCCCCl
Reactant: O=S([O-])([O-])=S
Agent: Cl
Agent: [Na+]
Solvent: O
Product: NCCC[SH]=S(=O)(O)O
Temperature: 80 °C
Reaction time: 4 h

Procedure:
In the reaction vessel purged with nitrogen, 580 g (4.47 moles) of hydrochloride of 3-chloropropylamine was added, and 1048 mL of water was further added thereto to dissolve hydrochloride of 3-chloropropylamine. The obtained solution was kept at from 60° C. to 70° C., and 1164 g (4.69 moles) of pentahydrate of sodium thiosulfate was added thereto. The total used amount of water was 1470 g (the total of 1048 g of water and 422 g of water contained in pentahydrate of sodium thiosulfate). The solution was stirred for 4 hours while the reaction vessel was heated at a bath temperature of 80° C. After 2 hours, a little amount of solid was precipitated. The obtained reaction mixture was cooled, and then stirred overnight at room temperature. The obtained mixture was filtrated to afford the solid mainly containing S-(3-aminopropyl)thiosulfuric acid.
Reaction SMILES: [C:1]1([C:7]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:11][N:10]=[C:9]([S:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH:25]3[CH2:27][CH:26]3[C:28]([O:30]C(C)(C)C)=[O:29])[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>ClCCl.C(O)(C(F)(F)F)=O>[C:1]1([C:7]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:11][N:10]=[C:9]([S:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH:25]3[CH2:27][CH:26]3[C:28]([OH:30])=[O:29])[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)C1CC1CCCCCSc1ncc(-c2ccccc2)c(-c2ccccc2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)C1CC1CCCCCSc1ncc(-c2ccccc2)c(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.7 %

Procedure:
96 mg (0.2 mmol) of tert-butyl 2-[5-(4,5-diphenylpyrimidin-2-ylsulfanyl)pentyl]-cyclopropanecarboxylate were dissolved in a mixture of 2 ml of dichloromethane and 2 ml of TFA and stirred at room temperature for 2 hours. The residue after removal of all volatile constituents in vacuo was purified by preparative HPLC (method A). 60 mg (87%) of the desired product were obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@:9]1([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=1)[C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH:25]1([N:29]2[CH2:35][CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH2:28][CH2:27][CH2:26]1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CN1CCOCC1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@:9]1([C:13]([N:32]1[CH2:33][CH2:34][CH2:35][N:29]([CH:25]2[CH2:26][CH2:27][CH2:28]2)[CH2:30][CH2:31]1)=[O:15])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: C1CC(N2CCCNCC2)C1
Reactant: CC(C)(C)OC(=O)N1CCC[C@]1(Cc1cccc(F)c1)C(=O)O
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)N1CCC[C@]1(Cc1cccc(F)c1)C(=O)N1CCCN(C2CCC2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 34.1 %

Procedure:
A mixture of (2S)-2-(3-fluoro-benzyl)-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (97.0 mg, 0.3 mmol), 1-cyclobutyl-[1,4]diazepane hydrochloride (75.0 mg, 0.3 mmol), HOBt (49.0 mg, 0.36 mmol), EDC (69.2 mg, 0.36 mmol) and N-methylmorpholine (98.0 mg, 0.96 mmol) in CH2Cl2 (10 mL) was stirred at rt for 18 h. The reaction mixture was diluted with CH2Cl2, washed successively with 1 N NaOH and water, dried, and concentrated. The residue (210 mg) was purified by FCC to provide the title compound (47.0 mg, 34%). MS (ESI): mass calcd. for C26H38FN3O3, 459.60; m/z found, 460.2 [M+H]+. 1H NMR (CDCl3): 7.25-7.18 (m, 1H), 6.99-6.83 (m, 3H), 3.61-3.48 (m, 2H), 3.37-3.10 (m, 4H), 2.92-2.52 (m, 3H), 2.49-2.25 (m, 2H), 2.23-1.80 (m, 9H), 1.76-1.55 (m, 5H), 1.51-1.48 (m, 9H).
Reaction SMILES: C(OC([NH:8][CH:9]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH:26]([C:33]([OH:35])=[O:34])[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=O)(C)(C)C.C(Cl)[Cl:37]>>[ClH:37].[NH2:8][CH:9]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH:26]([C:33]([OH:35])=[O:34])[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: ClCCl
Reactant: CCOC(=O)CC(CCCCCCCCCCC(CC(=O)OCC)C(=O)O)NC(=O)OC(C)(C)C
Product: CCOC(=O)CC(N)CCCCCCCCCCC(CC(=O)OCC)C(=O)O
Product: Cl
Reaction time: 2.5 h

