Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH2:9][C:10]([N:12]([CH:22]([CH3:24])[CH3:23])[NH:13][C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:11].C([O-])([O-])=O.[Na+].[Na+].[CH3:31][O:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1B(O)O>COCCOC>[CH3:31][O:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH2:9][C:10]([N:12]([CH:22]([CH3:24])[CH3:23])[NH:13][C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:11]
Reactant: COc1ccccc1B(O)O
Reactant: CC(C)N(NC(=O)c1ccccc1)C(=O)CSc1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1ccccc1-c1ccccc1SCC(=O)N(NC(=O)c1ccccc1)C(C)C
Yield: 55.2 %

Procedure:
A solution of benzoic acid N′-[2-(2-bromo-phenylsulfanyl)-acetyl]-N′-isopropyl-hydrazide (100 mg, 0.246 mmol) in DME (5 ml)/2M Na2CO3 (0.43 ml, 0.86 mmoles) was treated with 2-methoxyphenylboronic acid (75 mg, 0.49 mmol) and Pd[PPh3]4 (28 mg, 0.025 mmol) for 12 hours at 90° C. The reaction mixture was partitioned between water and DCM. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude was adsorbed on silica and purified on a silica gel column with a 20-50% ethyl acetate/hexane gradient to afford the product as a solid (59 mg, 54%). MS m/e 435.23 (M+H+)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:47]=[CH:46][CH:45]=[CH:44][C:4]=1[CH2:5][O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH:18]2[O:30][CH2:31][CH2:32]OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:13][CH:12]=1.[OH:48][CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=1[OH:56]>>[OH:48][CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=1[O:56][CH2:32][CH2:31][O:30][CH:18]1[CH:17]([C:14]2[CH:13]=[CH:12][C:11]([O:10][CH2:9][CH2:8][CH2:7][O:6][CH2:5][C:4]3[CH:44]=[CH:45][CH:46]=[CH:47][C:3]=3[O:2][CH3:1])=[CH:16][CH:15]=2)[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24])[CH2:19]1
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCCOS(=O)(=O)c2ccc(C)cc2)cc1
Reactant: OCc1ccccc1O
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCCOc2ccccc2CO)cc1

Procedure:
Analogously to Method G, 1.0 g of tert-butyl 4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}-3-[2-(toluene-4-sulphonyloxy)ethoxy]piperidine-1-carboxylate (Example 14b) and 0.37 g of 2-hydroxymethylphenol are reacted. The title compound is obtained as an opaque oil. Rf=0.16 (1:2 EtOAc-heptane); Rt=5.71.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][C:5]1[C:10]([CH2:11][CH3:12])=[N:9][C:8]2[N:13]([CH2:16][CH3:17])[N:14]=[CH:15][C:7]=2[C:6]=1[NH:18][CH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1.C(N(CC)C(C)C)(C)C.[CH2:34]([O:36][C:37]1[C:38](=O)[C:39](=[O:44])[C:40]=1[O:41]CC)[CH3:35]>C(O)C>[CH2:16]([N:13]1[C:8]2=[N:9][C:10]([CH2:11][CH3:12])=[C:5]([CH2:4][NH:3][C:38]3[C:39](=[O:44])[C:40](=[O:41])[C:37]=3[O:36][CH2:34][CH3:35])[C:6]([NH:18][CH:19]3[CH2:20][CH2:21][O:22][CH2:23][CH2:24]3)=[C:7]2[CH:15]=[N:14]1)[CH3:17]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CN
Reactant: CCOc1c(OCC)c(=O)c1=O
Agent: Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1c(NCc2c(CC)nc3c(cnn3CC)c2NC2CCOCC2)c(=O)c1=O
Reaction time: 8 h

