Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:6]=[C:7]([OH:16])[C:8](=[CH:14][CH:15]=1)[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[N+]=[N-].[ClH:17].[H][H]>[Pd].CO>[ClH:17].[NH2:1][CH2:4][C:5]1[CH:6]=[C:7]([OH:16])[C:8](=[CH:14][CH:15]=1)[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)c1ccc(CN=[N+]=[N-])cc1O
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CCOC(=O)c1ccc(CN)cc1O
Yield: 71 %

Procedure:
Palladium on carbon (0.5 g; 10% [w/w]) was added to a 1L hydrogenation flask under a nitrogen atmosphere. The crude ethyl 4-azidomethylsalicylate was dissolved in methanol (200 mL) and transferred to the hydrogenation flask. Concentrated-aqueous hydrochloric acid (2 mL) was then added, and the flask was affixed to the Parr hydrogenator. The reaction mixture was shaken under 35 psi of hydrogen for 4 hours at room temperature. The mixture was then filtered through Celite to remove the catalyst, and the filtrate was evaporated to dryness to afford an off-white solid. Finally, this solid was crystallized from EtOH to afford 3.1 g (71% yield) of ethyl 4-aminomethylsalicylate hydrochloride (m.p. 240°-241 ° C.).
Reaction SMILES: F[C:2]1[N:20]=[CH:19][CH:18]=[CH:17][C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]2[S:14][C:13]([CH3:15])=[N:12][C:11]=2[CH:16]=1)=[O:5].[NH:21]1[C:25]2=[N:26][CH:27]=[CH:28][C:29]([CH2:30][NH2:31])=[C:24]2[CH:23]=[N:22]1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[CH3:15][C:13]1[S:14][C:10]2[CH:9]=[CH:8][C:7]([NH:6][C:4]([C:3]3[C:2]([NH:31][CH2:30][C:29]4[CH:28]=[CH:27][N:26]=[C:25]5[NH:21][N:22]=[CH:23][C:24]=45)=[N:20][CH:19]=[CH:18][CH:17]=3)=[O:5])=[CH:16][C:11]=2[N:12]=1
Reactant: NCc1ccnc2[nH]ncc12
Reactant: Cc1nc2cc(NC(=O)c3cccnc3F)ccc2s1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: Cc1nc2cc(NC(=O)c3cccnc3NCc3ccnc4[nH]ncc34)ccc2s1
Temperature: 120 °C

Procedure:
2-Fluoro-N-(2-methyl-benzothiazol-5-yl)-nicotinamide (100 mg, 0.348 mmol) was dissolved in NMP (0.5 mL), then C-(1H-pyrazolo[3,4-b]pyridin-4-yl)-methylamine (52 mg, 0.348 mmol) and DIEA (91 μL, 0.522 mmol) were added. The reaction was heated at 120° C. for 20 h. Additional C-(1H-pyrazolo[3,4-b]pyridin-4-yl)-methylamine (25 mg, 0.174 mmol) and DIEA (91 μL, 0.522 mmol) were added and the mixture was heated at 120° C. for another 23 h. The mixture was partitioned between H2O and EtOAc then extracted with EtOAc. The organic layer was washed with brine and dried over MgSO4. Purification was achieved by preparative TLC (10% MeOH/CH2Cl2), followed by trituration with CH2Cl2 to give N-(2-methyl-1,3-benzothiazol-5-yl)-2-((1H-pyrazolo[3,4-b]pyridin-4-ylmethyl)amino)-3-pyridinecarboxamide as a light yellow solid. MS m/e 416.0 (M+H)+. Calc'd for C21H17N7O—415.48.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[NH:15]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C@@H:16]([C:24](O)=[O:25])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[CH2:14][CH2:13][N:12]([C:24](=[O:25])[C@H:16]([NH:15][C:27]([O:29][C:30]([CH3:32])([CH3:31])[CH3:33])=[O:28])[CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:11][CH2:10]1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)C(=O)O
Reactant: COc1ccccc1C1CCNCC1
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Product: COc1ccccc1C1CCN(C(=O)[C@@H](Cc2ccccc2)NC(=O)OC(C)(C)C)CC1
Yield: 81435.5 %