Procedure:
Diethyl 2-t-butoxycarbonylamino-13-carboxy-1,14-tetradecanedicarboxylate (3.98 g, 8.40 mmol) is dissolved in methylene chloride (150.0 mL), and hydrogen chloride gas is bubbled through the solution for 15 minutes. The sealed reaction is stirred for 2.5 hours, and then the solvent is evaporated to give diethyl 2-amino-13-carboxy-1,14-tetradecanedicarboxylate hydrochloride.
Reaction SMILES: [N-:1]([S:9]([C:12]([F:15])([F:14])[F:13])(=[O:11])=[O:10])[S:2]([C:5]([F:8])([F:7])[F:6])(=[O:4])=[O:3].[F:16][C:17]([F:27])([F:26])[CH2:18][I+]C1C=CC=CC=1.[CH3:28][N:29]1[CH:33]=[CH:32][N:31]=[CH:30]1>C(Cl)Cl>[N-:1]([S:2]([C:5]([F:8])([F:6])[F:7])(=[O:4])=[O:3])[S:9]([C:12]([F:15])([F:14])[F:13])(=[O:11])=[O:10].[CH3:28][N+:29]1[CH:33]=[CH:32][N:31]([CH2:18][C:17]([F:16])([F:26])[F:27])[CH:30]=1
Reactant: Cn1ccnc1
Reactant: FC(F)(F)C[I+]c1ccccc1
Agent: O=S(=O)([N-]S(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: C[n+]1ccn(CC(F)(F)F)c1

Procedure:
(2,2,2-Trifluoroethyl)(phenyl)iodonium bis(trifluoromethanesulfonyl)imide (compound 7) (3.4 g, 6 mmol) and methylene chloride (12 ml) were placed in a reaction vessel to convert the inside of the reaction vessel to a nitrogen atmosphere. While stirring and cooling in an ice bath, 1-methylimidazole (0.49 g, 6 mmol) was added dropwise thereto over the course of 1 minute. After the dropwise addition thereof, the ice bath was removed, and the mixture was allowed to react at room temperature for 3 hours. After the completion of the reaction, the solvent was removed by distillation. The resulting liquid product was washed with water and then with hexane in order to remove a side product, iodobenzene. Subsequently, this liquid product was dissolved in a small amount of ethyl acetate, and a large amount of ether was added thereto to separate the liquid product. The liquid product was separated from the solvent and then dried at 110° C. under reduced pressure using a vacuum pump. Thus, pure 1-methyl-3-(2′,2′,2′-trifluoroethyl)imidazolium bis(trifluoromethanesulfonyl)imide (compound 9) was obtained as a liquid substance (yield 1.94 g, 73%). When the product is colored, it may be subjected to decolorization with active carbon. Physical property, elemental analysis and spectral data of the compound 9 are shown in Table 8.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([Cl:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:13](Cl)(=O)C(Cl)=O>CN(C)C=O.ClCCl>[Cl:1][C:2]1[N:10]=[C:9]([Cl:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4]([O:6][CH3:13])=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cc(F)c(Cl)nc1Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)c1cc(F)c(Cl)nc1Cl
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To 60 ml of dichloromethane were added 21.0 g of 2,6-dichloro-5-fluoronicotinic acid, 10 ml of oxalylchloride, and 10 drops of N,N-dimethylformamide, and the mixture was stirred at room temperature for one day. The solvent and the excess reagents were distilled off under reduced pressure, and the residue was dissolved in 50 ml of chloroform. 10 ml of methanol was added dropwise to the solution, and the solution was stirred at room temperature for 60 minutes, and 15 g of anhydrous potassium carbonate was added to the solution and the solution was stirred for another 30 minutes. The solution was separated by adding 150 ml of chloroform and 150 ml of distilled water, and the chloroform layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 26.6 g of the title compound as a colorless crude oily residue.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[C:4](Cl)[N:3]=1.[CH:13]1([C:16]2[NH:20][N:19]=[C:18]([NH2:21])[CH:17]=2)[CH2:15][CH2:14]1.CCN(C(C)C)C(C)C.CS(C)=O>O>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[C:4]([NH:21][C:18]2[CH:17]=[C:16]([CH:13]3[CH2:15][CH2:14]3)[NH:20][N:19]=2)[N:3]=1
Reactant: Nc1cc(C2CC2)[nH]n1
Reactant: COC(=O)c1cc(Cl)nc(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)c1cc(Nc2cc(C3CC3)[nH]n2)nc(Cl)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 111.5 %

