Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C@@:3]([O:8][Si](C)(C)C)([CH3:7])[C:4](Cl)=[O:5].[C:15]([NH:18][C:19]1[C:20]([Cl:34])=[C:21]([CH:23]=[CH:24][C:25]=1[S:26][C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=1)[NH2:22])(=[O:17])[CH3:16]>C(Cl)Cl.C(N(CC)CC)C>[C:15]([NH:18][C:19]1[C:20]([Cl:34])=[C:21]([NH:22][C:4](=[O:5])[C@:3]([OH:8])([CH3:7])[C:2]([F:14])([F:13])[F:1])[CH:23]=[CH:24][C:25]=1[S:26][C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=1)(=[O:17])[CH3:16]
Reactant: C[C@@](O[Si](C)(C)C)(C(=O)Cl)C(F)(F)F
Reactant: CC(=O)Nc1c(Sc2ccc(F)cc2)ccc(N)c1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1c(Sc2ccc(F)cc2)ccc(NC(=O)[C@@](C)(O)C(F)(F)F)c1Cl
Temperature: 25 °C
Yield: 57.9 %

Procedure:
A solution of (S)-3,3,3-trifluoro-2-(trimethylsilyloxy)-2-methylpropanoyl chloride (prepared from (R)-3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid (Method 25) as described in J. Med. Chem., 1999, 42, 2741-2746) (1.179 g) in DCM (10 ml) was added dropwise to a stirred and ice-cooled suspension of 3-acetamido-2-chloro-4-(4-fluorophenylsulphanyl)aniline (Method 18) (1.315 g) in DCM (20 ml) and triethylamine (1.72 ml). The mixture was allowed to warm to ambient temperature overnight. More triethylamine (0.8 ml) followed by (S)-3,3,3-trifluoro-2-(trimethylsilyloxy)-2-methylpropanoyl chloride (0.6 g) in DCM (5 ml) was added. After a further 6 hours the mixture was concentrated by evaporation. MeOH (50 ml) and 2M aqueous HCl (5 ml) were added, the mixture was stirred overnight, and then diluted with water (20 ml). The MeOH was removed by evaporation and 2M aqueous HCl (30 ml) was added. The mixture was then extracted with ether (2×80 ml). The extracts were washed with brine then dried. Volatile material was removed by evaporation and the residue was purified by chromatography on a Biotage cartridge (40 g silica), eluting with 50% EtOAc/isohexane to give the title compound (1.104 g) as a foam. NMR: 1.6 (s, 3H), 2.05 (s, 3H), 7.0 (d, 1H), 7.26 (t, 2H), 7.38-7.48 (m, 2H), 7.8-7.9 (m, 2H), 9.76 (brs, 1H), 9.9 (brs, 1H); m/z: 449.
Reaction SMILES: C(OC(=O)[NH:10][C:11]([C:14](=[O:34])[NH:15][C:16]1[S:17][C:18]([C:25](=[O:33])[C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)=[C:19]([C:21]([F:24])([F:23])[F:22])[N:20]=1)([CH3:13])[CH3:12])C1C=CC=CC=1.Br>C(O)(=O)C.[OH-].[K+]>[NH2:10][C:11]([CH3:13])([CH3:12])[C:14]([NH:15][C:16]1[S:17][C:18]([C:25](=[O:33])[C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)=[C:19]([C:21]([F:23])([F:24])[F:22])[N:20]=1)=[O:34]
Reactant: CC(C)(NC(=O)OCc1ccccc1)C(=O)Nc1nc(C(F)(F)F)c(C(=O)c2ccc(F)cc2)s1
Agent: Br
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CC(C)(N)C(=O)Nc1nc(C(F)(F)F)c(C(=O)c2ccc(F)cc2)s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of {1-[5-(4-Fluoro-benzoyl)-4-trifluoromethyl-thiazol-2-ylcarbamoyl]-1-methyl-ethyl}-carbamic acid benzyl ester (1.42 g, 2.79 mmol) and 33% HBr (in acetic acid, 5 mL, 92 mmol) in acetic acid (10 mL) was stirred at RT for 1 h, diluted with aqueous KOH carefully to make pH=8-9, and the product was extracted with ethyl acetate, dried over MgSO4 and concentrated. Chromatography gave the title compound. m/z 376.1 (MH+).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[NH:15][C:14](=[O:16])[O:13][C:12]([CH3:18])([CH3:17])[C:11]=2[CH:19]=1.[C:20]([C:24]1[CH:29]=[CH:28][C:27]([SH:30])=[CH:26][CH:25]=1)([CH3:23])([CH3:22])[CH3:21]>>[C:20]([C:24]1[CH:25]=[CH:26][C:27]([S:30][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:8]=[CH:9][C:10]3[NH:15][C:14](=[O:16])[O:13][C:12]([CH3:18])([CH3:17])[C:11]=3[CH:19]=2)=[CH:28][CH:29]=1)([CH3:23])([CH3:21])[CH3:22]
Reactant: CC1(C)OC(=O)Nc2ccc(OCCCCCl)cc21
Reactant: CC(C)(C)c1ccc(S)cc1
Product: CC(C)(C)c1ccc(SCCCCOc2ccc3c(c2)C(C)(C)OC(=O)N3)cc1

