Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([CH2:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25][Br:26])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Br:26][CH2:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[CH2:18][CH2:17][CH2:16][CH:8]([NH2:7])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC(C)(C)OC(=O)NC(CCCc1ccccc1CBr)Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(CCCc1ccccc1CBr)Cc1ccccc1
Temperature: 25 °C

Procedure:
To a solution of 30j (680 mg, 1.58 mmol) in DCM (20 mL) was added CF3COOH (1.79 g, 15.8 mmol). The solution was left to stir at rt until TLC analysis indicated the total consumption of the SM. Then the solvent was removed to get the crude desired product as yellow oil, which was used without further purification in the next step.
Reaction SMILES: [CH3:1][N:2]([CH3:52])[CH:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[C:13]([C:15]3[C:23]4[C:22]([NH:24][C@H:25]([C:27]5[N:32]([C:33]6[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=6)[C:31](=[O:39])[C:30]6=[C:40]([CH3:43])[CH:41]=[CH:42][N:29]6[N:28]=5)[CH3:26])=[N:21][CH:20]=[N:19][C:18]=4[N:17](COCC[Si](C)(C)C)[CH:16]=3)[CH:12]=[CH:11][N:10]=2)[CH2:5][CH2:4]1.FC(F)(F)C(O)=O.N>>[CH3:52][N:2]([CH3:1])[CH:3]1[CH2:4][CH2:5][N:6]([C:9]2[CH:14]=[C:13]([C:15]3[C:23]4[C:22]([NH:24][C@H:25]([C:27]5[N:32]([C:33]6[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=6)[C:31](=[O:39])[C:30]6=[C:40]([CH3:43])[CH:41]=[CH:42][N:29]6[N:28]=5)[CH3:26])=[N:21][CH:20]=[N:19][C:18]=4[NH:17][CH:16]=3)[CH:12]=[CH:11][N:10]=2)[CH2:7][CH2:8]1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3ccnc(N5CCC(N(C)C)CC5)c3)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Agent: N
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4[nH]cc(-c5ccnc(N6CCC(N(C)C)CC6)c5)c34)n(-c3ccccc3)c(=O)c12
Yield: 42.5 %

Procedure:
(S)-2-(1-((5-(2-(4-(Dimethylamino)piperidin-1-yl)pyridin-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (12 mg, 0.02 mmol) was treated with trifluoroacetic acid (1 ml, 13 mmol) and a solution of ammonia (7N in methanol, 1 ml, 60 mmol) according to the method described in Example 27 to give 5 mg (50% yield) of the title compound as a solid. Purity 98%.
Reaction SMILES: [N:1]1([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=O.ON1C2C=CC=CC=2N=N1.[NH2:29][C@H:30]([C:37]([O:39][CH3:40])=[O:38])[CH2:31][C:32]1[N:36]=[CH:35][NH:34][CH:33]=1.Cl.Cl.C(N1CCOCC1)C>CN(C)C=O>[CH2:12]([O:11][C:9]([N:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([NH:29][C@H:30]([C:37]([O:39][CH3:40])=[O:38])[CH2:31][C:32]1[N:36]=[CH:35][NH:34][CH:33]=1)=[O:5])=[O:10])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Reactant: COC(=O)[C@@H](N)Cc1c[nH]cn1
Agent: CCN1CCOCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Reaction time: 2 h
Yield: 67.4 %

