Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:32]=[CH:31][C:23]([O:24][CH2:25][CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[C:22]([F:33])[CH:21]=2)[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=2)=O)=[C:4]([CH3:34])[CH:3]=1.Cl.[NH2:36][OH:37].C(=O)([O-])O.[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:32]=[CH:31][C:23]([O:24][CH2:25][CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[C:22]([F:33])[CH:21]=2)[CH2:9]/[C:10](=[N:36]\[OH:37])/[C:12]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=2)=[C:4]([CH3:34])[CH:3]=1
Reactant: Cc1cc(Cl)ccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(OCCCC(=O)O)c(F)c1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(Cl)ccc1C(C/C(=N\O)c1ccc(=O)n(C)c1)c1ccc(OCCCC(=O)O)c(F)c1

Procedure:
In analogy to example 151, step 3, 4-{4-[1-(4-chloro-2-methyl-phenyl)-3-(1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-3-oxo-propyl]-2-fluoro-phenoxy}-butyric acid was reacted with hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate to give the title compound containing less than 10% of the corresponding Z isomer as a colourless solid, MS (ESI−): m/z=499.2 [M−H]−.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]=[C:9]=[O:10].[NH2:11][C:12]1[C:13]2[C:20]([C:21]([C:23]3[CH:28]=[C:27]([CH3:29])[N:26]=[C:25]([NH2:30])[CH:24]=3)=[O:22])=[CH:19][N:18]([CH:31]([CH3:33])[CH3:32])[C:14]=2[N:15]=[CH:16][N:17]=1>N1C=CC=CC=1>[NH2:11][C:12]1[C:13]2[C:20]([C:21]([C:23]3[CH:28]=[C:27]([CH3:29])[N:26]=[C:25]([NH:30][C:9]([NH:8][C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[F:1])=[O:10])[CH:24]=3)=[O:22])=[CH:19][N:18]([CH:31]([CH3:33])[CH3:32])[C:14]=2[N:15]=[CH:16][N:17]=1
Reactant: Cc1cc(C(=O)c2cn(C(C)C)c3ncnc(N)c23)cc(N)n1
Reactant: O=C=Nc1ccccc1F
Solvent: c1ccncc1
Product: Cc1cc(C(=O)c2cn(C(C)C)c3ncnc(N)c23)cc(NC(=O)Nc2ccccc2F)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.6 %

Procedure:
1-Fluoro-2-isocyanato-benzene (48.5 mg, 035 mmol) was added to a solution of (4-Amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-(2-amino-6-methyl-pyridin-4-yl)-methanone (100 mg, 0.32 mmol) in pyridine (2 mL). The mixture was stirred for 2 h at room temperature. The reaction mixture was quenched with H2O (2 mL) and concentrated in vacuo. The resulting residue was triturated with MeOH, filtered, and dried to afford the title compound as an off-white solid (104 mg, 72%). MS: 448.3 (MH+); HPLC Rf: 6.36 min. (HPLC method 4).
Reaction SMILES: C(Cl)(=O)C([Cl:4])=O.[ClH:7].[C:8](O)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>ClCCl.CN(C)C=O>[ClH:4].[C:8]([Cl:7])(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Oxalic chloride (800 μL) is added dropwise to a solution of 4-[3-(cis and trans-3,5-dimethylpiperidino)propoxy]benzoic acid, hydrochloride (2.33 g) in dichloromethane (20 mL) containing one drop of N,N-dimethylformamide. The mixture is stirred for two hours at room temperature and concentrated under reduced pressure. Cyclohexane is added and evaporated under reduced pressure to afford 2.55 g of 4-[3-(cis and trans-3,5-dimethylpiperidino)propoxy]benzoyl chloride, hydrochloride used without further purification.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][C:8]([C:11]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[NH:13][CH:12]=3)=[CH:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[Br:20]C1C=C2C(=CC=1)NC=C2>>[O:4]1[C:5]2([CH2:10][CH2:9][C:8]([C:11]3[C:19]4[C:14](=[CH:15][CH:16]=[C:17]([Br:20])[CH:18]=4)[NH:13][CH:12]=3)=[CH:7][CH2:6]2)[O:1][CH2:2][CH2:3]1
Reactant: C1=C(c2c[nH]c3ccccc23)CCC2(C1)OCCO2
Reactant: Brc1ccc2[nH]ccc2c1
Product: Brc1ccc2[nH]cc(C3=CCC4(CC3)OCCO4)c2c1
Yield: 78 %