Procedure:
The title compound was prepared according to the procedure described in Example 1 (Step f) using 4-(2-methoxyphenyl)piperidine (Maybridge) (2.68 g, 0.014 mol), Boc-D-PheOH (Advanced ChemTech) (3.71 g, 0.014 mmol), HOAT (Aldrich) (1.9 g, 0.014 mol) and EDC (Advanced ChemTech) (4.02 g, 0.021 mol). Purification by silica gel chromatography (1:1 EtOAc:hexane) provided the title compound as a colorless oil (5.0 g). MS (ESI, pos. ion) m/z: 439 (M+1). Calc'd for C26H34N2O4: 438.56.
Reaction SMILES: [CH3:1][C:2]([N:14]1[C:18]2[CH:19]=[C:20]([CH3:23])[CH:21]=[CH:22][C:17]=2[NH:16][C:15]1=[O:24])([CH3:13])[CH2:3][CH2:4][NH:5]C(=O)OC(C)(C)C.Cl>O1CCOCC1>[NH2:5][CH2:4][CH2:3][C:2]([N:14]1[C:18]2[CH:19]=[C:20]([CH3:23])[CH:21]=[CH:22][C:17]=2[NH:16][C:15]1=[O:24])([CH3:13])[CH3:1]
Reactant: Cc1ccc2[nH]c(=O)n(C(C)(C)CCNC(=O)OC(C)(C)C)c2c1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1ccc2[nH]c(=O)n(C(C)(C)CCN)c2c1
Temperature: 90 °C

Procedure:
A solution of 1.50 g (4.5 mmol) tert-butyl [3-methyl-3-(6-methyl-2-oxo-2,3-dihydro-benzimidazol-1-yl)-butyl]-carbamate in 100 mL dioxane is combined with 10 mL 4 molar hydrochloric acid in dioxane and then heated to 90° C. for 90 minutes, during which time a white precipitate settles out. After cooling to ambient temperature the solvent is distilled off and the residue is stirred in diethyl ether. White solid. Yield: 1.04 g (86%; hydrochloride); mass spectroscopy: [M+H]+=234.
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[C:5]([C:8]2[CH:33]=[CH:32][C:11]([O:12][CH2:13][CH2:14][CH2:15][O:16][C:17]3[CH:18]=[C:19]4[C:23](=[CH:24][CH:25]=3)[C@H:22]([CH2:26][C:27]([O:29]CC)=[O:28])[CH2:21][CH2:20]4)=[C:10]([CH2:34][CH2:35][CH3:36])[CH:9]=2)[S:6][CH:7]=1)[CH3:2].O[Li].O>C1COCC1.O.CO>[CH2:1]([C:3]1[N:4]=[C:5]([C:8]2[CH:33]=[CH:32][C:11]([O:12][CH2:13][CH2:14][CH2:15][O:16][C:17]3[CH:18]=[C:19]4[C:23](=[CH:24][CH:25]=3)[C@H:22]([CH2:26][C:27]([OH:29])=[O:28])[CH2:21][CH2:20]4)=[C:10]([CH2:34][CH2:35][CH3:36])[CH:9]=2)[S:6][CH:7]=1)[CH3:2]
Reactant: CCCc1cc(-c2nc(CC)cs2)ccc1OCCCOc1ccc2c(c1)CC[C@H]2CC(=O)OCC
Agent: [Li]O
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CCCc1cc(-c2nc(CC)cs2)ccc1OCCCOc1ccc2c(c1)CC[C@H]2CC(=O)O
Temperature: 25 °C
Reaction time: 12 h
Yield: 62.5 %