Procedure:
Prepared analogously to Example 1 from 6-(4-chlorobutoxy)-4,4-dimethyl-4H-3,1-benzoxazin-2-one and 4-tert.butyl-thiophenol.
Reaction SMILES: C([Li])CCC.[Cl:6][C:7]1[CH:8]=[C:9]([CH:16]=[CH:17][CH:18]=1)[CH2:10][N:11]1[CH:15]=[CH:14][N:13]=[CH:12]1.[CH2:19]([C:22]1([CH:29]=[O:30])[CH2:27][CH:26]2[CH2:28][CH:23]1[CH:24]=[CH:25]2)[CH:20]=[CH2:21]>CCCCCC.C1COCC1>[CH2:19]([C:22]1([CH:29]([OH:30])[CH:10]([C:9]2[CH:16]=[CH:17][CH:18]=[C:7]([Cl:6])[CH:8]=2)[N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)[CH2:27][CH:26]2[CH2:28][CH:23]1[CH:24]=[CH:25]2)[CH:20]=[CH2:21]
Reactant: C=CCC1(C=O)CC2C=CC1C2
Reactant: Clc1cccc(Cn2ccnc2)c1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C=CCC1(C(O)C(c2cccc(Cl)c2)n2ccnc2)CC2C=CC1C2
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 38 %

Procedure:
13.8 ml (20 mmol) of a 1.45 molar solution of n-butyllithium in hexane were added dropwise to a solution of 3.85 g (20 mmol) of 1-(3-chlorobenzyl)-imidazole in 40 ml of absolute THF at -70° C. After stirring for 30 minutes at -70° C., a solution of 4.39 g of 74% purity (20 mmol) 2-allyl-5-norbornen-2-aldehyde in 30 ml of absolute THF was added dropwise at about -70° C. over about 12 minutes. The further procedure was subsequently carried out as described in Example 2. The residue (9.0 g) remaining from the organic component after removing the solvent by distillation was dissolved in diisopropyl ether/hexane 2:1, whereupon crystalline product precipitated. After isolation using 20 ml of acetonitrile, this was boiled briefly, filtered off under suction after cooling the mixture, and washed with acetonitrile. 2.70 g (≅38% yield) of pure 1-(2-allyl-5-norbornen-2-yl)-2-(3-chlorophenyl)-2-(1-imidazolyl)-ethanol were obtained in the form of a mixture, comprising 2 diastereomers, of melting point 134°-135° C.
Reaction SMILES: [CH3:1][CH:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]2[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][CH:9]=2)[CH2:3]1.CCN(CC)CC.[C:23](Cl)(=[O:25])[CH3:24]>C(Cl)Cl>[C:23]([N:7]1[CH2:6][CH2:5][N:4]([C:8]2[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][CH:9]=2)[CH2:3][CH:2]1[CH3:1])(=[O:25])[CH3:24]
Reactant: CC1CN(c2ccc(C=O)cc2)CCN1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CCN(c2ccc(C=O)cc2)CC1C
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 73.1 %