Procedure:
This compound was prepared in the manner described above for intermediate 1a by replacing indole with 5-bromoindole (7.84 g, 40 mmol) ) to afford 10.5 g (78%) of the title compound as a white solid; MS EI m/e 333 (M+).
Reaction SMILES: N1C=CC=C(CN)C=1.[CH3:9][C:10]1[N:11]=[CH:12][C:13]([CH2:16][NH2:17])=[N:14][CH:15]=1.FC1C=CC(CN2[C@@H](C)CN(C3SC(C(O)=O)=C(C)N=3)C2=O)=CC=1.[F:42][C:43]1[CH:44]=[C:45]([CH:63]=[C:64]([F:66])[CH:65]=1)[CH2:46][N:47]1[C@H:51]([CH3:52])[CH2:50][N:49]([C:53]2[S:54][C:55]([C:59](O)=[O:60])=[C:56]([CH3:58])[N:57]=2)[C:48]1=[O:62]>>[F:66][C:64]1[CH:63]=[C:45]([CH:44]=[C:43]([F:42])[CH:65]=1)[CH2:46][N:47]1[C@H:51]([CH3:52])[CH2:50][N:49]([C:53]2[S:54][C:55]([C:59]([NH:17][CH2:16][C:13]3[CH:12]=[N:11][C:10]([CH3:9])=[CH:15][N:14]=3)=[O:60])=[C:56]([CH3:58])[N:57]=2)[C:48]1=[O:62]
Reactant: Cc1cnc(CN)cn1
Reactant: Cc1nc(N2C[C@@H](C)N(Cc3cc(F)cc(F)c3)C2=O)sc1C(=O)O
Agent: Cc1nc(N2C[C@H](C)N(Cc3ccc(F)cc3)C2=O)sc1C(=O)O
Agent: NCc1cccnc1
Product: Cc1cnc(CNC(=O)c2sc(N3C[C@@H](C)N(Cc4cc(F)cc(F)c4)C3=O)nc2C)cn1

Procedure:
Following the procedure as described in Example 2, making variations as required to replace pyridin-3-ylmethanamine with (5-methylpyrazin-2-yl)methanamine and replace (S)-2-(3-(4-fluorobenzyl)-4-methyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid with (R)-2-(3-(3,5-difluorobenzyl)-4-methyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid, the title compound was obtained as a white solid: mp 131-132° C. (ethanol/water); 1H NMR (300 MHz, DMSO-d6) δ 8.58 (t, J=5.7 Hz, 1H), 8.47-8.46 (m, 2H), 7.19-7.08 (m, 3H), 4.60-4.37 (m, 4H), 4.23 (t, J=9.6 Hz, 1H), 3.87-3.80 (m, 1H), 3.59 (dd, J=10.1, 6.7 Hz, 1H), 2.48 (s, 3H), 2.47 (s, 3H), 1.22 (d, J=6.2 Hz, 3H); MS (ES+) m/z 473.0 (M+1).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([CH2:16][NH2:17])=[N:14][N:15]=3)[N:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:19]1[N:27]=[CH:26][N:25]=[C:24]2[C:20]=1[NH:21][CH:22]=[N:23]2.C(O)(CC)C>>[C:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([CH2:16][NH:17][C:19]4[N:27]=[CH:26][N:25]=[C:24]5[C:20]=4[NH:21][CH:22]=[N:23]5)=[N:14][N:15]=3)[N:12]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NCc1nnc2ccc(-c3ccccc3)nn12
Reactant: Clc1ncnc2nc[nH]c12
Solvent: CCC(C)O
Product: c1ccc(-c2ccc3nnc(CNc4ncnc5nc[nH]c45)n3n2)cc1
Temperature: 100 °C
Yield: 32.8 %