Procedure:
A round-bottom flask was charged with methyl 2,6-dichloropyrimidine-4-carboxylate (6.9 g, 33.2 mmol), 5-cyclopropyl-1H-pyrazol-3-amine (4.13 g, 33.6 mmol), DIPEA (11.6 mL) and DMSO (40 mL). The reaction was stirred at RT for 4 h then H2O (150 mL) was added. The mixture was vigorously stirred for 20 min, the resulting precipitate was filtered and washed with water, then dried under high vacuum to afford 10.87 g (>100%) of methyl 2-chloro-6-(5-cyclopropyl-1H-pyrazol-3-ylamino)pyrimidine-4-carboxylate (212): MS (ESI) m/z=294.2 [M+1]+.
Reaction SMILES: O.[OH-].[Li+].[CH3:4][O:5][C:6]([N:8]1[CH2:13][C:12](=[O:14])[N:11]2[CH:15]([C:18]([O:20]CC)=[O:19])[CH2:16][CH2:17][CH:10]2[CH2:9]1)=[O:7].Cl>O.CO.O1CCCC1>[CH3:4][O:5][C:6]([N:8]1[CH2:13][C:12](=[O:14])[N:11]2[CH:15]([C:18]([OH:20])=[O:19])[CH2:16][CH2:17][CH:10]2[CH2:9]1)=[O:7]
Reactant: CCOC(=O)C1CCC2CN(C(=O)OC)CC(=O)N21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COC(=O)N1CC(=O)N2C(CCC2C(=O)O)C1
Reaction time: 2 h
Yield: 100 %

Procedure:
A solution of lithium hydroxide monohydrate (16.8 mg, 0.38 mmol) in water (0.5 mL) was added to a solution of 4-oxo-hexahydro-pyrrolo[1,2-a]pyrazine-2,6-dicarboxylic acid 6-ethyl ester 2-methyl ester (86 mg, 0.32 mmol) in methanol (1 mL) and tetrahydrofuran (1 mL). After 2 hours, an aqueous solution of hydrogen chloride (1N, 0.41 mL, 0.41 mmol) was added and the organic solvents were removed under reduced pressure. The resulting aqueous solution was lyophilized for 16 hours to give 4-oxo-hexahydro-pyrrolo[1,2-a]pyrazine-2,6-dicarboxylic acid 2-methyl ester. A yield of 100% was assumed for the subsequent step. C10H14N2O5 calculated 242.1, observed [M+1]+ 242.9, [M+1]− 241.1; rt=1.54 min.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:13][C:14]1[S:15][CH:16]=[CH:17][CH:18]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].CI.[H-].[Na+].[C:23](OCC)(=O)C>O1CCCC1.O>[C:1]([O:5][C:6]([N:8]([C@H:9]([CH2:13][C:14]1[S:15][CH:16]=[CH:17][CH:18]=1)[C:10]([OH:12])=[O:11])[CH3:23])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(C)=O
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1cccs1)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Solvent: C1CCOC1
Product: CN(C(=O)OC(C)(C)C)[C@H](Cc1cccs1)C(=O)O
Temperature: 0 °C
Reaction time: 48 h