Procedure:
A solution of N,N1 -dicyclohexylcarbodiimide (DCC, 13.6 g, 66 mmol) in distilled dimethylformamide (DMF, 15 ml) is added dropwise to a cold solution (0° to 5° C.) of Z-Pro-OH (15 g, 60 mmol) and 1-hydroxybenzotriazole (HOBt, 12.16 g, 120 mmol), in distilled DMF (40 ml). The mixture is stirred at 0°-5° C. for 2 hr. Thereafter, a solution of H-His-OMe.2HCl (14.56 g, 60 mmol) and N-ethylmorpholine (15.2 g, 16.89 ml, 132 mmol) in distilled DMF is added to the cold reaction mixture. The pH of the reaction mixture is adjusted to 8 and the reaction mixture stirred for 18 hr at 20°-22° C. The solid (N,N1 -dicyclohexylurea) is removed from the mixture by filtration. The filtrate is concentrated to dryness under reduced pressure. The residue is subjected to chromatography on silica gel (2400 g) using chloroform-methanolpyridine (89:10:1) as the eluant. The pure fractions are pooled and evaporated under reduced pressure to give 16.2 g of the title compound; NMR (CDCl3) δ 3.70 (s, 3H), 5.12 (s, 2H), 7.25 (s, 5H); amino acid analysis: His (1.00), Pro (0.97).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH2:13][O:12][C:11](=[O:14])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[Cl:17][C:18]1[S:19][C:20]([CH2:23]Cl)=[CH:21][N:22]=1>C(COC)OC>[CH2:1]([N:8]([CH2:23][C:20]1[S:19][C:18]([Cl:17])=[N:22][CH:21]=1)[C:9]1[CH2:13][O:12][C:11](=[O:14])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: ClCc1cnc(Cl)s1
Reactant: O=C1C=C(NCc2ccccc2)CO1
Agent: [Na+]
Agent: [OH-]
Solvent: COCCOC
Product: O=C1C=C(N(Cc2ccccc2)Cc2cnc(Cl)s2)CO1
Temperature: 50 °C
Reaction time: 6 h
Yield: 71 %

Procedure:
6.3 g of 4-(benzylamino)furan-2(5H)-one (Example 16) are initially charged in 75 ml of dimethoxyethane at room temperature. Subsequently, 1.3 g of sodium hydroxide are added and, at 40° C., 34.4 g of a 15% solution of 2-chloro-5-(chloromethyl)-1,3-thiazole in dimethoxyethane are metered in. The mixture is stirred at 50° C. for a further 6 h. The solvent is substantially removed under reduced pressure and the residue is admixed with 50 ml of water and 50 ml of methylene chloride. The organic phase is removed, and the aqueous phase is extracted once again with 50 ml of methylene chloride. The combined methylene chloride phases are dried over sodium sulphate and the solvent is removed under reduced pressure. 6.9 g of 4-{benzyl[(2-chloro-1,3-thiazol-5-yl)methyl]amino}furan-2(5H)-one are obtained (this corresponds to 71% yield).
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]([CH2:23][C:24]([O:26][CH3:27])=[O:25])[CH2:18][C:19]([O:21][CH3:22])=[O:20])=[CH:13][CH:12]=1.[NH4+].[Cl-]>C1COCC1>[CH3:9][O:10][C:11]1[CH:12]=[CH:13][C:14]([CH:17]2[CH:23]([C:24]([O:26][CH3:27])=[O:25])[CH:18]2[C:19]([O:21][CH3:22])=[O:20])=[CH:15][CH:16]=1
Reactant: COC(=O)CC(CC(=O)OC)c1ccc(OC)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C1C(C(=O)OC)C1c1ccc(OC)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 43.8 %