Procedure:
To a solution of ethyl ((1S-5-{3-[4-(4-ethyl-1,3-thiazol-2-yl)2-propylphenoxy]propoxy}-2,3-dihydro-1H-inden-1-yl)acetate (60 mg 0.12 mmol) (Example 147) in THF (3.0 mL) was added a solution of LiOH.H2O (20 mg, 0.48 mmol) in water (1.0 mL) and MeOH (1.0 mL), and the mixture was stirred for 12 h at rt. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with water and extracted with Et2O (3×). The aqueous phase was brought to pH 3 using HCl (1N aqueous solution), and then the aqueous layer was extracted with EtOAc. The organic phase was dried over MgSO4, filtered, and concentrated under reduced pressure to give 36 mg (63%) of the title compound as a white solid. 1H NMR (300 MHz, CD3OD): δ 0.96 (t, 3H), 1.34 (t, 3H), 1.59-1.71 (m, 2H), 1.73-1.81 (m, 1H), 2.25-2.38 (m, 2H), 2.39-2.47 (m, 2H), 2.62-2.98 (m, 7H), 3.44-3.57 (m, 1H), 4.20 (t, 2H), 4.26 (t, 2H), 6.75 (d, 1H), 6.84 (s, 1H), 7.02 (d, 1H), 7.07 (s, 1H), 7.14 (d, 1H), 7.71 (s, 1H), 7.78 (d, 1H); LC-MS: RT=4.04 min, (M+H)+ 480.2.
Reaction SMILES: C1([C@H](N)C)C=CC=CC=1.[F:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]([CH:21]([CH3:23])[CH3:22])[C:18]([OH:20])=[O:19])=[CH:13][CH:12]=1.Cl>C(#N)C.CCOCC>[F:10][C:11]1[CH:12]=[CH:13][C:14]([C@@H:17]([CH:21]([CH3:23])[CH3:22])[C:18]([OH:20])=[O:19])=[CH:15][CH:16]=1
Reactant: CC(C)C(C(=O)O)c1ccc(F)cc1
Agent: C[C@@H](N)c1ccccc1
Agent: Cl
Solvent: CC#N
Solvent: CCOCC
Product: CC(C)[C@@H](C(=O)O)c1ccc(F)cc1

Procedure:
A solution of 63.0 g (0.52 mol) of [R]-(+)-1-phenylethylamine in 800 ml of acetonitrile was added with stirring to a solution of 204.1 g (1.04 mol) of rac. 2-(p-fluorophenyl)-3-methylbutyric acid in 1200 ml of acetonitrile. After 1 hour the crystalline precipitate was filtered off, washed with 300 ml of acetonitrile and dried overnight under reduced pressure at 50°. After repeated recrystallization from ethanol, the corresponding salt was obtained as colorless crystals, m.p. 209°-210°. The salt was suspended in ether and treated with 3N hydrochloric acid to pH 1. The ethereal solution was washed with water, dried and evaporated under reduced pressure, yielding [R]-(-)-2-(p-fluorophenyl)-3-methylbutyric acid, m.p. 56°-57°; [α]D20 =-48.4° (c=1, methanol).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH3:22])[C:7](=[O:21])[C:8]3[CH:18]=[C:17]([CH:19]=[O:20])[CH:16]=[N:15][C:9]=3[N:10]([CH2:13][CH3:14])[C:11]=2[N:12]=1.O.[BH4-].[Na+]>O1CCCC1.[Cl-].[Na+].O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH3:22])[C:7](=[O:21])[C:8]3[CH:18]=[C:17]([CH2:19][OH:20])[CH:16]=[N:15][C:9]=3[N:10]([CH2:13][CH3:14])[C:11]=2[N:12]=1
Reactant: CCN1c2ncc(C=O)cc2C(=O)N(C)c2ccc(Cl)nc21
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCN1c2ncc(CO)cc2C(=O)N(C)c2ccc(Cl)nc21
Reaction time: 0.5 h
Yield: 88.7 %