Procedure:
(2R)-2-(tert-Butoxycarbonylamino)-3-(thiophen-2-yl)propionic acid (5.00 g; 18.4 mmol) was dissolved in tetrahydrofuran (60 ml). Methyliodide (9.2 ml; 147 mmol) was added and the solution was cooled to 0° C. Sodiumhydride (60% in oil; 1.90 g; 55.3 mmol) was added in portions and the reaction mixture was stirred at room temperature for two days. Ethyl acetate (50 ml) and water (20 ml) were added dropwise. The solvent was removed in vacuo and the residue was dissolved in ether (30 ml) and water (30 ml). The phases were separated and the organic phase was washed with saturated aqueous sodium hydrogencarbonate (30 ml). The aqueous phase were mixed. Citric acid (5% (aq)) was added to pH 3 and the aqueous phase was extracted with ethyl acetate (4×30 ml). The combined organic phases were washed with water (2×30 ml), aqueous sodium thiosulfate (5%; 30 ml), water (30 ml) and dried over magnesium sulfate. The solvent was removed in vacuo. The residue was dissolved in ether (10 ml) and dicyclohexylamine (8.5 ml) was added and the mixture was left in a refrigerator overnight. The precipitate was filtered and washed with ether (2×15 ml) and then redissolved in methylene chloride and washed with a mixture of water (15 ml) and sodium hydrogensulfate (15 ml; 10%(aq)). The aqueous phase was washed with methylene chloride (3×15 ml). The combined organic phases were dried over magnesium sulfate and the solvent was removed in vacuo to give 5.10 g of (2R)-2-(N-(tert-Butoxycarbonyl)-N-methylamino)-3-(thiophen-2-yl)propionic acid.
Reaction SMILES: [CH:1]12[NH:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:9]1[N:18]=[C:17]3[C:12]([C:13](=[O:27])[C:14]([C:24]([OH:26])=[O:25])=[CH:15][N:16]3[C:19]34[CH2:23][CH:21]([CH2:22]3)[CH2:20]4)=[CH:11][C:10]=1[F:28])[CH2:2]2.[CH3:29][S:30]([O-:33])(=[O:32])=[O:31]>>[CH3:29][S:30]([OH:33])(=[O:32])=[O:31].[CH3:29][N:8]1[CH:5]2[CH2:6][CH2:7][CH:1]1[CH2:2][N:3]([C:9]1[N:18]=[C:17]3[C:12]([C:13](=[O:27])[C:14]([C:24]([OH:26])=[O:25])=[CH:15][N:16]3[C:19]34[CH2:22][CH:21]([CH2:20]3)[CH2:23]4)=[CH:11][C:10]=1[F:28])[CH2:4]2
Reactant: O=C(O)c1cn(C23CC(C2)C3)c2nc(N3CC4CCC(C3)N4)c(F)cc2c1=O
Reactant: CS(=O)(=O)[O-]
Product: CN1C2CCC1CN(c1nc3c(cc1F)c(=O)c(C(=O)O)cn3C13CC(C1)C3)C2
Product: CS(=O)(=O)O

Procedure:
7-(3,8-diazabicyclo[3.2.1]octan-3-yl)-1-(bicyclo[1.1.1]pent-1-yl)-1,4-dihydro-6-fluoro-4-oxo-1,8-naphthyridine-3-carboxylic acid, methanesulfonate;
Reaction SMILES: [C:1](Cl)(=[O:6])[CH2:2][C:3](Cl)=[O:4].[CH:8]([N:11]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH3:36])[CH:30]=1)[C:12](=[O:28])[CH2:13][NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([CH3:10])[CH3:9]>C1COCC1>[O:6]=[C:1]1[N:14]([CH2:13][C:12]([N:11]([CH:8]([CH3:10])[CH3:9])[C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH3:36])[CH:30]=2)=[O:28])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N:21]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:3](=[O:4])[CH2:2]1
Reactant: O=C(Cl)CC(=O)Cl
Reactant: COc1cccc(N(C(=O)CNc2ccccc2Nc2ccccc2)C(C)C)c1
Solvent: C1CCOC1
Product: COc1cccc(N(C(=O)CN2C(=O)CC(=O)N(c3ccccc3)c3ccccc32)C(C)C)c1
Reaction time: 8 h