Procedure:
A suspension of 5-(aminomethyl)-1,6-diethyl-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridin-4-amine dihydrochloride (0.60 g, 1.6 mmol) in ethanol (8 mL) was treated with N,N-diisopropylethylamine (DIEA, 0.57 mL, 3.3 mmol), giving a clear, homogeneous mixture, which was then cooled in an ice-water bath. 3,4-Diethoxycyclobut-3-ene-1,2-dione (TCI America, 0.41 g, 0.36 mmol) was then added dropwise via syringe. Following completion of the addition, the mixture was allowed to regain room temperature and stir overnight. The precipitated solid was collected by Büchner filtration, washed with ethanol, and dried under house vacuum to provide the title compound as a white solid. ES/MS calcd. for C22H30N5O4+ 428.2. found m/z=428.3 (M+H)+.
Reaction SMILES: C([N:14]1[CH2:17][CH:16]([O:18][Si:19]([C:32]([CH3:35])([CH3:34])[CH3:33])([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:15]1)(C1C=CC=CC=1)C1C=CC=CC=1.ClC(OC(Cl)=O)C>ClCCCl>[C:32]([Si:19]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[O:18][CH:16]1[CH2:15][NH:14][CH2:17]1)([CH3:35])([CH3:33])[CH3:34]
Reactant: CC(C)(C)[Si](OC1CN(C(c2ccccc2)c2ccccc2)C1)(c1ccccc1)c1ccccc1
Agent: CC(Cl)OC(=O)Cl
Solvent: ClCCCl
Product: CC(C)(C)[Si](OC1CNC1)(c1ccccc1)c1ccccc1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
A stirred solution of 1-benzhydryl-3-(tert-butyl-diphenyl-silanyloxy)-azetidine (162a) (4.0 g, 8.4 mmol) in DCE (60 ml) at room temperature is treated with 1-chloroethylchloroformate (1.2 ml, 10.9 mmol) and the reaction mixture is heated to 80° C. After 2 hours, the solvent is removed in vacuo and the residue is dissolved in methanol (60 ml) and heated to reflux. After 1 h the reaction mixture is poured into water (250 ml), acidified with hydrochloric acid (1M solution) and washed with EtOAc (3×75 ml). The aqueous solution is basified with saturated sodium bicarbonate solution and extracted with EtOAc (3×75 ml). The combined organic layers are washed with water (2×50 ml), brine (50 ml), dried over MgSO4. The solvent is removed in vacuo to yield the titled compound.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[F:16][C:17]1[CH:18]=[C:19]([CH:23]=[C:24]([F:27])[C:25]=1[F:26])[C:20]([OH:22])=[O:21].[CH2:28]([C@H:30]1[CH2:35][CH2:34][C@H:33]([C:36]2[CH:41]=[CH:40][C:39](O)=[CH:38][CH:37]=2)[CH2:32][CH2:31]1)[CH3:29]>ClCCl>[F:16][C:17]1[CH:18]=[C:19]([CH:23]=[C:24]([F:27])[C:25]=1[F:26])[C:20]([O:22][C:39]1[CH:38]=[CH:37][C:36]([C@H:33]2[CH2:34][CH2:35][C@H:30]([CH2:28][CH3:29])[CH2:31][CH2:32]2)=[CH:41][CH:40]=1)=[O:21]
Reactant: O=C(O)c1cc(F)c(F)c(F)c1
Reactant: CC[C@H]1CC[C@H](c2ccc(O)cc2)CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CC[C@H]1CC[C@H](c2ccc(OC(=O)c3cc(F)c(F)c(F)c3)cc2)CC1

Procedure:
1.03 g (5.00 mmol) of dicyclohexylcarbodiimide, 0.88 g (5.00 mmol) of 3,4,5-trifluorobenzoic acid and 1.02 g (5.00 mmol) of 4-(trans-4-ethylcyclohexyl)phenol are stirred at room temperature for 6 hours with 10 mg of 4-N,N-dimethylaminopyridine in 30 ml of dichloromethane. Filtration, evaporation of the solvent and purification by chromatography (silica gel/hexane) give 1.36 g of product. ##STR21## Phase sequence: X 90 (59) N (72) I
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([N:5]2[CH2:10][CH2:9][N:8]([C:11]([C:13]3[S:14][CH:15]=[CH:16][N:17]=3)=[O:12])[CH2:7][CH2:6]2)[CH2:2]1.[F:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[C:33]3[C:28](=[CH:29][C:30]([C:34](O)=[O:35])=[CH:31][CH:32]=3)[NH:27][CH:26]=2)=[CH:21][CH:20]=1.CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.O>[F:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[C:33]3[C:28](=[CH:29][C:30]([C:34]([N:1]4[CH2:2][CH:3]([N:5]5[CH2:6][CH2:7][N:8]([C:11]([C:13]6[S:14][CH:15]=[CH:16][N:17]=6)=[O:12])[CH2:9][CH2:10]5)[CH2:4]4)=[O:35])=[CH:31][CH:32]=3)[NH:27][CH:26]=2)=[CH:21][CH:20]=1
Reactant: O=C(c1nccs1)N1CCN(C2CNC2)CC1
Reactant: O=C(O)c1ccc2c(-c3ccc(F)cc3)c[nH]c2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: O=C(c1ccc2c(-c3ccc(F)cc3)c[nH]c2c1)N1CC(N2CCN(C(=O)c3nccs3)CC2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.3 %