Procedure:
A solution of 4-(3-methylpiperazin-1-yl)benzaldehyde (1.0 g, 4.89 mmol) in methylene chloride (15 mL) was cooled to 0° C. and treated with Et3N (0.68 mL, 4.89 mmol), followed by acetyl chloride (0.34 mL, 4.89 mmol). The resulting solution was stirred at 0° C. for 20 minutes and then concentrated in vacuo. The material was purified by flash chromatography on silica gel, eluting with 0% to 5% of EtOAc/CH2Cl2, to afford 4-(4-acetyl-3-methylpiperazin-1-yl)benzaldehyde (0.88 g, 73%).
Reaction SMILES: C1(C2C=CC(C([O:13][C@@H:14]3[CH2:21][C@H:20]4[C@H:16]([CH2:17][C:18](=[O:22])[O:19]4)[C@H:15]3/[CH:23]=[CH:24]/[C@@H:25]([O:33][CH:34]3[CH2:39][CH2:38][CH2:37][CH2:36][O:35]3)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=O)=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>CO>[OH:13][C@@H:14]1[CH2:21][C@H:20]2[C@H:16]([CH2:17][C:18](=[O:22])[O:19]2)[C@H:15]1/[CH:23]=[CH:24]/[C@@H:25]([O:33][CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][O:35]1)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: CCCCCCC[C@@H](/C=C/[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1OC(=O)c1ccc(-c2ccccc2)cc1)OC1CCCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CCCCCCC[C@@H](/C=C/[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1O)OC1CCCCO1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
The tetrahydropyranyl ether (5) (5.03 g) was dissolved into a dry methanol (300 ml), into which potassium carbonate (1.49 g) was added, and stirred at room temperature for 6 hours. A crude compound obtained by a usual work-up was column-chromatographed to give the title compound (6). Yield: 3.25 g.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[C:10]2[C:15]3[CH2:16][CH2:17][CH2:18][CH2:19][C:14]=3[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:20][CH2:21][C:22]3[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=3)[C:10]3[C:15]4[CH2:16][CH2:17][CH2:18][CH2:19][C:14]=4[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: Fc1ccc(CNc2nc(Cl)nc3sc4c(c23)CCCC4)cc1
Reactant: c1cn[nH]c1
Product: Fc1ccc(CNc2nc(-n3cccn3)nc3sc4c(c23)CCCC4)cc1

Procedure:
Following the procedure of Example 97, the reaction of pyrazole with 2-chloro-5,6,7,8-tetrahydro-4-(4-fluorobenzylamino)-[1]-benzothieno-[2,3-d]-pyrimidine gives 2-(pyrazol-1-yl)-5,6,7,8-tetrahydro-4-(4-fluorobenzylamino)-[1]-benzothieno-[2,3-d]-pyrimidine.
Reaction SMILES: C([O:3][C:4](=[O:14])[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Br:13])[CH:8]=1)=[O:6])C.[OH-].[K+].Cl>CO>[Br:13][C:9]1[CH:8]=[C:7]([C:5](=[O:6])[C:4]([OH:14])=[O:3])[CH:12]=[CH:11][CH:10]=1
Reactant: CCOC(=O)C(=O)c1cccc(Br)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C(=O)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89 %

Procedure:
To a solution of (3-Bromo-phenyl)-oxo-acetic acid ethyl ester (1 g, 3.9 mmol) in methanol (10 mL) was added potassium hydroxide (2 mL, 50% w/v in water) and the resulting mixture was stirred at room temperature for 30 minutes. Hydrochloric acid (1 N) was added to adjust to pH 4. The mixture was extracted with ethyl acetate (5 mL×4) and the combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The residue was used in next step without further purification (0.8 g, 89% yield). MS: m/z 230 (M−H+).
Reaction SMILES: [OH-].[Na+].O1CCOCC1.[CH2:9]([O:16][C:17]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)=[CH:23][C:18]=1[C:19]([O:21]C)=[O:20])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(O)(=O)C>[CH2:9]([O:16][C:17]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)=[CH:23][C:18]=1[C:19]([OH:21])=[O:20])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: COC(=O)c1cc(N2CCCCC2)ccc1OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: O=C(O)c1cc(N2CCCCC2)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.9 %