Procedure:
Malonyl dichloride (1.48 mL) in THF (50 mL) is added dropwise over 35 min to a 0° C. solution of N-Isopropyl-N-(3-methoxy-phenyl)-2-(2-phenylamino-phenylamino) acetamide, prepared as in Part C, (5.45 g, 14.1 mmol) in THF (140 mL) and the resultant mixture allowed to attain RT overnight. The solvents were removed in vacuo and the residue diluted with ethyl acetate (100 mL) and washed with saturated aqueous sodium hydrogen carbonate (100 mL), water (100 mL), brine (100 mL), dried (MgSO4), and concentrated in vacuo. The resulting oil is purified by silica gel flash column chromatography using 3% methanol in methylene chlorideas eluent to afford 2-(-2,4-dioxo-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]diazepin-1-yl)-N-isopropyl-N-(3-methoxy-phenyl) acetamide (2.4 g) as an amber foam: 1H NMR (300 MHz, CDCl3) δ7.3-7.1 (m, 10H), 7.02 (t, 1H, J=7.2), 6.92 (dd 1H, J=8.6,2.4), 6.83 (d, 1H, J=7.2), 4.95 (m, 1H, J=6.8), 4.38 (m, 1H), 4.02 (m, 1H), 3.78 (s, 3H), 3.48 (dd, 2H, J=39.3, 11.9), 1.06 (m, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[NH:26][C:11]3=[N:12][CH:13]=[C:14]([NH:16][C:17](=[O:25])[C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[Cl:24])[CH:15]=[C:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:27](Cl)(=[O:29])[CH3:28]>N1C=CC=CC=1>[C:27]([NH:1][C:2]1[CH:3]=[C:4]([C:8]2[NH:26][C:11]3=[N:12][CH:13]=[C:14]([NH:16][C:17](=[O:25])[C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[Cl:24])[CH:15]=[C:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1)(=[O:29])[CH3:28]
Reactant: Nc1cccc(-c2nc3cc(NC(=O)c4ccccc4Cl)cnc3[nH]2)c1
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Product: CC(=O)Nc1cccc(-c2nc3cc(NC(=O)c4ccccc4Cl)cnc3[nH]2)c1

Procedure:
10 mg of the product from example 10-1 were dissolved in 1 ml dry pyridine and 6 μl acetyl chloride were added at room temperature. After stirring over night, the solvent was evaporated and the residue dissolved in 3 ml methanol. 1 ml conc. ammonia were added and the mixture stirred for 1 hr at room temperature. The solvents were again evaporated and the residue purified by chromatography on C-18 RP silica in water methanol mixtures. Yield 7.3 mg
Reaction SMILES: [CH:1]1([CH:7]([C:9]2[C:10]([CH:22]3[CH2:24][CH2:23]3)=[N:11][N:12]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[CH:13]=2)O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]([NH:34][CH2:35][CH2:36][C:37]([O:39]CC)=[O:38])=[O:33])=[CH:28][CH:27]=1>>[CH:1]1([CH:7]([NH:25][C:26]2[CH:27]=[CH:28][C:29]([C:32]([NH:34][CH2:35][CH2:36][C:37]([OH:39])=[O:38])=[O:33])=[CH:30][CH:31]=2)[C:9]2[C:10]([CH:22]3[CH2:24][CH2:23]3)=[N:11][N:12]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCNC(=O)c1ccc(N)cc1
Reactant: COc1ccc(-n2cc(C(O)C3CCCCC3)c(C3CC3)n2)cc1
Product: COc1ccc(-n2cc(C(Nc3ccc(C(=O)NCCC(=O)O)cc3)C3CCCCC3)c(C3CC3)n2)cc1
Yield: 5.5 %