Procedure:
To a solution of LDA (18.8 mmol) in THF (60 mL) at −78° C. was added a solution of dimethyl 3-(4-methoxyphenyl)pentanedioate (2.0 g, 7.52 mmol) in THF (10 mL) dropwise. After stirring at −78° C. for 1 h, the dry ice-acetone bath was removed. The reaction mixture was stirred for 30 min before being cooled to −78° C. Solid AgCl (2.2 g, 15.4 mmol) was added all at once. The reaction mixture was stirred at −78° C. for 1 h and then room temperature overnight. Saturated aqueous NH4Cl was added. The mixture was vigorously stirred for 10 min. The suspension was filtered through celite. The filtrate was extracted with EtOAc (3×). The combined organic extract was dried over MgSO4, filtered, and concentrated. The residue was purified by flash column chromatography with EtOAc in hexane (10%, 15%, 20%, then 30%) to give the title compound as a pale yellow solid (0.87 g, 44% yield). 1HNMR (CDCl3, 400 Hz) δ 7.09 (d, J=8.8 Hz, 2H), 6.86 (d, J=8.8 Hz, 2H), 3.82 (s, 3H), 3.77 (s, 6H), 3.17 (t, J=7.6 Hz, 1H), 2.36 (d, J=7.6 Hz, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:41])[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]([C:15]1[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([CH3:22])[CH:16]=1)=[C:9]2[CH2:23][CH2:24][NH:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([NH:36][S:37]([CH3:40])(=[O:39])=[O:38])=[CH:32][CH:31]=1)[CH3:2].Cl[C:43]([O:45][CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)=[O:44]>>[CH2:1]([O:3][C:4](=[O:41])[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]([C:15]1[CH:16]=[C:17]([CH3:22])[CH:18]=[C:19]([CH3:21])[CH:20]=1)=[C:9]2[CH2:23][CH2:24][N:25]([C:43]([O:45][CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)=[O:44])[CH2:26][CH2:27][CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([NH:36][S:37]([CH3:40])(=[O:39])=[O:38])=[CH:32][CH:31]=1)[CH3:2]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCOC(=O)Cc1ccc2[nH]c(-c3cc(C)cc(C)c3)c(CCNCCCCc3ccc(NS(C)(=O)=O)cc3)c2c1
Product: CCOC(=O)Cc1ccc2[nH]c(-c3cc(C)cc(C)c3)c(CCN(CCCCc3ccc(NS(C)(=O)=O)cc3)C(=O)OCc3ccccc3)c2c1
Yield: 73 %

Procedure:
The reaction of (2-(3,5-dimethylphenyl)-3-{2-[4-(4-methanesulfonylaminophenyl)butylamino]ethyl}-1H-indol-5-yl)acetic acid ethyl ester with benzyl chloroformate was carried out according to the procedure of Example 14.1, Step 14.1C, to give the titled compound in 73% yield as a stiff foam; homogeneous by TLC in 95:5 CH2Cl2 --MeOH. 500 MHz 1H NMR was complex, owing to the existence of rotamers, but was consistent with the assigned structure. Mass spectrum (ESI): m/e=710 (M+H).
Reaction SMILES: [CH3:1][N:2]1[C@@H:7]2[CH2:8][C:9]3[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]4[O:17][C@H:18]5[C@@H:19]([O:22][CH3:23])[CH:20]=[CH:21][C@@H:6]2[C@:5]5([C:10]=34)[CH2:4][CH2:3]1>C1COCC1>[CH3:1][N:2]1[C@@H:7]2[CH2:8][C:9]3[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]4[O:17][C@H:18]5[C:19]([O:22][CH3:23])=[CH:20][CH:21]=[C:6]2[C@:5]5([C:10]=34)[CH2:4][CH2:3]1
Reactant: COc1ccc2c3c1O[C@H]1[C@@H](OC)C=C[C@H]4[C@@H](C2)N(C)CC[C@@]341
Solvent: C1CCOC1
Product: COC1=CC=C2[C@H]3Cc4ccc(OC)c5c4[C@@]2(CCN3C)[C@H]1O5
Reaction time: 24 h
Yield: 66.5 %