Procedure:
To a mixture of compound 5e (42.9 mg, 0.132 mmol), compound 53e (30.6 mg, 0.12 mmol), and Et3N (0.084 mL, 0.6 mmol) in CH2Cl2 (1 mL) at room temperature was added HATU (70 mg, 0.168 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was diluted with CH2Cl2 and H2O, washed with aq. NaHCO3 and brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 2-4% MeOH/EtOAc) to give Cpd 1317 (45.4 mg). 1H NMR (400 MHz, CDCl3): δ 8.56 (br. s., 1H), 7.83-7.94 (m, 3H), 7.57-7.65 (m, 2H), 7.55 (d, J=3.2 Hz, 1H), 7.46 (d, J=2.4 Hz, 1H), 7.40-7.45 (m, 1H), 7.13-7.20 (m, 2H), 4.07-4.66 (m, 6H), 3.76-4.01 (m, 2H), 3.21-3.36 (m, 1H), 2.38-2.64 (m, 4H). MS m/z (M+H+) 490.2.
Reaction SMILES: [CH3:1][C:2]1([O:19][C@H:18]([CH2:20][O:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=2[Cl:30])[C@@H:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[Cl:17])[C@H:5]1[OH:6])[O:3][CH3:4].[CH3:31][C:32](OC(C)=O)=[O:33].O>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[CH3:1][C:2]1([O:19][C@H:18]([CH2:20][O:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=2[Cl:30])[C@@H:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[Cl:17])[C@H:5]1[O:6][C:32](=[O:33])[CH3:31])[O:3][CH3:4]
Reactant: CC(=O)OC(C)=O
Reactant: COC1(C)O[C@H](COCc2ccc(Cl)cc2Cl)[C@@H](OCc2ccc(Cl)cc2Cl)[C@H]1O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: O
Product: COC1(C)O[C@H](COCc2ccc(Cl)cc2Cl)[C@@H](OCc2ccc(Cl)cc2Cl)[C@H]1OC(C)=O

Procedure:
To the solution of raw oil from Step 2 above (173.6 g, 0.3600 mol) in 1.379 L pyridine, were added Ac2O (33.970 mL, 0.3600 mol) and DMAP (1.3766 g, 0.01127 mol). After 21 hours of stirring at room temperature 1.4 L H2O were added. The solution was acidified with 1.45 L concentrated HCL. The acidified product was extracted with EtOAc, dried with MgSO4 and concentrated in vacuo. The residue was isolated as 85.75 g (0.1636 mol) of clear oil.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH3:14])[C:11]([OH:13])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].O=S(Cl)Cl.[CH3:19][O:20][C:21](=[O:31])[C:22]1[C:27]([Cl:28])=[CH:26][C:25]([Cl:29])=[CH:24][C:23]=1[NH2:30].C(OCC)(=O)C>C(OCC)C>[CH3:19][O:20][C:21](=[O:31])[C:22]1[C:27]([Cl:28])=[CH:26][C:25]([Cl:29])=[CH:24][C:23]=1[NH:30][C:11](=[O:13])[CH:10]([C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=1)[CH3:14]
Reactant: CC(C(=O)O)c1ccc([N+](=O)[O-])cc1
Reactant: COC(=O)c1c(N)cc(Cl)cc1Cl
Solvent: CCOC(C)=O
Solvent: O=S(Cl)Cl
Solvent: CCOCC
Product: COC(=O)c1c(Cl)cc(Cl)cc1NC(=O)C(C)c1ccc([N+](=O)[O-])cc1
Yield: 99.1 %