Procedure:
Using cyclohexyl[3-cyclopropyl-1-(4-methoxyphenyl)-1H-pyrazol-4-yl]methanol (0.5 g) synthesized above and ethyl 3-{[(4-aminophenyl)carbonyl]amino}propanoate (0.36 g) synthesized in Example 1(2) and in the same manner as in Example 1(7), the title object compound (43 mg, 5%) was obtained as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[C:17]([C:19]3[CH:20]=[N:21][C:22]([NH2:34])=[C:23](B4OC(C)(C)C(C)(C)O4)[CH:24]=3)[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:35][C:36]1[CH:45]=[CH:44][CH:43]=[C:42]2[C:37]=1[CH2:38][CH2:39][NH:40][CH2:41]2.N1C=CC=CC=1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]2[CH:18]=[C:17]([C:19]3[CH:20]=[N:21][C:22]([NH2:34])=[C:23]([N:40]4[CH2:39][CH2:38][C:37]5[C:42](=[CH:43][CH:44]=[CH:45][C:36]=5[F:35])[CH2:41]4)[CH:24]=3)[CH:16]=[N:15]2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Fc1cccc2c1CCNC2
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc(N)c(B4OC(C)(C)C(C)(C)O4)c3)cn2)CC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc(N)c(N4CCc5c(F)cccc5C4)c3)cn2)CC1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
A mixture of 4-{4-[6-Amino-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-yl]-pyrazol-1-yl}-piperidine-1-carboxylic acid tert-butyl ester (BB4) (170 mg, 0.358 mmol), 5-fluoro-1,2,3,4-tetrahydroisoquinoline (114 mg, 0.716 mmol), cupric acetate (65.7 mg, 0.358 mmol), pyridine (59 μL, 0.72 mmol), 4 Å molecular sieves (95 mg, 264 mg/mmol SM), and DCM (9 mL, 100 mmol) was stirred at rt under an atmosphere of air for 5 d. The mixture was diluted with DCM (50 ml), washed with EDTA solution (2%, 3×50 ml), water (3×50 ml) and brine (50 ml), dried over MgSO4, filtered, and concentrated in vacuo to give a dark black oil that was purified by MDPS to give the title compound as a brown oil. 1H NMR (400 MHz, CDCl3): δ=1.48 (s, 9H), 1.87-1.99 (m, 2H), 2.12-2.19 (m, 2H), 2.84-2.98 (m, 2H), 3.00 (t, J=5.6 Hz, 2H), 3.34 (t, J=6.0 Hz, 2H), 4.17 (s, 2H), 4.22-4.36 (m, 3H), 6.90 (d, J=7.2 Hz, 1H), 6.98 (t, J=8.4 Hz, 1H), 7.18-7.24 (m, 1H), 7.50 (d, J=2.0 Hz, 1H), 7.59 (s, 1H), 7.65 (s, 1H), 7.67 (d, J=1.6 Hz, 1H). MS(ES+): m/z=494.38 (100) [MH+]. HPLC: tR=2.84 min (ZQ2, polar—5 min).
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][CH:8]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=1)[C:9]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)=[O:10])([CH3:4])([CH3:3])[CH3:2].[O:27]1[CH2:32][CH2:31][CH:30]([CH2:33]O)[CH2:29][CH2:28]1>>[C:1]([O:5][C:6](=[O:26])[NH:7][CH:8]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=1)[C:9](=[O:10])[C:11]1[CH:12]=[CH:13][C:14]([O:17][CH2:33][CH:30]2[CH2:31][CH2:32][O:27][CH2:28][CH2:29]2)=[CH:15][CH:16]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: OCC1CCOCC1
Reactant: CC(C)(C)OC(=O)NC(C(=O)c1ccc(O)cc1)c1ccc(Cl)c(Cl)c1
Product: CC(C)(C)OC(=O)NC(C(=O)c1ccc(OCC2CCOCC2)cc1)c1ccc(Cl)c(Cl)c1

Procedure:
The title compound was prepared from rac-[1-(3,4-dichloro-phenyl)-2-(4-hydroxy-phenyl)-2-oxo-ethyl]-carbamic acid tert-butyl ester and tetrahydro-2H-pyran-4-ylmethanol in analogy to Example 9c): MS (ISP): 494.2 and 496.1 (M+H)+.
Reaction SMILES: [C:1]1([CH:9]=[C:7]([OH:8])[CH:6]=[C:4]([OH:5])[CH:3]=1)O.CN(C)[CH:12]=[O:13].P(Cl)(Cl)(Cl)=O.O1CCOC[CH2:21]1>>[OH:8][C:7]1[C:6]([CH3:21])=[C:4]([OH:5])[CH:3]=[C:12]([OH:13])[C:9]=1[CH3:1]
Reactant: Oc1cc(O)cc(O)c1
Reactant: CN(C)C=O
Reactant: C1COCCO1
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1c(O)cc(O)c(C)c1O
Temperature: 40 °C

Procedure:
0.6 kg of phloroglucinol is dissolved in 1.4 liters of dioxan and a mixture containing 0.8 liters of N,N-dimethylformamide and 0.96 liters of phosphorus oxychloride is added slowly and with vigorous stirring. The addition of the reagent having been completed, the reaction is maintained at 40° C. for 12 hours containing the stirring and then the whole is poured over 10 kg of crushed ice.
Reaction SMILES: [C:1]([C:3]1([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4]1)#[N:2].N>C(O)C.[Rh]>[NH2:2][CH2:1][C:3]1([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: CCOC(=O)C1(C#N)CCCC1
Agent: [Rh]
Agent: N
Solvent: CCO
Product: CCOC(=O)C1(CN)CCCC1