Procedure:
A 4 mol/L aqueous solution of sodium hydroxide (9.8 mL) was added to a dioxane (45 mL) solution of the obtained methyl 2-(benzyloxy)-5-(piperidin-1-yl)benzoate (4.3 g), followed by stirring at room temperature for 1 hour and then at 50 to 55° C. for 2 hours. After cooling the reaction mixture to room temperature, the reaction mixture was adjusted to a pH of 6.3 with acetic acid, and the solvent was evaporated under reduced pressure. Water was added to the obtained residue, and the solid substance was collected by filtration to obtain 3.7 g of 2-(benzyloxy)-5-(piperidin-1-yl)benzoic acid as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][C:7]2([C:11]#N)[CH2:10][CH2:9][CH2:8]2)=[C:4](I)[CH:3]=1.C([Li])(C)(C)C.C1C[O:24]CC1>>[Br:1][C:2]1[CH:14]=[C:13]2[C:5]([CH2:6][C:7]3([CH2:10][CH2:9][CH2:8]3)[C:11]2=[O:24])=[CH:4][CH:3]=1
Reactant: C1CCOC1
Reactant: N#CC1(Cc2ccc(Br)cc2I)CCC1
Agent: [Li]C(C)(C)C
Product: O=C1c2cc(Br)ccc2CC12CCC2
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 63 %

Procedure:
A dried flask charged with 1-(4-bromo-2-iodobenzyl)cyclobutanecarbonitrile (Intermediate 37, 2.60 g, 6.91 mmol), was dissolved in dry THF (100 mL) under an argon atmosphere. The resulting mixture was cooled to −78° C. and then was tert-butyllithium (1.7 M in pentane, 8.13 mL, 13.83 mmol), added dropwise. The reaction was stirred for 1.5 h at −78° C. and then the reaction was quenched with MeOH (0.5 mL), followed by aq. hydrochloric acid (2M, 10 mL). The resulting solution was concentrated to remove the organic solvent and then partitioned between DCM and water. The organic phase was dried over MgSO4 and concentrated to give a crude product which was purified by flash chromatography (eluent: heptane/EtOAc20:1-15:1-10:1) to afford the title compound (1.1 g, 63% yield): 1H NMR (500 MHz, CDCl3) δ ppm 1.97-2.13 (m, 3 H), 2.13-2.24 (m, 1 H), 2.45-2.60 (m, 2 H), 3.24 (s, 2 H), 7.31 (d, 1 H), 7.67 (dd, 1 H), 7.88 (d, 1 H); GC MS (EI) m/z 250 M+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:19]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[C:18]3[CH:26]=[CH:27][C:28]([C:30]#[N:31])=[CH:29][C:17]=3[N:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Sn]([N:36]=[N+:37]=[N-:38])(C)C>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[N:19]([CH:20]3[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]3)[C:18]3[CH:26]=[CH:27][C:28]([C:30]4[NH:38][N:37]=[N:36][N:31]=4)=[CH:29][C:17]=3[N:16]=2)=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Reactant: N#Cc1ccc2c(c1)nc(-c1ccc(OCc3ccccc3)cc1)n2C1CCCCC1
Solvent: Cc1ccccc1
Product: c1ccc(COc2ccc(-c3nc4cc(-c5nnn[nH]5)ccc4n3C3CCCCC3)cc2)cc1
Reaction time: 48 h
Yield: 20 %

Procedure:
A suspension of compound 12 (0.041 g, 0.10 mmol) and trimethyltin azide (0.023 g, 0.11 mmol) in toluene (2 mL) was refluxed for 15 h. The reaction mixture was allowed to stand at rt for 48 h. The resulting suspension was filtered and washed with toluene (2×). The solid was treated with hydrogen chloride (4 M in dioxane, several mL) for 4 h at rt. The reaction mixture was concentrated on a rotary evaporator. The residue was purified by reverse phase HPLC (C18 column, water/acetonitrile gradient containing 0.05% trifluoroacetic acid) to afford 13 as a white solid (0.009 g, 20%). 1H NMR (CDCl3) δ 8.22 (br s, 1H), 8.05 (br m, 1H), 7.82 (br m, 3H), 7.52-7.38 (m, 5H), 7.30 (br m, 2H), 5.23 (s, 2H), 4.53 (br m, 1H), 2.27 (br m, 4H), 2.06 (br m, 2H), 1.84 (br m, 1H), 1.40 (br m, 3H); ESI-MS m/e 451.3 (M+1); HPLC purity (ELSD)>95%.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7](B(O)O)=[CH:6][CH:5]=1)([OH:3])=[O:2].Br[C:14]1[CH:15]=[CH:16][C:17]([CH:20]([F:22])[F:21])=[N:18][CH:19]=1>>[F:21][CH:20]([F:22])[C:17]1[N:18]=[CH:19][C:14]([C:7]2[CH:8]=[CH:9][C:4]([C:1]([OH:3])=[O:2])=[CH:5][CH:6]=2)=[CH:15][CH:16]=1
Reactant: FC(F)c1ccc(Br)cn1
Reactant: O=C(O)c1ccc(B(O)O)cc1
Product: O=C(O)c1ccc(-c2ccc(C(F)F)nc2)cc1

