Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:15][NH:16][CH3:17])[C:5]([Cl:18])=[CH:4][N:3]=1.C(O[C:23](=[O:25])[CH3:24])(=O)C.N1C=CC=CC=1>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:15][N:16]([CH3:17])[C:23](=[O:25])[CH3:24])[C:5]([Cl:18])=[CH:4][N:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: CNCc1ccccc1Nc1nc(Cl)ncc1Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(=O)N(C)Cc1ccccc1Nc1nc(Cl)ncc1Cl
Yield: 24 %

Procedure:
A solution of (2,5-dichloro-pyrimidin-4-yl)-(2-methylaminomethyl-phenyl)-amine in THF (25 mL) was treated with acetic anhydride (60 mg, 0.59 mmol, 1.2 eq) and pyridine (50 mg, 0.63 mmol, 1.3 eq.) at 25° C. for 2 h. The solvent was evaporated and the residue was purified by semi-preparative HPLC to give N-[2-(2,5-dichloro-pyrimidin-4-ylamino)-benzyl]-N-methyl-acetamide (40 mg, 0.12 mmol, 24%). 1H NMR (300 MHz, CDCl3): δ 8.22 (s, 1H), 7.73 (d, 1H), 7.3 (m, 3H), 4.48 (s, 2H), 3.24 (s, 3H), 2.12 (s, 3H); MS (m/e) 325 (M+1).
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[CH2:9]([O:11][C:12](=[O:25])[CH2:13][CH:14]1[C:19](=[O:20])[NH:18][C:17]2[CH:21]=[CH:22][CH:23]=[CH:24][C:16]=2[S:15]1)[CH3:10].Br[CH2:27][C:28]([OH:30])=[O:29].Cl>C1COCC1.C(OCC)C>[C:28]([CH2:27][N:18]1[C:19](=[O:20])[CH:14]([CH2:13][C:12]([O:11][CH2:9][CH3:10])=[O:25])[S:15][C:16]2[CH:24]=[CH:23][CH:22]=[CH:21][C:17]1=2)([OH:30])=[O:29]
Reactant: CCOC(=O)CC1Sc2ccccc2NC1=O
Reactant: O=C(O)CBr
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOC(=O)CC1Sc2ccccc2N(CC(=O)O)C1=O
Reaction time: 2 h
Yield: 50 %

Procedure:
To a solution of LDA (2M) in THF (3.26 mmol) in 2 mL of anhydrous THF at 0° C. and under nitrogen, a solution of (3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-2-yl)-acetic acid ethyl ester (1.62 mmol) in 4 mL of dry THF is added dropwise. The temperature of the reaction mixture is held at room temperature for 2 hours and then dropped to −78° C. A solution of 2-bromo acetic acid (1.64 mmol) in 2 mL of anhydrous THF is added and the temperature of the reaction is slowly let to rise to room temperature. HCl (1M) is added to reach pH=1. Ethyl ether is added and the phases are separated. The organic phase is dried on Na2SO4, the drying agent is filtered and the solvent evaporated. The crude product is purified by automated column chromatography (hexane/EtOAc) to give the product ethyl 2-(3,4-dihydro-4-(carboxymetyl)-3-oxo-2H-benzo[b][1,4]thiazin-2-yl)acetate. Yield: 50%. 1H NMR (400 MHz, CDCl3): δ 9.07 (bs, 1H), 7.38 (d, J=7.6 Hz, 1H), 7.27 (t, J=7.6 Hz, 1H), 7.07 (t, J=7.6 Hz, 1H), 6.93 (d, J=7.6 Hz, 1H), 4.69 (dd, 2H), 4.18 (dd, 2H), 3.99 (t, J=6.4 Hz, 1H), 3.04 (dd, J1=6.4 Hz, J2=16.8 Hz, 1H), 2.58 (dd, 1H), 1.26 (m, 3H).
Reaction SMILES: O[C:2]1[C:7]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:9])=[CH:6][N:5]=[C:4]2[N:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:17]=[CH:18][C:3]=12.P(Cl)(Cl)([Cl:27])=O.[OH-].[Na+]>>[Cl:27][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:9])=[CH:6][N:5]=[C:4]2[N:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:17]=[CH:18][C:3]=12
Reactant: O=C(c1ccccc1)c1cnc2c(cnn2-c2ccccc2)c1O
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(c1ccccc1)c1cnc2c(cnn2-c2ccccc2)c1Cl
Temperature: 110 °C
Reaction time: 1.5 h
Yield: 66 %