Procedure:
A 15 mL tube was charged with (6-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methanamine (0.100 g, 0.444 mmol), 6-chloropurine (0.103 g, 0.666 mmol), and sec-butanol (3.00 ml, 32.4 mmol), sealed, then heated in a 100° C. oil bath for 5 hours. The reaction mixture was concentrated and the yellow residue was purified by MPLC using a 40 g RediSep column, eluting with a gradient of 3-8% MeOH/DCM over 80 minutes. N-((6-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)-7H-purin-6-amine (0.0500 g, 32.8% yield) was isolated as the hydrochloride salt.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:14]=[CH:15][C:16]4[S:22][CH2:21][CH2:20][C:19]([C:23](O)=[O:24])=[CH:18][C:17]=4[CH:26]=3)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[CH3:49][N:50]([CH2:57][C:58]1[CH:64]=[CH:63][C:61]([NH2:62])=[CH:60][CH:59]=1)[CH:51]1[CH2:56][CH2:55][O:54][CH2:53][CH2:52]1>CN(C=O)C.C(N(CC)CC)C>[CH3:49][N:50]([CH2:57][C:58]1[CH:59]=[CH:60][C:61]([NH:62][C:23]([C:19]2[CH2:20][CH2:21][S:22][C:16]3[CH:15]=[CH:14][C:13]([C:10]4[CH:11]=[CH:12][C:7]([N:4]5[CH2:3][CH2:2][O:1][CH2:6][CH2:5]5)=[CH:8][CH:9]=4)=[CH:26][C:17]=3[CH:18]=2)=[O:24])=[CH:63][CH:64]=1)[CH:51]1[CH2:56][CH2:55][O:54][CH2:53][CH2:52]1
Reactant: CN(Cc1ccc(N)cc1)C1CCOCC1
Reactant: O=C(O)C1=Cc2cc(-c3ccc(N4CCOCC4)cc3)ccc2SCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(Cc1ccc(NC(=O)C2=Cc3cc(-c4ccc(N5CCOCC5)cc4)ccc3SCC2)cc1)C1CCOCC1
Reaction time: 1 h
Yield: 49 %

Procedure:
To a solution of 7- (4-morpholinophenyl) -2,3-dihydro-1-benzothiepine-4-carboxylic acid (150 mg) and 1-hydroxy-benzotriazole (0.11 g) in DMF (5 ml) was added at room temperature 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.16 g), and the mixture was stirred for 1 hour. To the mixture was added a solution of 4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]aniline (135 mg) and triethylamine (0.11 ml) in DMF (5 ml), and the mixture was stirred for 18 hours. Under reduced pressure, the mixture was concentrated, and to the mixture was added water. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with column chromatography (ethanol/ethyl acetate=1:2) to give yellow crystals of N-[4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]phenyl]-7-(4-morpholinophenyl)-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 285) (113.9 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[CH2:9][N:8]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[CH2:7]2)([O-])=O.O.O.Cl[Sn]Cl.C([O-])(O)=O.[Na+]>CN(C=O)C>[NH2:1][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[CH2:9][N:8]([C:13]([O:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[O:14])[CH2:7]2
Reactant: O=C(OCc1ccccc1)N1Cc2ccc([N+](=O)[O-])cc2C1
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ccc2c(c1)CN(C(=O)OCc1ccccc1)C2
Reaction time: 8 h