Procedure:
The objective compound was prepared by the same procedure for the intermediate 1, using a 2-(4-nitro-phenyl)-propionic acid (1.40 g, 7.17 mmol), SOCl2 (5.1 mL, 71.7 mmol), and 2-amino-4,6-dichloro-benzoic acid methyl ester (1.6 g, 5.74 mmol). After normal workup, the pure objective compound (2.26 g, 99%) was obtained as pale yellow solid by recrystallization (ethyl acetate:ethyl ether=1:5): 1H NMR (200 MHz, CDCl3) δ 1.63 (d, J=7.1 Hz, 3H, CH3), 3.85-3.86 (m, 4H, CO2CH3 & CH), 7.18 (d, J=2.0 Hz, 1H, ArH), 7.54 (d, J=8.7 Hz, 2H, ArH), 8.24 (d, J=8.7 Hz, 2H, ArH), 8.45 (d, J=2.0 Hz, 1H, ArH), 9.59 (br s, 1H, ArH).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C@@H:4]([O:15][CH2:16][CH3:17])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]=1[CH2:13][CH3:14].Cl[CH2:20][C:21]1[N:22]=[C:23]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[O:24][C:25]=1[CH3:26].C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+]>>[CH3:1][O:2][C:3](=[O:18])[C@@H:4]([O:15][CH2:16][CH3:17])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:20][C:21]2[N:22]=[C:23]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[O:24][C:25]=2[CH3:26])=[CH:8][C:7]=1[CH2:13][CH3:14]
Reactant: Cc1oc(-c2ccccc2)nc1CCl
Reactant: CCO[C@@H](Cc1ccc(O)cc1CC)C(=O)OC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Product: CCO[C@@H](Cc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1CC)C(=O)OC

Procedure:
In analogy to the procedure described in example 1 f], (2S)-2-ethoxy-3-(2-ethyl-4-hydroxy-phenyl)-propionic acid methyl ester was reacted with 4-chloromethyl-5-methyl-2-phenyl-oxazole in the presence of cesium carbonate and potassium iodide to yield (S)-2-ethoxy-3-[2-ethyl-4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl]-propionic acid methyl ester as colorless liquid.
Reaction SMILES: Cl[CH2:2][C:3]([O:5][CH:6]1[CH:10]2[O:11][C:12](=[O:22])[CH:13]3[CH:14]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:7]1[CH2:8][CH:9]23)=[O:4].[C:23]([OH:28])(=[O:27])[C:24]([CH3:26])=[CH2:25].C(N(CC)CC)C.O>CN(C)C=O.[I-].[Na+]>[C:23]([O:28][CH2:2][C:3]([O:5][CH:6]1[CH:10]2[O:11][C:12](=[O:22])[CH:13]3[CH:14]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:7]1[CH2:8][CH:9]23)=[O:4])(=[O:27])[C:24]([CH3:26])=[CH2:25]
Reactant: C=C(C)C(=O)O
Reactant: CC(C)(C)OC(=O)C1C2CC3C(OC(=O)C31)C2OC(=O)CCl
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: C=C(C)C(=O)OCC(=O)OC1C2CC3C1OC(=O)C3C2C(=O)OC(C)(C)C
Yield: 91.3 %