Procedure:
A mixture of (4-hydroxy-1-phenyl-1H-pyrazolo[3,4-b]pyridin-5-yl)(phenyl)methanone (0.38 g, 1.2 mmol) and phosphorus oxychloride (1.3 mL) was stirred at 110° C. for 1.5 hr. The mixture was cooled, poured onto ice, basified with sodium hydroxide aqueous solution to pH=8, and extracted with ethyl acetate. Combined extracts were dried (Na2SO4) and concentrated. Flash chromatography gave (4-chloro-1-phenyl-1H-pyrazolo[3,4-b]pyridin-5-yl)(phenyl)methanone (0.26 g, 0.79 mmol, 66% yield) as a yellow solid.
Reaction SMILES: [CH3:1][N:2]([CH3:21])[C:3]([C:5]1[N:14]([CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[C:8]2[N:9]=[C:10](Cl)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].[CH3:22][O:23][C:24](=[O:32])[C:25]1[CH:30]=[CH:29][C:28]([NH2:31])=[N:27][CH:26]=1>>[CH3:22][O:23][C:24](=[O:32])[C:25]1[CH:30]=[CH:29][C:28]([NH:31][C:10]2[N:11]=[CH:12][C:7]3[CH:6]=[C:5]([C:3](=[O:4])[N:2]([CH3:21])[CH3:1])[N:14]([CH:15]4[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]4)[C:8]=3[N:9]=2)=[N:27][CH:26]=1
Reactant: CN(C)C(=O)c1cc2cnc(Cl)nc2n1C1CCCCC1
Reactant: COC(=O)c1ccc(N)nc1
Product: COC(=O)c1ccc(Nc2ncc3cc(C(=O)N(C)C)n(C4CCCCC4)c3n2)nc1
Yield: 65.1 %

Procedure:
Following general N—C coupling procedure 1, 2-chloro-7-cyclohexyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (800 mg, 2.61 mmol), was combined with 6-amino-nicotinic acid methyl ester (397 mg, 2.61 mmol) which gave 6-(7-cyclohexyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-nicotinic acid methyl ester (720 mg, 1.70 mmol) in 65% yield. MS m/z 423.6 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[C:9]1[C:14]([C:15]2[O:19][N:18]=[C:17]([C:20]3[CH:25]=[CH:24][C:23]([CH2:26][N:27]([CH3:35])[C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:22][C:21]=3[F:36])[CH:16]=2)=[CH:13][C:12](B2OC(C)(C)C(C)(C)O2)=[CH:11][N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:54]1[CH:59]=[CH:58][C:57]([S:60]([CH:63]([CH3:65])[CH3:64])(=[O:62])=[O:61])=[CH:56][N:55]=1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:49]([O:48][C:46]([N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:9]1[C:14]([C:15]2[O:19][N:18]=[C:17]([C:20]3[CH:25]=[CH:24][C:23]([CH2:26][N:27]([CH3:35])[C:28](=[O:34])[O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[CH:22][C:21]=3[F:36])[CH:16]=2)=[CH:13][C:12]([C:54]2[CH:59]=[CH:58][C:57]([S:60]([CH:63]([CH3:65])[CH3:64])(=[O:61])=[O:62])=[CH:56][N:55]=2)=[CH:11][N:10]=1)=[O:47])([CH3:51])([CH3:50])[CH3:52]
Reactant: CN(Cc1ccc(-c2cc(-c3cc(B4OC(C)(C)C(C)(C)O4)cnc3N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)on2)c(F)c1)C(=O)OC(C)(C)C
Reactant: CC(C)S(=O)(=O)c1ccc(Br)nc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)S(=O)(=O)c1ccc(-c2cnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c(-c3cc(-c4ccc(CN(C)C(=O)OC(C)(C)C)cc4F)no3)c2)nc1
Temperature: 95 °C
Reaction time: 2 h