Procedure:
To a solution of 2-chloro-5,11-dihydro-11-ethyl-8-formyl-5-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one (0.5822 g, 1.84 mmol) in tetrahydrofuran (20 mL) was added water (0.1 mL) followed by sodium borohydride (0.0695 g, 1.84 mmol). The mixture was stirred for 0.5 hour then diluted with brine (20 mL) and extracted with dichloromethane (3×30 mL). The combined organics were dried, concentrated and the residue was purified by flash chromatography (gradient hexanes to ethyl acetate to yield the title compound (0.52 g, 89%), m.p. 166°-168° C.
Reaction SMILES: [CH:1]([C:4]([CH3:19])([N:8]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=O)[C:5]([NH2:7])=[O:6])([CH3:3])[CH3:2].O.CCCCCC>C1(C)C=CC=CC=1>[CH:1]([C:4]1([CH3:19])[N:8]2[C:16](=[O:17])[C:15]3[C:10]([C:9]2=[N:7][C:5]1=[O:6])=[CH:11][CH:12]=[CH:13][CH:14]=3)([CH3:3])[CH3:2]
Reactant: CC(C)C(C)(C(N)=O)N1C(=O)c2ccccc2C1=O
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCCCCC
Product: CC(C)C1(C)C(=O)N=C2c3ccccc3C(=O)N21
Temperature: 100 °C
Yield: 81.5 %

Procedure:
A solution of 130.1 g (0.5 mole) of α-isopropyl-α-methyl-1,3-dioxo-2-isoindolineacetamide in 650 ml toluene is heated with vigorous stirring under a Dean-Stark water separator in order to remove traces of water. The solution was cooled to 100° C and 2.0 g sodium hydroxide in the form of pels is added and the mixture rapidly heated to reflux. Water collects in the water separator. One-half hour after the addition of the sodium hydroxide, a further 2 g is added and heating is continued for a further 11/4 hours when no further water is removed from the reaction mixture and the infrared spectrum of an aliquot indicates the reaction to be complete. The reaction mixture is cooled to room temperature, filtered and the solids washed with toluene and the toluene removed in vacuo to leave a white solid which is transferred to a filter funnel with hexane and air-dried to give 98.7 g of 3-isopropyl-3-methyl-3H-imidazo[2,1-a]isoindole-2,5-dione, melting point 93°-96° C. The product may be purified by recrystallization from hexane to give an analytically pure sample, melting point 98°-100.5° C.
Reaction SMILES: [CH3:1][SiH:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C([O:18][CH2:19][CH:20]=[CH2:21])(=O)C>C(O)(C)C.[H+].[H+].Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl>[OH:18][CH2:19][CH2:20][CH2:21][Si:2]([CH3:1])([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C[SiH](c1ccccc1)c1ccccc1
Reactant: C=CCOC(C)=O
Agent: Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl
Agent: [H+]
Solvent: CC(C)O
Product: C[Si](CCCO)(c1ccccc1)c1ccccc1
Reaction time: 2 h
Yield: 51.7 %

Procedure:
Methyldiphenylsilane (100 g, 0.49 mol) was added at 90° over a period of 4 hrs, with stirring, to a mixture of 100 g (1.0 mol) of allyl acetate and 0.10 ml of a 0.1 M chloroplatinic acid solution in isopropanol. When half of the methyldiphenylsilane was added an additional 0.10 ml of the chloroplatinic acid solution was added. Excess allyl acetate was distilled 15 min. after the addition was completed. The residue was dissolved in 150 ml of methanol and a solution of 20 g of sodium hydroxide in 40 ml of water was added dropwise. After the mixture was stirred for 2 hrs, 200 ml of water was added, and the mixture was neutralized with hydrochloric acid. The product was extracted with methylene chloride, dried over magnesium sulfate and distilled to give 65 g (50%) of (3-hydroxypropyl) methyldiphenylsilane, bp 130°-140° (0.03 to 0.07 mm). p-Toluenesulfonyl chloride 3.5 g, 0.184 mol) was added to a solution of 29 g (0.118 mol) of (3-hydroxypropyl)methyldiphenylsilane and 14.6 g (0.184 mol) of pyridine in 60 ml of methylene chloride at 0°. The mixture was kept at 0°-5° for 18 hrs and 40 ml of ice water was added. The water layer was extracted with 40 ml of methylene chloride, and the combined organic layers were washed with 2-30 ml portions of water. Solvent was removed and the product was crystallized from ether to give 46 g (95%) (3-propyl)methyldiphenyl p-toluenesulfonate, mp 68°-69°.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[N:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=13)[C:6]([CH2:13][CH3:14])=[C:5]2[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1.C([Li])(C)(C)C.CCCCC.CN(C)[C:35](=[O:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.[Cl-].[NH4+]>O1CCCC1>[C:35]([C:2]1[CH:3]=[C:4]2[N:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=13)[C:6]([CH2:13][CH3:14])=[C:5]2[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)(=[O:42])[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: CN(C)C(=O)c1ccccc1
Reactant: CCc1c(-c2ccc(OC)cc2)c2cc(Br)c3cccc1n32
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCC
Product: CCc1c(-c2ccc(OC)cc2)c2cc(C(=O)c3ccccc3)c3cccc1n32
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 39.5 %