Procedure:
In 800 ml of dimethylformamide were dissolved 199 g of the 2-chloroacetate obtained in Example 1-6-1, 64.8 g of methacrylic acid, and 4.50 g of sodium iodide. To the solution below 30° C., 73.1 g of triethylamine was added dropwise. The reaction solution was stirred at the temperature overnight, whereupon 500 ml of deionized water below 30° C. was added, followed by ordinary workup. Recrystallization from hexane yielded 209 g of the title compound. Yield 91%.
Reaction SMILES: Cl[CH2:2][Si:3]([CH3:6])([CH3:5])[CH3:4].[Li].C[Si](C[Li])(C)C.[CH3:14][C:15]1[C:16](=[O:26])[C:17]([CH3:25])([CH3:24])[CH2:18][CH:19]2[C:23]=1[O:22][CH2:21][O:20]2>CCCCC.O1CCCC1.O>[CH3:14][C:15]1[C:16]([CH2:2][Si:3]([CH3:6])([CH3:5])[CH3:4])([OH:26])[C:17]([CH3:25])([CH3:24])[CH2:18][CH:19]2[C:23]=1[O:22][CH2:21][O:20]2
Reactant: C[Si](C)(C)CCl
Reactant: CC1=C2OCOC2CC(C)(C)C1=O
Agent: [Li]
Agent: [Li]C[Si](C)(C)C
Solvent: CCCCC
Solvent: O
Solvent: C1CCOC1
Product: CC1=C2OCOC2CC(C)(C)C1(O)C[Si](C)(C)C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 100 %

Procedure:
24.7 ml (20.6 g, 0.17 mol) of chloromethyltrimethylsilane were reacted with 2.92 g (0.42 mol) of lithium powder in 150 ml of pentane (according to the method described in Example 3). The resulting solution of trimethylsilylmethyllithium (about 0.14 mol) in pentane was placed in a 500 ml flask under argon gasification. A solution of 20 g (0.11 mol) of 4,6,6-trimethyl-5,6,7,7a-tetrahydro-1,3-benzodioxol-5-one in 25 ml of tetrahydrofuran was added thereto at −20° C. within about 20 minutes. After a further 20 minutes, the mixture was warmed slowly to room temperature and then cooled to 0° C. Thereafter, 90 ml of water were added dropwise thereto. Subsequently, the water was separated in a water separator and extracted twice with 100 ml of pentane each time. The pentane phases were washed in succession with sodium bicarbonate solution and sodium chloride solution, dried over anhydrous sodium sulphate and concentrated. The crude product (31.9 g) was then crystallized in 60 ml of pentane and cooled to −25° C. The resulting white crystals were filtered off, washed with a small amount of pentane at −20° C. and dried at room temperature under a high vacuum. This gave 30.5 g (almost 100% yield) of 4,6,6-trimethyl-5,6,7,7a-tetrahydro-5-trimethylsilylmethyl-1,3-benzodioxol-5-ol as white crystals, m.p. 63-64.5° C. IR (Nujol, cm−1): 3510 (OH); mass spectrum: 253 (M+-OH, 5), 214 (M-C4H8); 1H-NMR (C6D6, 400 MHz): inter alia 0.27 (s, 9H), 4.9 (s, 1H), 5.19 (s, 1H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:33])[C:25]4[C:30](F)=[CH:29][CH:28]=[CH:27][C:26]=4F)[CH:20]=[CH:21][CH:22]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1.CN(C)CCO[C:39]1[CH:45]=[CH:44][C:42]([NH2:43])=[CH:41][CH:40]=1>>[CH2:2]1[C:40]2[C:39](=[CH:45][CH:44]=[C:42]([NH:43][C:2]3[N:7]=[C:6]([C:8]4[C:9]([C:17]5[CH:18]=[C:19]([NH:23][C:24](=[O:33])[C:25]6[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=6)[CH:20]=[CH:21][CH:22]=5)=[N:10][N:11]5[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=45)[CH:5]=[CH:4][N:3]=3)[CH:41]=2)[CH2:5][CH2:4][NH:3]1
Reactant: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Cl)n2)c1)c1c(F)cccc1F
Reactant: CN(C)CCOc1ccc(N)cc1
Product: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3ccc4c(c3)CNCC4)n2)c1)c1ccccc1