Procedure:
A solution of codeine methyl ether (343 mg, 1.00 mmol) in THF (10 ml, distilled from LiAlH4) was shaken vigorously with γ-MnO2 (440 mg, 5.0 mmol) under a nitrogen atmosphere at room temperature. Further portions of γ-MnO2 (440 mg, 5.0 mmol) were added at intervals of 1, 3, 5, and 10 hr. After 24 hr. the black mixture was filtered through a fine sintered glass funnel, the residue was washed with THF (4 × 50 ml), and the washings were combined with the original filtrate and evaporated to give 207 mg of crude thebaine. The MnO2 was then washed with methanol (4 × 30 ml) which yielded an additional 119 mg of crude thebaine. The two fractions were combined and crystallized from ethanol to give thebaine (251 mg, 80%) identical with an authentic sample by mp (191°-192°), TLC, GC, mass spectrum [m/e 311 (M+)] , and NMR.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:8]([CH3:9])=[C:7]([C:10]#[N:11])[O:6][N:5]=1)[CH3:2].C[O-].[Na+].CO.C(O)(=O)C.N[C:22]([CH3:26])([CH3:25])[CH2:23][OH:24].[OH-].[K+]>CCO.O>[CH3:25][C:22]1([CH3:26])[CH2:23][O:24][C:10]([C:7]2[O:6][N:5]=[C:4]([O:3][CH2:1][CH3:2])[C:8]=2[CH3:9])=[N:11]1
Reactant: CC(C)(N)CO
Reactant: CCOc1noc(C#N)c1C
Agent: C[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CCO
Product: CCOc1noc(C2=NC(C)(C)CO2)c1C
Temperature: 25 °C
Reaction time: 20 h
Yield: 52.2 %

Procedure:
3-Ethoxy-4-methylisoxazole-5-carbonitrile (2.6 g, 17.1 mmol), 5.4 M NaOMe in MeOH (0.6 mL, 3.4 mmol) and EtOH (80 mL) was stirred at room temperature for 30 min. Acetic acid (2.2 mL, 39.3 mmol) and 2-amino-2-methylpropan-1-ol (1.8 mL, 18.8 mmol) were added, and the resulting mixture was boiled under reflux for 20 h. The reaction mixture was cooled, added water (100 mL) and extracted with EtOAc (3×100 mL). The organic extracts were washed with 1 M NaOH (50 mL), brine, dried (MgSO4) and evaporated in vacuo. The residue was dissolved in EtOH (60 mL), a solution of KOH (1.8 g, 32 mmol) in water (12 mL) was added, and the mixture was stirred at room temperature for 20 h. EtOH was removed in vacuo, water was added (80 mL) and the aqueous phase extracted with EtOAc (3×100 mL). The organic extracts were washed with brine, dried (MgSO4) and evaporated in vacuo. Flash chromatography (silica gel, eluent: EtOAc/heptane/triethylamine=75:25:1) gave crude title compound as a yellow oil (2.0 g, 52%).
Reaction SMILES: C([O:3][C:4]([C@H:6]1[CH2:8][C@@H:7]1[C:9]1[CH:14]=[CH:13][C:12]([O:15][C@H:16]2[C:24]3[C:19](=[C:20]([OH:26])[CH:21]=[CH:22][C:23]=3[F:25])[CH2:18][CH2:17]2)=[CH:11][CH:10]=1)=[O:5])C.N1C=CC=CC=1.[C:33]1(B(O)O)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.[NH4+].[OH-]>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[F:25][C:23]1[CH:22]=[CH:21][C:20]([O:26][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[C:19]2[C:24]=1[C@H:16]([O:15][C:12]1[CH:13]=[CH:14][C:9]([C@H:7]3[CH2:8][C@@H:6]3[C:4]([OH:3])=[O:5])=[CH:10][CH:11]=1)[CH2:17][CH2:18]2
Reactant: CCOC(=O)[C@H]1C[C@@H]1c1ccc(O[C@@H]2CCc3c(O)ccc(F)c32)cc1
Reactant: OB(O)c1ccccc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(O)[C@H]1C[C@@H]1c1ccc(O[C@@H]2CCc3c(Oc4ccccc4)ccc(F)c32)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 23.5 %