Procedure:
Operations similar to those of Production Example 14 were conducted using 4-carboxyphenylboronic acid and 5-bromo-2-(difluoromethyl)pyridine, to provide the title compound as white solid.
Reaction SMILES: N1C=CN=C1.[C:6]([Si:10](Cl)([CH3:12])[CH3:11])([CH3:9])([CH3:8])[CH3:7].[C:14]1([CH2:20][CH2:21][C@H:22]([OH:25])[C:23]#[CH:24])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl>C(Cl)Cl>[C:6]([Si:10]([CH3:12])([CH3:11])[O:25][C@@H:22]([CH2:21][CH2:20][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:23]#[CH:24])([CH3:9])([CH3:8])[CH3:7]
Reactant: C#C[C@@H](O)CCc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: C#C[C@H](CCc1ccccc1)O[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 14 h

Procedure:
Following a procedure of Noyori (Suzuki, M. et al., J. Med. Chem. 41, 3084-3090 (1998)); Imidazole (919.1 mg, 13.5 mmol, 1.8 eq.) and t-butylchlorodimethylsilane (1.35 g, 9.0 mmol) were added to a solution of (S)-5-phenylpent-1-yn-3-ol 86 (1.2 g, 7.5 mmol, 1 eq.) in CH2Cl2 (18 ml), cooled to 0° C. The reaction mixture was then stirred at room temperature for 14 h before being poured into 1 M HCl (50 ml). The mixture was extracted with 40/60 petroleum ether (3×50 ml). The combined organic phases were washed with brine (50 ml) before being dried (MgSO4), filtered and concentrated to give the crude product. This was purified by column chromatography on silica, eluting with petrol/Et2O (99:1), giving the title product 88 as a clear, colourless oil (1.77 g, 86%). Analytical data consistent with the literature (Kiyotsuka, Y. et al., Org. Lett. 10, 1719-1722 (2008); Sato, F. et al., EP 1211241 A1, Taisho Pharmaceutical co., LTD (2002)).
Reaction SMILES: C([O:5][C:6]([C@H:8]([C@@H:18]([CH2:54][CH:55]([CH3:57])[CH3:56])[C:19]([NH:21][N:22]([CH2:50][CH:51]([CH3:53])[CH3:52])[C:23](=[O:49])[C@@H:24]([CH2:43][O:44]C(C)(C)C)[NH:25][C:26]([O:28][CH2:29][CH:30]1[C:42]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[C:36]2[C:31]1=[CH:32][CH:33]=[CH:34][CH:35]=2)=[O:27])=[O:20])[CH2:9]/[CH:10]=[CH:11]/[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:7])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[C:6]([C@H:8]([C@@H:18]([CH2:54][CH:55]([CH3:57])[CH3:56])[C:19]([NH:21][N:22]([CH2:50][CH:51]([CH3:52])[CH3:53])[C:23](=[O:49])[C@@H:24]([CH2:43][OH:44])[NH:25][C:26]([O:28][CH2:29][CH:30]1[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:36]=2[C:37]2[C:42]1=[CH:41][CH:40]=[CH:39][CH:38]=2)=[O:27])=[O:20])[CH2:9]/[CH:10]=[CH:11]/[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)([OH:7])=[O:5]
Reactant: CC(C)C[C@@H](C(=O)NN(CC(C)C)C(=O)[C@@H](COC(C)(C)C)NC(=O)OCC1c2ccccc2-c2ccccc21)[C@H](C/C=C/c1ccccc1)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C[C@@H](C(=O)NN(CC(C)C)C(=O)[C@@H](CO)NC(=O)OCC1c2ccccc2-c2ccccc21)[C@H](C/C=C/c1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 86.7 %