Procedure:
The title compound was prepared from N-{3-[3-(2-chloro-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]phenyl}-2,6-difluorobenzamide and 4-{[2-(dimethylamino)ethyl]oxy}aniline in a manner analogous to Example 64. 1H NMR (400 MHz, DMSO-d6) δ 2.30 (s, 6H), 2.71 (t, 2H, J=5.7 Hz), 4.05 (t, 2H, J=5.7 Hz), 6.54 (d, 1H, J=5.2 Hz), 6.87 (d, 2H, J=9.0 Hz), 7.15 (t, 1H, J=6.9 Hz), 7.29 (t, 2H, J=7.9 Hz), 7.37 (d, 1H, J=7.7 Hz), 7.47-7.66 (m, 5H), 7.86 (d, 1H, J=8.0 Hz), 8.04 (s, 1H), 8.26 (d, 1H, J=5.2 Hz), 8.46 (bd, 1H, J=8.9 Hz), 8.87 (d, 1H, J=6.9 Hz), 9.39 (s, 1H), 10.98 (s, 1H); ESIMS (M+H)+=606.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]=[C:11]1[NH:19][CH:20]1[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][NH:28]C(=O)OCC)[CH2:22][CH2:21]1.[BrH:34]>O>[BrH:1].[BrH:34].[BrH:1].[NH2:28][CH2:27][CH2:26][N:23]1[CH2:24][CH2:25][CH:20]([NH:19][C:11]2[N:10]([CH2:9][C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[Br:1])[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[N:12]=2)[CH2:21][CH2:22]1
Reactant: CCOC(=O)NCCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2Br)CC1
Agent: Br
Solvent: O
Product: NCCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2Br)CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 65 %

Procedure:
A mixture of 33 parts of ethyl [2-[4-[[1-[(2-bromo-4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinyl ]ethyl]carbamate and 750 parts of a hydrobromic acid solution 48% in water was stirred overnight at 80° C. The reaction mixture was evaporated. The residue was crystallized from ethanol. The product was filtered off and dried, yielding 22.5 parts (65%) of N-[1-(2-aminoethyl)-4-piperidinyl]-1-[(2-bromo-4-fluorophenyl)methyl]-1H-benzimidazol-2-amine trihydrobromide.monohydrate; mp. 224.7° C. (164).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH:11]=O)=[CH:8][C:6]=2[N:7]=1.[CH3:19][C:20]1([CH3:30])[NH:25][CH2:24][CH2:23][N:22]([CH:26]2[CH2:29][O:28][CH2:27]2)[CH2:21]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH2:11][N:25]3[CH2:24][CH2:23][N:22]([CH:26]4[CH2:29][O:28][CH2:27]4)[CH2:21][C:20]3([CH3:30])[CH3:19])=[CH:8][C:6]=2[N:7]=1
Reactant: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: CC1(C)CN(C2COC2)CCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CC1(C)CN(C2COC2)CCN1Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Temperature: 25 °C
Yield: 49 %

Procedure:
A mixture of 2-chloro-4-morpholin-4-ylthieno[3,2-d]pyrimidine-6-carbaldehyde (400 mg, 1.42 mmol), 3,3-dimethyl-1-oxetan-3-ylpiperazine (290 mg, 1.71 mmol) and 4 Å powdered molecular sieves (500 mg) in DCE (20 mL) were allowed to stir at r.t. 3 h before the addition of sodium triacetoxyborohydride (420 mg, 1.98 mmol). The resulting mixture was allowed to stir for 18 h then filtered through Celite®. The filtrate was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH. The resulting residue was purified by column chromatography (Si—PCC, MeOH:EtOAc, 0-10%) affording the title compound as a cream solid (305 mg, 49%)._LCMS (method H): RT 2.12 min, [M+H]+ 438.3
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.[C:9]1(B(O)O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[Br:8][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=1
Reactant: OB(O)c1ccccc1
Reactant: Brc1cncc(Br)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Brc1cncc(-c2ccccc2)c1
Temperature: 25 °C