Procedure:
(1S,2S)-2-[4-((R)-7-Fluoro-4-hydroxy-indan-1-yloxy)-phenyl]-cyclopropanecarboxylic acid ethyl ester (Intermediate 5, 150 mg, 0.42 mmol), pyridine (dry; 0.133 mL, 1.68 mmol) and phenylboronic acid (308 mg, 2.53 mmol) are suspended in dichloromethane (10 mL), 4 Å molecular sieves and copper(II)acetate (153 mg, 1.52 mmol) are added and the mixture is stirred under oxygen atmosphere at room temperature for 20 h. NH4OH (2 M aqueous solution, 20 mL) is added and the mixture is extracted with dichloromethane. The organic phase is collected, dried over sodium sulfate and concentrated under vacuum. The crude product is purified by flash chromatography (10-100% ethyl acetate in cyclohexane) to give the title compound (Yield: 40 mg). LC (METHOD 9): tR=2.52 min; Mass spectrum (ES+): m/z=405 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH2:4][NH2:5].C(N(C(C)C)CC)(C)C.[F:20][C:21]1[CH:22]=[C:23]2[C:28](=[C:29]([O:43][CH3:44])[C:30]=1[N:31]1[CH2:36][CH2:35][N:34]([CH2:37][CH2:38][O:39][CH2:40][CH2:41][OH:42])[CH2:33][CH2:32]1)[N:27]([C@@H:45]1[CH2:47][C@@H:46]1[F:48])[CH:26]=[C:25]([C:49](O)=[O:50])[C:24]2=[O:52]>CN(C)C=O.O>[Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH2:4][NH:5][C:49]([C:25]1[C:24](=[O:52])[C:23]2[C:28](=[C:29]([O:43][CH3:44])[C:30]([N:31]3[CH2:32][CH2:33][N:34]([CH2:37][CH2:38][O:39][CH2:40][CH2:41][OH:42])[CH2:35][CH2:36]3)=[C:21]([F:20])[CH:22]=2)[N:27]([C@@H:45]2[CH2:47][C@@H:46]2[F:48])[CH:26]=1)=[O:50]
Reactant: NCc1ccc(Cl)cc1Cl
Reactant: COc1c(N2CCN(CCOCCO)CC2)c(F)cc2c(=O)c(C(=O)O)cn([C@@H]3C[C@@H]3F)c12
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COc1c(N2CCN(CCOCCO)CC2)c(F)cc2c(=O)c(C(=O)NCc3ccc(Cl)cc3Cl)cn([C@@H]3C[C@@H]3F)c12
Temperature: 25 °C
Reaction time: 48 h
Yield: 59.4 %

Procedure:
140 mg (0.27 mmol) of 1-benzotriazolyloxytripyrrolidinophosphonium hexafluorophosphate, 47 mg (0.27 mmol) of 2,4-dichlorobenzylamine and 35 mg (0.27 mmol) of diisopropylethylamine are added under argon to 105 mg (0.14 mmol) of the carboxylic acid of Example 6A in 2 ml of dimethylformamide and the mixture is stirred at room temperature for 2 days. The reaction mixture is diluted with 2 ml of water and without further work-up purified by preparative HPLC (Method 4). 52 mg of the target compound are obtained.
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4]>OCC(CO)O>[CH2:2]([OH:1])[C@@H:3]([C@H:5]([C@@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)CO
Solvent: OCC(O)CO
Product: OC[C@@H](O)[C@H](O)[C@@H](O)CO