Procedure:
20 g of ethyl 1-cyanocyclopentanecarboxylate are placed in 200 ml of a 10% solution of ammonia in ethanol and hydrogenated at 60° C. under a pressure of 100 bar in the presence of rhodium-on-alumina for 72 hours. After filtration on cellite® -- and evaporation, the residue is chromatographed on silica using a DCM/methanol/20% aqueous ammonia mixture (98/2/0.5; v/v/v) as the eluent.
Reaction SMILES: [CH3:1][C:2]1([CH3:8])[CH2:6][CH2:5][O:4][C:3]1=[O:7].[OH-:9].[K+:10]>C1C=CC2C(C3C=CC(O)=CC=3)(C3C=CC(O)=CC=3)OC(=O)C=2C=1.CCO.O>[OH:4][CH2:5][CH2:6][C:2]([CH3:8])([CH3:1])[C:3]([O-:9])=[O:7].[K+:10]
Reactant: CC1(C)CCOC1=O
Reactant: [OH-]
Agent: O=C1OC(c2ccc(O)cc2)(c2ccc(O)cc2)c2ccccc21
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CC(C)(CCO)C(=O)[O-]
Temperature: 105 °C
Reaction time: 3.5 h
Yield: 71.1 %

Procedure:
A mixture of dihydro-3,3-dimethyl-2(3H)-furanone (10 mmol; 1.14 g), aqueous 1 M KOH solution (10 mmol) and one drop of phenolphthalein indicator (0.5% w/v in EtOH/water (1:1)) is stirred at 105° C. for 3.5 hours. The mixture is cooled to ambient temperature and concentration under reduced pressure. To the residue is added 10 mL of EtOH. To the solution is added 50 ml of Et2O, and the solid isolated by filtration and dried under 100 mbar at 50° C. to give potassium 4-hydroxy-2,2-dimethylbutyrate (1.21 g, 71%).
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][C:8]([OH:10])=O)=[C:5]([CH3:11])[O:4][N:3]=1.CN(C=O)C.C(Cl)(C(Cl)=O)=O.[NH2:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]2[CH2:35][CH2:34][N:33]([CH:36]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[C:37]([N:39]([CH2:42][CH3:43])[CH2:40][CH3:41])=[O:38])[CH2:32][CH2:31]2)=[C:26]([F:50])[CH:25]=1>ClCCCl>[CH3:1][C:2]1[C:6]([CH2:7][C:8]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([N:30]3[CH2:35][CH2:34][N:33]([CH:36]([C:44]4[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=4)[C:37]([N:39]([CH2:40][CH3:41])[CH2:42][CH3:43])=[O:38])[CH2:32][CH2:31]3)=[C:26]([F:50])[CH:25]=2)=[O:10])=[C:5]([CH3:11])[O:4][N:3]=1
Reactant: Cc1noc(C)c1CC(=O)O
Reactant: CCN(CC)C(=O)C(c1ccccc1)N1CCN(c2ccc(N)cc2F)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CCN(CC)C(=O)C(c1ccccc1)N1CCN(c2ccc(NC(=O)Cc3c(C)noc3C)cc2F)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.8 %

Procedure:
A mixture of (3,5-dimethyl-isoxazol-4-yl)-acetic acid (1.0 mmol) and DMF (0.050 mL) in DCE (10 mL) was treated with (COCl)2 (10 mmol) dropwise, and was stirred at rt for 1 h. The mixture was concentrated and dried under vacuum. The residue was diluted with DCE (10 mL) and 2-[4-(4-amino-2-fluoro-phenyl)-piperazin-1-yl]-N,N-diethyl-2-phenyl-acetamide (0.30 mmol) and TEA (2.0 mmol) were added. The mixture was stirred at rt for 16 h, then was washed with H2O (10 mL). The organic layer was concentrated, and the residue was purified by PTLC to provide the title compound (78 mg, 45%). MS (ESI): mass calcd. for C29H36FN5O3, 521.28. m/z found, 522.4 [M+H]+. 1H NMR (CDCl3): 7.59-7.25 (m, 6H), 7.09-6.98 (m, 1H), 6.68-6.57 (m, 1H), 4.21 (s, 1H), 3.50-3.36 (m, 4H), 3.35-3.15 (m, 2H), 3.13-3.00 (m, 4H), 2.73-2.60 (m, 4H), 2.37 (s, 3H), 2.23 (s, 3H), 1.16-1.06 (m, 6H).