Procedure:
A mixture of tert-butyl N-[[4-[5-[2-[bis(tert-butoxycarbonyl)amino]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridyl]isoxazol-3-yl]-3-fluoro-phenyl]methyl]-N-methyl-carbamate (322.6 mg, 0.3339 mmol) and 2-bromo-5-isopropylsulfonyl-pyridine (105.8 mg, 0.4007 mmol) in DMF (3 mL) was degassed and placed under an atmosphere of nitrogen. Pd(PPh3)2Cl2 (13.81 mg, 0.03339 mmol) was added and the reaction again degassed. 2M aqueous Na2CO3 (501.0 μL, 1.002 mmol) was added and the reaction was stirred at 95° C. for 2 hours. The reaction mixture was partitioned between EtOAc and brine and the aqueous layer extracted with EtOAc (×3). The combined organic extracts were washed with water (×3) and brine (×2), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (ISCO Companion™, 40 g column, loading with DCM and eluting with 0 to 50% EtOAc/Petroleum Ether) to give the impure sub-title compound as a yellow oil which was used in the next step without purification.
Reaction SMILES: [CH:1]1([C:6]2([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22]C(=O)C)=[C:18]([CH:26]([CH3:28])[CH3:27])[CH:17]=3)[CH2:11][C:10](=[O:12])[CH2:9][C:8](=[O:13])[O:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C1(C2(CCC3C=CC(OC(=O)C)=C(CC)C=3)CC(=O)CC(=O)O2)CCCC1>>[CH:1]1([C:6]2([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([CH:26]([CH3:28])[CH3:27])[CH:17]=3)[O:7][C:8](=[O:13])[CH2:9][C:10](=[O:12])[CH2:11]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(=O)Oc1ccc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1C(C)C
Agent: CCc1cc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)ccc1OC(C)=O
Product: CC(C)c1cc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)ccc1O

Procedure:
The title compound was prepared analogously to Example A(22) where Acetic acid 4-[2-(2-cyclopentyl-4,6-dioxo-tetrahydro-pyran-2-yl)-ethyl]-2-isopropyl-phenyl ester (Example A(94)) was substituted in place of acetic acid 4-[2-(2-cyclopentyl-4,6-dioxo-tetrahydro-pyran-2-yl)-ethyl]-2-ethyl-phenyl ester.
Reaction SMILES: C(OC([NH:8][C:9]1[CH:17]=[C:16]2[C:12]([C:13]([C:29](=[O:33])[CH:30]([CH3:32])[CH3:31])=[C:14]([CH2:26][CH2:27][CH3:28])[N:15]2[CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:25])=[CH:11][CH:10]=1)=O)(C)(C)C.Cl>C(OCC)(=O)C.[OH-].[Na+]>[NH2:8][C:9]1[CH:17]=[C:16]2[C:12]([C:13]([C:29](=[O:33])[CH:30]([CH3:32])[CH3:31])=[C:14]([CH2:26][CH2:27][CH3:28])[N:15]2[CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:25])=[CH:11][CH:10]=1
Reactant: CCCc1c(C(=O)C(C)C)c2ccc(NC(=O)OC(C)(C)C)cc2n1Cc1ccccc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CCCc1c(C(=O)C(C)C)c2ccc(N)cc2n1Cc1ccccc1Cl
Temperature: 20 °C
Reaction time: 6.5 h
Yield: 79 %

Procedure:
To a stirred solution of 6-tert-butoxycarbonylamino-1-(2-chlorobenzyl)-3-isobutyryl-2-propylindole (581 mg) in ethyl acetate (5 ml) was added 4N hydrogen chloride in ethyl acetate (5 ml) at 20° C. The reaction mixture was stirred at 20° C. for 6.5 hours, then diluted with 1N aqueous sodium hydroxide and extracted. The organic phase was dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel eluting with a mixture of ethyl acetate and hexane (1:6 to 1:4) to give 6-amino-1-(2-chlorobenzyl)-3-isobutyryl-2-propylindole (361 mg) as yellow oil.
Reaction SMILES: [CH:1]1[C:20]([OH:21])=[C:19]([OH:22])[C:18]2[O:17][C:15](=O)[C:5]3=[CH:6][C:7](O)=[C:8]([OH:13])[C:9]4[O:10]C(=O)[C:2]=1[C:3]=2[C:4]=43>CS(C)=O>[CH2:4]1[C:9]2([OH:10])[CH2:8][O:17][C:18]3[C:19]([OH:22])=[C:20]([OH:21])[CH:1]=[CH:2][C:3]=3[C:4]2=[C:5]2[C:6]1=[CH:7][C:8]([C:9]([OH:10])=[CH:15]2)=[O:13]
Reactant: O=c1oc2c(O)c(O)cc3c(=O)oc4c(O)c(O)cc1c4c23
Solvent: CS(C)=O
Product: O=C1C=C2CC3(O)COc4c(ccc(O)c4O)C3=C2C=C1O