Procedure:
When the genetically modified mutant of Candida tropicalis was cultured batchwise using glycerol as a cosubstrate, D-xylose in the medium was consumed completely in about 48 hours and produced xylitol with 98.3% of yield and 0.97 g l−1 h−1 of volumetric productivity. However, in case of fed-batch culture, D-xylose in the medium was consumed in about 14-15 hours and produced xylitol with 97-100% of yield and 3.48 g l−1 h−1 of volumetric productivity. As a result, it was demonstrated that fed-batch culture was more efficient to produce xylitol than batch culture.
Reaction SMILES: [NH2:1][CH:2]1[CH:9]2[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:11][CH:3]1[CH2:4]3)[CH2:8]2.[C:12](OC(=O)C)(=[O:14])[CH3:13]>N1C=CC=CC=1.CCOC(C)=O>[CH:9]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:11][CH:3]([CH2:4]3)[CH:2]1[NH:1][C:12](=[O:14])[CH3:13])[CH2:8]2
Reactant: CC(=O)OC(C)=O
Reactant: NC1C2CC3CC(C2)CC1C3
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(=O)NC1C2CC3CC(C2)CC1C3
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.9 %

Procedure:
A solution of 2-aminoadamantane (20 g, 108 mmol) in dry pyridine (120 mL) was treated with acetic anhydride (12 mL, 128 mmol) and stirred overnight at rt. The mixture was dilute with EtOAc and washed with water, 1 N aq phosphoric acid and brine. The organic layer was dried, filtered and concentrated to give N-(2-adamantyl)acetamide (12.5 g, 60%). 1H NMR (400 MHz, CDCl3): δ=1.57 (m, 2H), 1.67 (m, 3H), 1.72 (m, 1H), 1.77 (m, 6H), 1.85 (m, 2H), 1.94 (s, 3H), 3.97 (t, 1H), 5.78 (br, 1H).
Reaction SMILES: C[O:2][C:3](=[O:34])[C@@H:4]([NH:9][C:10]([C:12]1[O:16][N:15]=[C:14]([C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24]([NH:26][C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)=[O:25])=[CH:19][CH:18]=2)[CH:13]=1)=[O:11])[CH2:5][CH:6]([CH3:8])[CH3:7].[K+].[Br-]>>[F:33][C:30]1[CH:29]=[CH:28][C:27]([NH:26][C:24](=[O:25])[NH:23][C:20]2[CH:19]=[CH:18][C:17]([C:14]3[CH:13]=[C:12]([C:10]([NH:9][C@@H:4]([CH2:5][CH:6]([CH3:7])[CH3:8])[C:3]([OH:34])=[O:2])=[O:11])[O:16][N:15]=3)=[CH:22][CH:21]=2)=[CH:32][CH:31]=1
Reactant: COC(=O)[C@H](CC(C)C)NC(=O)c1cc(-c2ccc(NC(=O)Nc3ccc(F)cc3)cc2)no1
Agent: [Br-]
Agent: [K+]
Product: CC(C)C[C@H](NC(=O)c1cc(-c2ccc(NC(=O)Nc3ccc(F)cc3)cc2)no1)C(=O)O
Yield: 58 %

Procedure:
The title compound was prepared from (S)-2-[(3-{4-[3-(4-Fluoro-phenyl)-ureido]-phenyl}-isoxazole-5-carbonyl)-amino]-4-methyl-pentanoic acid methyl ester using the procedure as set forth in Example 8 and was obtained in 58% yield. Mass (ES+): 455 (M++1); IR (KBr): 3336 (br), 2962, 1724, 1664 (br), 1600, 1543 (br), 1510 (br); 1H NMR (DMSO-d6) δ: 0.87, 0.91 (2×d, 6H), 1.57-1.68 (m, 2H), 1.74-1.82 (m, 1H), 4.41 (m, 1H), 7.12 (t, 2H), 7.46 (m, 2H), 7.59 (d, 2H), 7.61 (s, 1H), 7.82 (d, 2H), 8.80 (s, 1H), 8.97 (s, 1H), 9.17 (d, 1H).
Reaction SMILES: [CH3:1][C:2]([CH3:24])([CH3:23])[C:3]([C:5]1[C:13]2[NH:12][C:11](=[O:14])[CH:10]=[N:9][C:8]=2[N:7](COCC[Si](C)(C)C)[CH:6]=1)=[O:4].I[CH2:26][CH3:27].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:26]([O:14][C:11]1[N:12]=[C:13]2[C:5]([C:3](=[O:4])[C:2]([CH3:1])([CH3:23])[CH3:24])=[CH:6][NH:7][C:8]2=[N:9][CH:10]=1)[CH3:27]
Reactant: CC(C)(C)C(=O)c1cn(COCC[Si](C)(C)C)c2ncc(=O)[nH]c12
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOc1cnc2[nH]cc(C(=O)C(C)(C)C)c2n1