Procedure:
A solution of 1.05 g of (E)-2(R)-[1(S)-(tert-butoxycarbonyl)-4-phenyl-3-butenyl]-2′-isobutyl-2′-[N-(9-fluorenylmethyloxycarbonyl)-O-tert.butyl-D-seryl]-4-methylvalerohydrazide in 5 ml of dichloromethane was treated at room temperature under nitrogen with 5 ml of trifluoroacetic acid. The mixture was stirred at room temperature for 2.5 hours and evaporated. Final traces of trifluoroacetic acid were removed by the addition and evaporation of three 10 ml portions of toluene. The residue in diethyl ether was treated with hexane to yield 0.78 g of (E)-2(R)-[1(S)-(carboxy)-4-phenyl-3-butenyl]-2′-isobutyl-2′[N-(9-fluorenylmethyloxycarbonyl)-D-seryl]-4-methylvalerohydrazide as a white solid.
Reaction SMILES: COC1C=CC(C[NH:8][CH:9]2[CH2:18][CH2:17][C:12]3([O:16][CH2:15][CH2:14][O:13]3)[CH2:11][C:10]2([CH3:20])[CH3:19])=CC=1>CO.[OH-].[OH-].[Pd+2]>[CH3:19][C:10]1([CH3:20])[CH:9]([NH2:8])[CH2:18][CH2:17][C:12]2([O:13][CH2:14][CH2:15][O:16]2)[CH2:11]1
Reactant: COc1ccc(CNC2CCC3(CC2(C)C)OCCO3)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC1(C)CC2(CCC1N)OCCO2
Reaction time: 2 h
Yield: 72 %

Procedure:
N-(4-Methoxybenzyl)-7,7-dimethyl-1,4-dioxaspiro[4.5]decan-8-amine (2.3 g, 7.54 mmol, 1 eq) was dissolved in MeOH (30 ml); Pd(OH)2 (690 mg) was added, and hydrogenation was carried out for 2 h at RT under balloon pressure (H2). After monitoring by thin-layer chromatography, the reaction mixture was filtered off over Celite and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (Alox neutral, 1% methanol in dichloromethane). The desired product was obtained in the form of a yellow oil. Yield: 72% (1.0 g, 5.41 mmol).
Reaction SMILES: [O:1]([CH3:10])[CH:2]1[O:7][C@H:6]([CH2:8][OH:9])[C@@H:4]([OH:5])[CH2:3]1.[C:11]1([C:17](Cl)([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.CO>N1C=CC=CC=1>[C:17]([O:9][CH2:8][C@H:6]1[O:7][CH:2]([O:1][CH3:10])[CH2:3][C@@H:4]1[OH:5])([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: COC1C[C@H](O)[C@@H](CO)O1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CO
Solvent: c1ccncc1
Product: COC1C[C@H](O)[C@@H](COC(c2ccccc2)(c2ccccc2)c2ccccc2)O1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 11.2 g (0.07 mole) of methyl 2-deoxyribofuranoside (90% pure) in 60 ml of dry pyridine under a dry nitrogen atmosphere were added 19.0 g (0.07 mole) of triphenylmethyl chloride. The mixture was stirred at ambient temperature for three days. Methanol (35 ml) was then added. The solvents were then evaporated under reduced pressure. The residue was taken up in 200 ml of ethyl acetate, washed with 75 ml of 5% sodium bicarbonate followed by a 75 ml wash with DI (deionized) water. The organic layer was dried (Na2SO4), filtered and the solvent removed under vacuum affording a sticky, viscous oil. This crude methyl 2-deoxy-5-O-tritylriboruanoside compound was used without further purification in subsequent synthetic procedures.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([CH2:7][N:8]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][NH:27][C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.Br[C:42]1[CH:57]=[CH:56][C:45]([C:46]([NH:48][CH2:49][C:50]2[CH:51]=[N:52][CH:53]=[CH:54][CH:55]=2)=[O:47])=[CH:44][C:43]=1[CH3:58]>>[CH3:38][O:37][C:34]1[CH:33]=[CH:32][C:31]([CH2:30][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:40][CH:39]=2)[C:9]2[N:10]=[CH:11][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:42]5[CH:57]=[CH:56][C:45]([C:46]([NH:48][CH2:49][C:50]6[CH:51]=[N:52][CH:53]=[CH:54][CH:55]=6)=[O:47])=[CH:44][C:43]=5[CH3:58])[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:13][N:14]=2)=[CH:36][CH:35]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4)cn2)cc1
Reactant: Cc1cc(C(=O)NCc2cccnc2)ccc1Br
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(C(=O)NCc4cccnc4)cc3C)cn2)cc1