Procedure:
In a second series of experiments, the influence of ellagic acid, another stimulator of the interaction between tPA and misfolded proteins, on Aβ induced platelet aggregation was assessed. Ellagic acid was first dissolved to 100 mg/ml in DMSO, and then further diluted to 1 mg/ml in HBS buffer. Final concentrations of Aβ and ellagic acid in the aggregation assay were 50 μg/ml and 25/50 μg/ml, respectively. In addition, the influence of ellagic acid alone on platelet aggregation was tested. As a control, the influence of 0.08% DMSO on 50 μg/ml Aβ-induced platelet aggregation was analyzed. The 100% DMSO of the ellagic acid stock was diluted 2000 and 4000×, resulting in 0.005% and 0.0025% final DMSO concentrations in the aggregation assay.
Reaction SMILES: [Si:1]([O:8][CH:9]1[CH2:12][N:11]([C:13]([C:15]2[S:23][C:22]3[C:17](=[N:18][CH:19]=[CH:20][C:21]=3Cl)[CH:16]=2)=[O:14])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[F:25][C:26]1[CH:31]=[C:30]([N+:32]([O-:34])=[O:33])[CH:29]=[CH:28][C:27]=1[OH:35].C([O-])([O-])=O.[K+].[K+].O(C1C=CC=CC=1)C1C=CC=CC=1>C(Cl)Cl>[Si:1]([O:8][CH:9]1[CH2:12][N:11]([C:13]([C:15]2[S:23][C:22]3[C:17](=[N:18][CH:19]=[CH:20][C:21]=3[O:35][C:27]3[CH:28]=[CH:29][C:30]([N+:32]([O-:34])=[O:33])=[CH:31][C:26]=3[F:25])[CH:16]=2)=[O:14])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OC1CN(C(=O)c2cc3nccc(Cl)c3s2)C1
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CC(C)(C)[Si](C)(C)OC1CN(C(=O)c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)C1
Temperature: 170 °C
Reaction time: 1.5 h
Yield: 34.2 %

Procedure:
A mixture of (3-(tert-butyldimethylsilyloxy)azetidin-1-yl)(7-chlorothieno[3,2-b]pyridin-2-yl)methanone 272 (749.7 mg, 1.96 mmol) (WO 2006/010264), 2-fluoro-4-nitrophenol (461 mg, 2.94 mmol), K2CO3 (518 mg, 3.92 mmol) and Ph2O (2.6 mL) was stirred in a sealed tube for 1.5 h at 170° C. The mixture was diluted with DCM, extracted with water, the organic phase dried over anhydrous Na2SO4 and concentrated. The residue was purified by flash chromatography (eluted successively with: EtOAc/hexanes 1:1, EtOAc, EtOAc/MeOH 4:1) affording 273 (336 mg, 0.67 mmol, 34% yield). MS (m/z): (M+1) 504.1 (100%).
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:9]([C:11]1[CH:31]=[CH:30][C:14]2[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:28])[NH2:27])=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10].Cl[C:39]([O:41][CH3:42])=[O:40]>ClCCl.C(O)C>[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:9]([C:11]1[CH:31]=[CH:30][C:14]2[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:27])[NH:28][C:39]([O:41][CH3:42])=[O:40])=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10]
Reactant: CCOC(=O)CN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1ccccn1
Reactant: COC(=O)Cl
Agent: Cl
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)CN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)NC(=O)OC)cc1)n2C)c1ccccn1
Yield: 62 %