Procedure:
4-Bromo-1-ethyl-2-(4-methoxyphenyl)pyrrolo[2,1,5-cd]indolizine (0.345 g, 1.0 mmol), was dissolved in 10 ml of dry tetrahydrofuran under a nitrogen atmosphere, and the solution was cooled to -78° C., while 1.35 M t-butyllithium in pentane (1.5 ml, 2.03 mmol) was added slowly. The orange solution was stirred for 30 minutes at -78° C. N,N-dimethylbenzamide (0.19 g, 1.27 mmol) dissolved in 5 ml of tetrahydrofuran was added and the reaction was stirred for 20 minutes. The reaction mixture was heated to room temperature, and stirred for 2 days. The mixture was poured into 50 ml of a saturated ammonium chloride solution and the organic material was extracted into dichloromethane (4×50 ml). The combined organic layers was washed with brine, dried overmagnesium sulfate, and evaporated to a yellow gum. The crude product was purified by column chromatography over silica gel 60, using 20% of diethyl ether in hexane as the eluent to afford 0.15 g (40%) of 4-benzoyl-1-ethyl-2-(4-methoxyphenyl)pyrrolo[2,1,5-cd]indolizine as a yellow solid. MS(SP): m/z 379 (M+). 1H--NMR (CDCl3, 200 MHz) δ: 1.47 (t, 3 H); 3.21 (q, 2 H); 3.89 (s, 3 H); 7.08 (d, 2 H); 7.46-7.60 (m,3 H); 7.69 (d, 2 H); 7.81-7.98 (m, 5 H); 8.39 (dd, 1 H).
Reaction SMILES: C(N(C(C)C)CC)(C)C.[Br:10][C:11]1[CH:12]=[C:13]([NH:17][C:18]2[C:27]3[C:22](=[CH:23][C:24]([O:32][CH3:33])=[C:25]([O:28][CH2:29][CH2:30]Br)[CH:26]=3)[N:21]=[CH:20][N:19]=2)[CH:14]=[CH:15][CH:16]=1.[OH:34][C@@H:35]([CH3:46])[CH2:36][NH:37][CH2:38][C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40]>C(#N)C>[Br:10][C:11]1[CH:12]=[C:13]([NH:17][C:18]2[C:27]3[C:22](=[CH:23][C:24]([O:32][CH3:33])=[C:25]([O:28][CH2:29][CH2:30][N:37]([CH2:38][C:39]([O:41][C:42]([CH3:43])([CH3:45])[CH3:44])=[O:40])[CH2:36][C@@H:35]([OH:34])[CH3:46])[CH:26]=3)[N:21]=[CH:20][N:19]=2)[CH:14]=[CH:15][CH:16]=1
Reactant: C[C@H](O)CNCC(=O)OC(C)(C)C
Reactant: COc1cc2ncnc(Nc3cccc(Br)c3)c2cc1OCCBr
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COc1cc2ncnc(Nc3cccc(Br)c3)c2cc1OCCN(CC(=O)OC(C)(C)C)C[C@H](C)O
Temperature: 50 °C
Reaction time: 8 h