Procedure:
Using bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (70 mg) and 4-bromo-3-methyl-N-pyridin-3-ylmethyl-benzamide (60 mg) instead of 4-chloropicolinic acid t-butylamide, in the same manner as Example 1-D-07, a crude product of 4-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-3-methyl-N-pyridin-3-ylmethyl-benzamide was obtained, and then the PMB groups were removed according to the above Deprotection method 3, to obtain the desired compound (D-301) as a grayish white powder (32 mg, 47%).
Reaction SMILES: Cl.C[O:3]C(=O)[C@H](CCC(OC)=O)N.COC(=O)[C@H](CCC(OC)=O)NN[C:20](=[O:38])[C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[CH:23][C:22]=1[N+:35]([O-:37])=[O:36]>>[C:31]([O:30][C:28]([NH:27][C:24]1[CH:25]=[CH:26][C:21]([C:20]([OH:38])=[O:3])=[C:22]([N+:35]([O-:37])=[O:36])[CH:23]=1)=[O:29])([CH3:32])([CH3:33])[CH3:34]
Reactant: COC(=O)CC[C@H](N)C(=O)OC
Reactant: COC(=O)CC[C@H](NNC(=O)c1ccc(NC(=O)OC(C)(C)C)cc1[N+](=O)[O-])C(=O)OC
Agent: Cl
Product: CC(C)(C)OC(=O)Nc1ccc(C(=O)O)c([N+](=O)[O-])c1

Procedure:
The synthesis was achieved in analogy to example 2 by using L-glutamic acid-dimethylester-hydrochloride instead of the L-glutamic acid-di-tert.-butylester-hydrochloride. From 14.8 g of 4-(tert-butoxycarbonylamino)-2-nitrobenzoic acid 27.4 g of crude dimethyl-N-(4-(tert.-butoxycarbonylamino)-2-nitrobenzamido)-L-glutamate were obtained which were purified twice by flash chromatography using silicagel 60 and ethylacetate/n-heptane/65:35 as eluent. After purification 17.38 g of dimethyl-N-(4-(tert.-butoxycarbonylamino)-2-nitrobenzamido)-L-glutamate were obtained.
Reaction SMILES: [Br-].[CH3:2][C:3]1[C:16]2[NH2+:15][C:14]3[C:9](=[CH:10][C:11]([Br:17])=[CH:12][CH:13]=3)[S:8][C:7]=2[CH:6]=[C:5](Br)[CH:4]=1.[CH3:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>C(Cl)(Cl)Cl>[Br-:17].[CH3:19][N:20]1[CH2:25][CH2:24][N:23]([C:5]2[CH:4]=[C:3]([CH3:2])[C:16]3[C:7]([CH:6]=2)=[S+:8][C:9]2[C:14](=[CH:13][CH:12]=[C:11]([N:23]4[CH2:24][CH2:25][N:20]([CH3:19])[CH2:21][CH2:22]4)[CH:10]=2)[N:15]=3)[CH2:22][CH2:21]1
Reactant: CN1CCNCC1
Reactant: Cc1cc(Br)cc2c1[NH2+]c1ccc(Br)cc1S2
Agent: [Br-]
Solvent: ClC(Cl)Cl
Product: Cc1cc(N2CCN(C)CC2)cc2[s+]c3cc(N4CCN(C)CC4)ccc3nc12
Reaction time: 3 h

Procedure:
To a solution of 1-methyl-3,7-dibromophenothiazinium bromide (300 mg, 0.7 mmol) in chloroform (15 mL) kept under argon, 1-methylpiperazine (350 mg, 3.5 mmol) was added (30 min) with vigorous stirring. The mixture was stirred for 3 h and after that extracted once with aqueous HBr (10 mL, 1% v/v) and twice with water. The organic layer was dried (Na2SO4), concentrated and dried under vacuum. Compound was purified by flash chromatography (solvent system—dichloromethane-methanol).