Procedure:
Prepared analogously to Example 90 from 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-ethoxycarbonylmethyl-amide-hydrochloride and methyl chloroformate. Yield: 62% of theory, C28H29N7O5 (543.6) Rf value: 0.19 (silica gel; dichloromethane/ethanol=19:1) ##EQU86##
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[C:4]([Cl:9])[CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].P(OC1C=CC=CC=1)(OC1C=CC=CC=1)(O[CH2:19][CH2:20][C:21]([CH3:23])=[CH2:22])=O>CN(C=O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:19][CH2:20][C:21]([CH3:23])=[CH2:22])=[C:4]([Cl:9])[CH:3]=1
Reactant: Sc1ccc(Br)cc1Cl
Reactant: C=C(C)CCOP(=O)(Oc1ccccc1)Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: C=C(C)CCSc1ccc(Br)cc1Cl
Temperature: 85 °C

Procedure:
To a mixture of 4-bromo-2-chlorobenzenethiol (1.68 g, 7.54 mmol) and Cs2CO3 (4.09 g, 12.6 mmol) in DMF (8.98 mL) at room temperature was added 3-methylbut-3-en-1-yl diphenyl phosphate (2.00 g, 6.28 mmol, synthesized according to a procedure in U.S. Pat. No. 5,006,550, 9 Apr. 1991) dropwise via a syringe. The reaction mixture was heated to 85° C. for 1 hour. It was then allowed to cool to room temperature and diluted with water (20.0 mL). The resulting mixture was extracted with EtOAc:hexanes mixture (1:1, 75.0 mL, 2×) and the combined organic layers were dried over Na2SO4, filtered and concentrated under vacuum. The crude mixture was purified by silica gel chromatography eluting with 0-10% EtOAc/hexanes to give the desired product as a colorless oil.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([OH:12])[CH:7]=[C:8]([CH2:10][OH:11])[CH:9]=1)[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+].Br[CH2:22][CH:23]([CH3:25])[CH3:24]>CN(C=O)C.O>[CH2:1]([O:3][C:4]1[CH:9]=[C:8]([CH2:10][OH:11])[CH:7]=[C:6]([O:12][CH2:22][CH:23]([CH3:25])[CH3:24])[CH:5]=1)[CH3:2]
Reactant: CCOc1cc(O)cc(CO)c1
Reactant: CC(C)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1cc(CO)cc(OCC(C)C)c1
Temperature: 100 °C
Reaction time: 24 h

Procedure:
To a solution of 3-ethoxy-5-hydroxymethyl-phenol (0.3 g, 1.78 mmol, 1.0 equiv; prepared as described for intermediate 41 [3-ethoxy-5-(3-hydroxy-2-2-dimethylpropoxy)-benzaldehyde]) in DMF (2 mL) was added cesium carbonate (2.32 g, 7.14 mmol, 4.0 equiv), potassium iodide (0.59 g, 3.57 mmol, 2.0 equiv) and 1-bromo-2-methyl-propane (0.58 mL, 0.73 g, 5.35 mmol, 3.0 equiv) and the reaction mixture stirred under Ar at 100° C. for 24 h. The reaction mixture was filtered, the solid material washed with DMF and the organic filtrate evaporated to dryness under reduced pressure. The crude reaction mixture was suspended in water (20 mL), extracted with dichloromethane (3×50 mL), the combined organic phases washed with a sat. solution of sodium chloride (1×20 ml) and dried over Na2SO4 providing 0.30 g (75%) of the title compound in sufficient purity for the next reaction step. 1H NMR (300 MHz, CDCl3): δ 1.01 (d, J=6.7 Hz, 6H), 1.40 (t, J=7.0 Hz, 3H), 2.07 (h, J=6.7 Hz, 1H), 3.70 (d, J=6.7 Hz, 2H), 4.02 (q, J=7.0 Hz, 2H), 4.61 (br s, 2H), 6.37-6.39 (m, 1H), 6.49-6.51 (m, 2H). 13C NMR (75 MHz, CDCl3): δ 14.84, 19.26, 28.31, 63.56, 65.49, 74.62, 100.76, 105.14, 105.32, 143.29, 160.41, 160.78. MS (ISP): 225.1 [M+H]+.
Reaction SMILES: O[CH:2]([CH:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)[CH3:3].[BrH:10]>C(O)C>[BrH:10].[Br:10][CH:2]([CH:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)[CH3:3]
Reactant: CC(O)C1CCNCC1
Agent: Br
Solvent: CCO
Product: CC(Br)C1CCNCC1