Procedure:
0.25 ml of diisopropylethylamine are added to 650 mg of 4-[(3-bromo-phenyl)amino]-6-(2-bromoethoxy)-7-methoxy-quinazoline and 1.10 g of tert.butyl (S)-(2-hydroxy-propylamino)-acetate in 15 ml of acetonitrile. The reaction mixture is stirred overnight at 50° C. Since no reaction can be detected, the reaction mixture is concentrated by evaporation, combined with 20 ml of N,N-dimethylformamide and stirred for eight hours at 60° C. Then the temperature is increased to 80° C. After another eight hours the reaction is complete. The reaction mixture is concentrated by evaporation and chromatographed over a silica gel column with ethyl acetate as eluant. The desired product is obtained as a white solid.
Reaction SMILES: C([O:3][C:4](=[O:28])[CH2:5][CH2:6][NH:7][C:8]([NH:10][C:11](=[O:27])[CH:12]([C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=1)[CH2:13][CH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:9])C.[OH-].[K+]>C(O)C.O>[CH:14]1([CH2:13][CH:12]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=2)[C:11]([NH:10][C:8](=[O:9])[NH:7][CH2:6][CH2:5][C:4]([OH:28])=[O:3])=[O:27])[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: CCOC(=O)CCNC(=O)NC(=O)C(CC1CCCC1)c1ccc(Cl)c(Cl)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)CCNC(=O)NC(=O)C(CC1CCCC1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 34 %

Procedure:
A solution of 3-{3-[3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionyl]-ureido}-propionic acid ethyl ester (prepared in Example 12B-c, 94 mg, 0.22 mmol) in ethanol (5 mL) at 25° C. was treated with a solution of potassium hydroxide (43 mg, 0.77 mmol) in water (1 mL). This solution was stirred at 25° C. for 2 h. At this time, the reaction was diluted with water (5 mL) and the ethanol was removed in vacuo. The aqueous layer was acidified to pH=2 with a 1N aqueous hydrochloric acid solution and extracted with methylene chloride (3×15 mL). The organic layers were then dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 50/50 hexanes/ethyl acetate plus 1% acetic acid) afforded 3-{3-[3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionyl]-ureido}-propionic acid (30 mg, 35%) as a white foam: FAB-HRMS m/e calcd for C18H22Cl2N2O4 (M+H)+401.1035, found 401.1022.
Reaction SMILES: [F:1][CH:2]([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]([OH:14])=O)=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[NH2:26][C:27]1[CH:28]=[C:29]([S:34]([NH2:37])(=[O:36])=[O:35])[CH:30]=[CH:31][C:32]=1[Cl:33]>>[Cl:33][C:32]1[CH:31]=[CH:30][C:29]([S:34](=[O:35])(=[O:36])[NH2:37])=[CH:28][C:27]=1[NH:26][C:12]([C:11]1[CH:10]=[N:9][N:8]2[C:3]([CH:2]([F:1])[F:25])=[CH:4][C:5]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:17][CH:16]=3)=[N:6][C:7]=12)=[O:14]
Reactant: O=C(O)c1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: Nc1cc(S(N)(=O)=O)ccc1Cl
Product: NS(=O)(=O)c1ccc(Cl)c(NC(=O)c2cnn3c(C(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)c1