Procedure:
A mixture of 7-(2,2-dimethyl-propionyl)-5-(2-trimethylsilanyl-ethoxymethyl)-1,5-dihydro-pyrrolo[2,3-b]pyrazin-2-one (0.080 g, 0.23 mmol), iodoethane (0.018 mL, 0.24 mmol) and potassium carbonate (0.038 g, 0.28 mmol) in 3 mL of acetone was stirred at reflux overnight, then concentrated. The residue was partitioned between 30 mL of ethyl acetate and 30 mL of water. The organic layer was dried over MgSO4, filtered and concentrated to 0.075 g (86%) of crude 1-[2-ethoxy-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-2,2-dimethyl-propan-1-one as a yellow oil that was used without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[C:9]1[C:10]2[NH:14][C:13]([C:15]([CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])=[C:16]3[N:39]=[C:19]([CH:20]=[C:21]4[NH:38][C:24](=[C:25]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[C:26]5[CH:27]=[CH:28][C:29]=1[N:30]=5)[CH:23]=[CH:22]4)[CH:18]=[CH:17]3)=[CH:12][CH:11]=2.CO.C([O-])(=O)C.[Zn+2:53].C([O-])(=O)C>C(Cl)(Cl)Cl>[Zn:53].[OH:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[C:9]1[C:10]2[NH:14][C:13]([C:15]([CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])=[C:16]3[N:39]=[C:19]([CH:20]=[C:21]4[NH:38][C:24](=[C:25]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[C:26]5[CH:27]=[CH:28][C:29]=1[N:30]=5)[CH:23]=[CH:22]4)[CH:18]=[CH:17]3)=[CH:12][CH:11]=2
Reactant: [Zn+2]
Agent: CC(=O)[O-]
Agent: CCCCCCCc1c2nc(c(-c3cc(O)ccc3O)c3ccc([nH]3)c(CCCCCCC)c3nc(cc4ccc1[nH]4)C=C3)C=C2
Solvent: ClC(Cl)Cl
Solvent: CO
Product: [Zn]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A starting compound (9)(14.0 mg, 22.8 μmol) was dissolved in 1 mL of chloroform. A saturated methanol solution of zinc acetate (0.3 mL) was added thereto and stirred at room temperature for 30 minutes. The chloroform solution was washed with water and solvent was removed by distillation. As a result, the compound (10) (14.6 mg) was obtained in a yield of 95%.
Reaction SMILES: [I:1][C:2]1[CH:7]=[N:6][C:5]2=[CH:8][N:9]([CH2:11][C:12](=[O:14])[CH3:13])[N:10]=[C:4]2[CH:3]=1.Cl[CH2:16]C(=O)C.C(=O)([O-])[O-].[K+].[K+].[I:26][C:27]1[CH:28]=[C:29]2[NH:35][N:34]=[CH:33][C:30]2=[N:31][CH:32]=1>>[NH2:6][C:5]([CH3:16])([CH2:4][N:34]1[CH:33]=[C:30]2[N:31]=[CH:32][C:27]([I:26])=[CH:28][C:29]2=[N:35]1)[C:8]#[N:9].[I:1][C:2]1[CH:7]=[N:6][C:5]2=[CH:8][N:9]([CH2:11][C:12](=[O:14])[CH3:13])[N:10]=[C:4]2[CH:3]=1.[I:1][C:2]1[CH:3]=[C:4]2[NH:10][N:9]=[CH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(=O)CCl
Agent: CC(=O)Cn1cc2ncc(I)cc2n1
Agent: Ic1cnc2cn[nH]c2c1
Agent: O=C([O-])[O-]
Product: CC(N)(C#N)Cn1cc2ncc(I)cc2n1
Yield: 66 %