Procedure:
A solution of 4-(1'-hydroxyethyl)-piperidine (13 g, m.p. 65°-68° C.) in ethanol (25 ml) was neutralized with 5 N hydrogen bromide in ethanol. After removal of the solvent in vacuo, the residue was distilled twice with chloroform and finally dried at 0.05 mm Hg. The oily residue was mixed with phosphorous tribromide (25 ml) and heated on the steam bath for 2 hours. After cooling, the mixture was treated with ether (250 ml) to give a crystalline precipitate which was filtered off and washed with ether to give (A) as hygroscopic crystals. Recrystallization from acetonitrile gave material with m.p. 146°-48° C.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[S:4][CH:5]=[C:6]([CH2:8]O)[N:7]=1.S(Cl)(Cl)=O.[CH3:16][S-:17].[Na+].O>C(Cl)(Cl)Cl>[F:1][C:2]([F:11])([F:10])[C:3]1[S:4][CH:5]=[C:6]([CH2:8][S:17][CH3:16])[N:7]=1
Reactant: C[S-]
Reactant: OCc1csc(C(F)(F)F)n1
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: O
Solvent: ClC(Cl)Cl
Product: CSCc1csc(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.4 %

Procedure:
2-(Trifluoromethyl)-4-thiazolemethanol (EP 402246; 1.5 g, 8.3 mmol) was dissolved in 15 ml chloroform, treated with thionyl chloride (1.8 ml, 2.4 g, 21 mmol) and heated to reflux. After 1 h, the mixture was cooled and volatiles were removed under vacuum. The residue was taken up in 25 ml ethyl acetate and washed with 10 ml sat. NaHCO3, 10 ml sat. NaCl, dried (Na2SO4) and evaporated. The residue was taken up in 5 ml ethanol and treated in portions with sodium thiomethoxide (800 mg, 12 mmol) and stirred for 1 h at 25° C. The mixture was poured into 15 ml water and extracted 2×15 ml ethyl acetate. The combined extracts were washed with sat. NaCl, dried (Na2SO4) and evaporated to obtain 1.3 g of 2-(Trifluoro-methyl)-4(methylthio)methyl thiazole (A).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([C@H:12]2[CH2:17][CH2:16][C@H:15]([N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)[CH2:14][CH2:13]2)[N:3]=1.[Cl:25][C:26]1[CH:31]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:29]=[CH:28][C:27]=1[NH:41][C:42](=[O:48])[O:43][C:44]([CH3:47])([CH3:46])[CH3:45].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:11][C:9]1[N:8]=[CH:7][N:6]=[C:5]2[N:4]([C@H:12]3[CH2:17][CH2:16][C@H:15]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[CH2:14][CH2:13]3)[N:3]=[C:2]([C:30]3[CH:29]=[CH:28][C:27]([NH:41][C:42](=[O:48])[O:43][C:44]([CH3:45])([CH3:46])[CH3:47])=[C:26]([Cl:25])[CH:31]=3)[C:10]=12
Reactant: CC(C)(C)OC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cc1Cl
Reactant: CN1CCN([C@H]2CC[C@H](n3nc(I)c4c(N)ncnc43)CC2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CN1CCN([C@H]2CC[C@H](n3nc(-c4ccc(NC(=O)OC(C)(C)C)c(Cl)c4)c4c(N)ncnc43)CC2)CC1