Procedure:
Portions of 3,5-dibromopyridine (1.0 g, 4.22 mmol), phenylboronic acid (570 mg, 4.6 mmol) and palladium tetra(triphenylphosphine) (60 mg) were combined in toluene (20 mL) with aqueous sodium carbonate solution (2M, 3.0 mL) and heated at reflux for 6 hours. The mixture was cooled to ambient temperature, and the solvent was removed. The residue was purified by chromatography (silica gel, eluting with ether:hexane 1:10 to give the title compound: MS (CI/NH3) m/z: 234/236 (M+H)+, 251/153 (M+NH4)+ ; 1H NMR (CDCl3, 300 MHz) δ7.21-8.02 (dd, J=2.0, 2.0 Hz), 8.65 (d, J=2.0 Hz), 8.75 (d, J=2.0 Hz).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:8]1[N:13]=[C:12]([N:14]([CH2:17][CH3:18])[CH2:15][CH3:16])[CH:11]=[CH:10][N:9]=1>C(O)C>[CH2:17]([N:14]([CH2:15][CH3:16])[C:12]1[CH:11]=[CH:10][N:9]=[C:8]([N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)[N:13]=1)[CH3:18]
Reactant: C1CNCCN1
Reactant: CCN(CC)c1ccnc(Cl)n1
Solvent: CCO
Product: CCN(CC)c1ccnc(N2CCNCC2)n1
Yield: 63.3 %

Procedure:
A solution of piperazine (5.8 g, 67.33 mmol) and N-(2-chloro-4-pyrimidinyl)-N,N-diethylamine (5.0 g, 26.93 mmol; preparation see: L. Strekowski, Pol. J. Chem. 1980, 54, 1557–62) in ethanol (200 ml) is heated at 100° C. for 16 hours. The mixture is then concentrated under reduced pressure and extracted with water/ethyl acetate. The organic phase is washed with saturated sodium chloride solution, dried over sodium sulphate, filtered and concentrated under reduced pressure. Silica gel chromatography (mobile phase: dichloromethane/methanol) gives 4.01 g of the product (63%) as a yellow oil.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[N:7][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:9][CH:10]=1)=O.[C:17]([NH2:25])(=[S:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(O)C>[C:18]1([C:17]2[S:24][CH:2]=[C:3]([C:5]3[CH:6]=[N:7][C:8]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)=[N:9][CH:10]=3)[N:25]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(CBr)c1cnc(-c2ccccc2)nc1
Reactant: NC(=S)c1ccccc1
Solvent: CCO
Product: c1ccc(-c2ncc(-c3csc(-c4ccccc4)n3)cn2)cc1
Temperature: 25 °C
Yield: 45.8 %

Procedure:
A mixture consisting of 2-bromo-1-(2-phenylpyrimidin-5-yl)ethanone (Example 14, Step B, 50 mg, 0.18 mmol), thiobenzamide (TCl America, 25 mg, 0.18 mmol) and absolute ethanol (4 mL) in a capped scintillation vial was heated to near boiling for several minutes and was subsequently allowed to cool to room temperature. A white solid precipitated within minutes. The precipitate was collected by vacuum filtration. Light ethanol rinse, suction, and drying under high vacuum at room temperature afforded the title compound (26 mg, 46% yield) as an off-white solid; melting point 214.4-216.1° C.; 1H-NMR (400 MHz; DMSO-d6) δ 9.54 (s, 2H), 8.54 (s, 1H), 8.47 (m, 2H), 8.08 (m, 2H), 7.62-7.54 (m, 6H); LC/MS (ESI+) m/z 316.1, (ESI−) m/z 337.2 (M−1+Na+); H-PGDS FPBA IC50: >20 μM.
Reaction SMILES: [C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:2]([C:7](Cl)=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.[NH2:16][C:17]1[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[C:19]([Cl:27])[CH:18]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:2]([C:7]([NH:16][C:17]2[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[C:19]([Cl:27])[CH:18]=2)=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(Cl)c1ccccc1-c1ccccc1
Reactant: COC(=O)c1ccc(N)cc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1ccc(NC(=O)c2ccccc2-c2ccccc2)cc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 30.3 %

Procedure:
A solution of 2.37 g of [1,1'-biphenyl]-2-carbonyl chloride in 10 ml of methylene chloride is added dropwise to an ice cold solution of 1.84 g of methyl 4-amino-2-chlorobenzoate and 1.49 g of N,N-diisopropylethylamine in 50 ml of methylene chloride. The reaction mixture is stirred at room temperature for 18 hours and washed with water, saturated aqueous NaHCO3 and the organic layer dried(Na2SO4). The organic layer is passed through a pad of hydrous magnesium silicate and hexane added at the boil to give 1.1 g of the desired product as a crystalline solid, m.p. 132°-134° C. M+H=365