Procedure:
Using a procedure similar to that described in Example 1, except using 2-amino-3-(6-iodo-2H-pyrazolo[4,3-b]pyridin-2-yl)-2-methylpropionitrile (25 mg), the title compound was isolated as a white solid (17 mg, 43%). MS (ES): M/Z [M+H]=516. 1H NMR: (400 MHz, CHLOROFORM-d): 1.94 (s, 3H), 4.85 (d, J=14.1 Hz, 1H), 5.03 (d, J=13.9 Hz, 1H), 7.33 (d, J=8.4 Hz, 2H), 7.88 (d, J=8.6 Hz, 2H), 8.01 (s, 1H), 8.39 (s, 1H), 8.46 (s, 1H) and 8.75 (d, J=1.6 Hz, 1H). 19F NMR (376 MHz, CHLOROFORM-d): −58.1 (s, 3F). 2-Amino-3-(6-iodo-2H-pyrazolo[4,3-b]pyridin-2-yl)-2-methylpropionitrile (25 mg, 66%; MS (ES): M/Z [M+H]=328) was prepared using a procedure similar to that described in Example 1, part b, except starting from 1-(6-iodo-2H-pyrazolo[4,3-b]pyridin-2-yl)propan-2-one (35 mg; MS (ES): M/Z [M+H]=302). 1-(6-Iodo-2H-pyrazolo[4,3-b]pyridin-2-yl)propan-2-one was prepared using a procedure similar to that described in Example 182 part g using chloroacetone and potassium carbonate except starting from 6-iodo-1H-pyrazolo[4,3-b]pyridine. 6-Iodo-1H-pyrazolo[4,3-b]pyridine was prepared as follows:
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].N1CCC(C(NC2C=CC=CC=2C(N)=O)=O)CC1.C(OC([N:33]1[CH2:38][CH2:37][CH:36]([C:39]([NH:41][C:42]2[CH:57]=[CH:56][C:55](/[CH:58]=[CH:59]\[C:60]#[N:61])=[CH:54][C:43]=2[C:44]([NH:46][C:47]2[CH:52]=[CH:51][C:50]([Cl:53])=[CH:49][N:48]=2)=[O:45])=[O:40])[CH2:35][CH2:34]1)=O)(C)(C)C>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:53][C:50]1[CH:51]=[CH:52][C:47]([NH:46][C:44](=[O:45])[C:43]2[CH:54]=[C:55](/[CH:58]=[CH:59]\[C:60]#[N:61])[CH:56]=[CH:57][C:42]=2[NH:41][C:39]([CH:36]2[CH2:35][CH2:34][NH:33][CH2:38][CH2:37]2)=[O:40])=[N:48][CH:49]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2ccc(/C=C\C#N)cc2C(=O)Nc2ccc(Cl)cn2)CC1
Agent: NC(=O)c1ccccc1NC(=O)C1CCNCC1
Solvent: O=C(O)C(F)(F)F
Product: N#C/C=C\c1ccc(NC(=O)C2CCNCC2)c(C(=O)Nc2ccc(Cl)cn2)c1

Procedure:
Using methods substantially equivalent to those described in Example 244-E, (Z)-N-(5-chloropyridin-2-yl)-5-(2-cyanovinyl)]-2-[(4-piperidinylcarbonyl)amino]benzamide trifluoroacetate (0.13 g, 84%) was prepared from (Z)-2-[(1-tert-butoxycarbonylpiperidin-4-ylcarbonyl)amino]-N-(5-chloropyridin-2-yl)-5-(2-cyanovinyl)benzamide.