Procedure:
A mixture of trans 3-iodo-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (2.20 g, 0.00498 mol), tert-butyl N-[2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamate (1.93 g, 0.00548 mol), sodium carbonate (1.32 g, 0.01245 mol) in 1,2-dimethoxyethane (50 mL) and water (100 mL) was stirred rapidly and tetrakis(triphenylphosphine)palladium(0) (0.345 g, 0.00030 mol) was added. The reaction mixture was stirred 6 hours at 80° C., after which time additional tetrakis(triphenylphosphine)palladium(0) (0.345 g, 0.00030 mol) was added. The reaction mixture was stirred an additional 16 hours at 80° C. The solvents were removed in vacuo and the residue was partitioned between ethyl acetate (100 mL) and saturated aqueous sodium bicarbonate (200 mL). The phases were separated and the aqueous phase was extracted with ethyl acetate (3×75 mL). The combined organic phases were dried over magnesium sulfate, and the solvent was removed in vacuo. The product was purified by flash column chromatography on silica using dichloromethane/methanol/ammonium hydroxide (90:10:0.5). The solvent was removed in vacuo to give trans tert-butyl N-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-chlorophenyl)carbamate as a white solid (1.993 g, 0.00368 mol):
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[OH:13][C@H:14]1[CH2:18][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C@@H:16]([C:26](=[O:41])[NH:27][C:28]2[CH:33]=[CH:32][C:31]([N:34]3[CH2:39][CH2:38][O:37][CH2:36][C:35]3=[O:40])=[CH:30][CH:29]=2)[CH2:15]1.[N+:42]([C:45]1[CH:53]=[CH:52][C:48]([C:49](O)=[O:50])=[CH:47][CH:46]=1)([O-:44])=[O:43].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[C:22]([O:21][C:19]([N:17]1[CH2:18][C@@H:14]([O:13][C:49](=[O:50])[C:48]2[CH:47]=[CH:46][C:45]([N+:42]([O-:44])=[O:43])=[CH:53][CH:52]=2)[CH2:15][C@@H:16]1[C:26](=[O:41])[NH:27][C:28]1[CH:33]=[CH:32][C:31]([N:34]2[CH2:39][CH2:38][O:37][CH2:36][C:35]2=[O:40])=[CH:30][CH:29]=1)=[O:20])([CH3:25])([CH3:24])[CH3:23]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@@H]1C(=O)Nc1ccc(N2CCOCC2=O)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@@H](OC(=O)c2ccc([N+](=O)[O-])cc2)C[C@@H]1C(=O)Nc1ccc(N2CCOCC2=O)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 211.1 %

Procedure:
8.1 5.51 ml (35 mmol) of diethyl azodicarboxylate (DEAD) are added dropwise at 0° C. under nitrogen to a solution of 7.0 g (7.26 mmol) of tert-butyl (2R,4R)-4-hydroxy-2-(4-(3-oxomorpholin-4-yl)phenylcarbamoyl]pyrrolidine-1-carboxylate, 5.77 g (34.5 mmol) of p-nitrobenzoic acid and 9.18 g (35 mmol) of triphenylphosphine in 350 ml of tetrahydrofuran. The reaction mixture is subsequently left to stir at room temperature for 12 hours and evaporated to dryness-under reduced pressure, 20 ml of methylene chloride are added to the residue, and the methylene chloride solution is washed successively with 10 ml of saturated sodium chloride solution and 10 ml of water and dried over sodium sulfate. After the drying agent has been filtered off and the solvent has been stripped off in a rotary evaporator, the residue is triturated with 30 ml of diethyl ether, giving 8.5 g (88.8%) of tert-butyl-(2R,4S)-4-(4-nitrobenzoyloxy)-2-[4-(3-oxomorpholin-4-yl)phenylcarbamoyl]pyrrolidine-1-carboxylate as slightly yellow crystals, ESI 555. 8.2 Analogously to Example 7, reaction of tert-butyl (2R,4S)-4-(4-nitro-benzoyloxy)-2-[4-(3-oxomorpholin-4-yl)phenylcarbamoyl]pyrrolidine-1-carboxylate gives the compound (3S,5R)-1-(4-chlorophenylcarbamoyl)-5-[4-(3-oxomorpholin-4-yl)phenylcarbamoyl]pyrrolidin-3-yl 4-nitrobenzoate as yellowish crystals, ESI 608. 8.3 0.075 ml of 1N sodium hydroxide solution is added with ice cooling to the solution of 50 mg (0.082 mmol) of (3S,5R)-1-(4-chlorophenyl-carbamoyl)-5-[4-(3-oxomorpholin-4-yl)phenylcarbamoyl]pyrrolidin-3-yl 4-nitrobenzoate in 2 ml of methanol, and the reaction mixture is stirred for 15 minutes. The precipitate is filtered off and washed with 2 ml of methanol and dried, giving 35 mg (93%) of 1-N-[(4-chlorophenyl)]-2-N-{[4-(3-oxomorpholin-4-yl)phenyl]}-(2R,4S)-4-hydroxypyrrolidine-1,2-dicarboxamide as colourless crystals, ESI 459, m.p. 243° (decomposition).