Procedure:
The title compound was prepared from 7-difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.1) and 3-amino-4-chloro-benzenesulfonamide [CAS-No. 29092-34-0; commercially available] according to general procedure II. Light yellow solid. MS (ISP) 545.1 [(M−H−]; mp 286° C.
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[N:9]([CH2:10][C:11]2[NH:15][N:14]=[N:13][N:12]=2)[C:8]2[CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[S:18][C:7]=2[C:6](=[O:25])[N:5]1[CH:26]1[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]1.[CH3:39][O:40][CH2:41]Cl>C1COCC1.CN(C=O)C>[CH3:39][O:40][CH2:41][N:13]1[N:14]=[N:15][C:11]([CH2:10][N:9]2[C:8]3[CH:16]=[C:17]([C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)[S:18][C:7]=3[C:6](=[O:25])[N:5]([CH:26]3[CH2:27][CH2:28][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:30][CH2:31]3)[C:4]2=[O:3])=[N:12]1
Reactant: COCCl
Reactant: CC(C)(C)OC(=O)N1CCC(n2c(=O)c3sc(-c4ccccc4)cc3n(Cc3nnn[nH]3)c2=O)CC1
Agent: CC(C)(C)OC(=O)N1CCC(n2c(=O)c3sc(-c4ccccc4)cc3n(Cc3nn[nH]n3)c2=O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COCn1nnc(Cn2c(=O)n(C3CCN(C(=O)OC(C)(C)C)CC3)c(=O)c3sc(-c4ccccc4)cc32)n1
Temperature: 50 °C
Reaction time: 16 h

Procedure:
To a stirred suspension of sodium hydride (206 mg, 60% dispersion in mineral oil) in 7 ml absolute THF in a sealed tube is added a solution of a tautomeric mixture of tert-butyl 4-[2,4-dioxo-6-phenyl-1-(1H-tetrazol-5-ylmethyl)-1,4-dihydrothieno[3,2-d]pyrimidin-3(2H)-yl]piperidine-1-carboxylate and 4-[2,4-dioxo-6-phenyl-1-(2H-tetrazol-5-ylmethyl)-1,4-dihydro-2H-thieno[3,2-d]pyrimidin-3-yl-]-piperidine-1-carboxylic acid tert-butyl ester (1.74 g; compound 14b) in absolute THF (7 ml) and absolute DMF (7 ml) at 0° C. After stirring for 40 min at 40° C. chloromethyl methyl ether (452 mg) dissolved in absolute DMF (3.5 ml) is added. The reaction mixture is stirred for 3 h at 50° C. and for 16 h at RT. The reaction is quenched by addition of a saturated aqueous solution of sodium bicarbonate and extracted with diethyl ether (two times). The combined organic phases are dried over magnesium sulfate, filtered and the solvent is removed under reduced pressure. The resulting residue is purified by flash chromatography [silica gel, eluent: cyclohexane/diethyl ether, 1/1 (v/v)] to give the separated title compounds as solids.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38])[CH2:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]2[C:19]([C:25]([F:28])([F:27])[F:26])=[N:20][C:21]([C:22]([OH:24])=O)=[C:15]2[CH2:14]1)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:39][N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1.O=C1N([ClH]P([ClH]N2CCOC2=O)=O)CCO1.C(N(CC)CC)C>ClCCl>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38])[CH2:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]2[C:19]([C:25]([F:28])([F:27])[F:26])=[N:20][C:21]([C:22]([N:43]3[CH2:44][CH2:45][N:40]([CH3:39])[CH2:41][CH2:42]3)=[O:24])=[C:15]2[CH2:14]1)=[O:12])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)O)c2C1)Cc1cc(F)c(F)cc1F
Reactant: CN1CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN1CCN(C(=O)c2nc(C(F)(F)F)n3c2CN(C(=O)C[C@@H](Cc2cc(F)c(F)cc2F)NC(=O)OC(C)(C)C)CC3)CC1
Yield: 46.8 %

Procedure:
(R)-7-[3-tert-Butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid 2a (150 mg, 0.27 mmol), 1-methylpiperazine (54 mg, 0.54 mmol) and bis(2-oxo-3-oxazolidinyl)phosphonic chloride (0.138 g, 0.54 mmol) were dissolved in 8 mL of dichloromethane under stirring, and triethylamine (0.25 mL, 1.62 mmol) was then added to the solution. The reaction mixture was reacted at room temperature overnight and monitored by thin layer chromatography until the disappearance of the starting materials. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (R)-[3-[1-(4-methyl-piperazine-1-carbonyl)-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl]-3-oxo-1-(2,4,5-trifluoro-benzyl)-propyl]-carbamic acid tert-butyl ester 5a (80 mg, yield 49%) as a white solid.