Procedure:
To a solution of benzyl 5-nitro-1,3-dihydro-2H-isoindole-2-carboxylate (1.34 g, 4.49 mmol) in DMF (30 mL) was added SnCl2.2H2O (5.1 g, 22.5 mmol) as a powder. The mixture was stirred overnight. The reaction mixture was adjusted to basic pH with sat. aq. NaHCO3. The white precipitate formed was extracted with EtOAc (3×150 mL). The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel to provide benzyl 5-amino-1,3-dihydro-2H-isoindole-2-carboxylate. LCMS calc.=269.1; found=268.9 (M+H)+. 1H NMR (500 MHz, CDCl3): δ 7.46-7.34 (m, 5H); 7.12-6.93 (2 d, J=8.1, 1H); 6.66-6.53 (m, 2H); 5.25 (s, 2H); 4.69 (t, J=9.8 Hz, 4H); 3.71 (br s, 2H).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](Cl)=[O:11])=[CH:6][CH:5]=1.[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[C:30]3[C:25](=[N:26][CH:27]=[N:28][C:29]=3[NH2:31])[N:24]([C@H:32]3[CH2:37][CH2:36][C@H:35]([N:38]4[CH2:43][CH2:42][N:41]([CH3:44])[CH2:40][CH2:39]4)[CH2:34][CH2:33]3)[N:23]=2)=[CH:18][C:17]=1[O:45][CH3:46]>ClCCl.N1C=CC=CC=1>[NH2:31][C:29]1[N:28]=[CH:27][N:26]=[C:25]2[N:24]([C@H:32]3[CH2:37][CH2:36][C@H:35]([N:38]4[CH2:39][CH2:40][N:41]([CH3:44])[CH2:42][CH2:43]4)[CH2:34][CH2:33]3)[N:23]=[C:22]([C:19]3[CH:20]=[CH:21][C:16]([NH:15][C:10](=[O:11])[C:7]4[CH:8]=[CH:9][C:4]([O:3][C:2]([F:14])([F:13])[F:1])=[CH:5][CH:6]=4)=[C:17]([O:45][CH3:46])[CH:18]=3)[C:30]=12
Reactant: O=C(Cl)c1ccc(OC(F)(F)F)cc1
Reactant: COc1cc(-c2nn([C@H]3CC[C@H](N4CCN(C)CC4)CC3)c3ncnc(N)c23)ccc1N
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cc(-c2nn([C@H]3CC[C@H](N4CCN(C)CC4)CC3)c3ncnc(N)c23)ccc1NC(=O)c1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-(Trifluoromethoxy)-1-benzenecarbonyl chloride (283 mg, 1.256 mmol) in dichloromethane (1 mL) was added to a solution of trans-3-(4-amino-3-methoxyphenyl)-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (500 mg, 1.145 mmol) in pyridine (8 mL) at 0° C. After 30 minutes, the ice bath was removed the reaction mixture was stirred at room temperature for 1.5 hour. Solvent was evaporated and the residue was purified by flash column chromatography using dichloromethane/methanol (80:20) as mobile phase to give trans-N1-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-4-(trifluoromethoxy)benzamide (526 mg, 74%). 1H NMR (CDCl3) δ 1.57 (m, 2H), 1.74 (m, 2H), 2.10-2.27 (m, 6H), 2.30 (s, 3H), 2.51 (m, 4H), 2.66 (m, 3H), 4.03 (s, 3H), 4.77 (m, 3H), 5.56 (bs, 2H), 7.26-7.37 (m, 4H), 7.99 (m, 2H), 8.38 (s, 1H), 8.59 (s, 1H), 8.67 (d, J=8.21 Hz, 1H).
Reaction SMILES: [CH:1]1[CH2:5][CH:4]=[CH:3][CH:2]=1.[CH2:6]([Li])[CH2:7][CH2:8][CH3:9]>[Cl-].[Cl-].[Cl-].[Cl-].[Zr+4]>[CH2:6]([C:2]1[CH2:1][CH:5]=[CH:4][CH:3]=1)[CH2:7][CH2:8][CH3:9]
Reactant: [Li]CCCC
Reactant: C1=CCC=C1
Agent: [Zr+4]
Agent: [Cl-]
Product: CCCCC1=CC=CC1
Temperature: 0 °C

Procedure:
n-Butylcyclopentadiene was prepared analogously to Example 1 and freed or inorganic salts and excess cyclopentadiene. The solution so obtained was cooled to 0° C. and subsequently admixed dropwise with 9.7 g of n-butyllithium (90% strength in hexane; 136 mmol). The mixture was allowed to react for a further 30 minutes while stirring. 15.8 g of ZrCl4 (68 mmol) was added at 0°-10° C. and the mixture was stirred for 2 hours at room temperature.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH:9]([CH3:11])[CH3:10])[CH:5]=[C:4]([O:12][CH:13]([CH3:15])[CH3:14])[CH:3]=1.[Li]CCCC.[I:21]I>C1COCC1.CCOC(C)=O>[I:21][C:2]1[CH:7]=[C:6]([O:8][CH:9]([CH3:11])[CH3:10])[CH:5]=[C:4]([O:12][CH:13]([CH3:15])[CH3:14])[CH:3]=1
Reactant: CC(C)Oc1cc(Br)cc(OC(C)C)c1
Reactant: II
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)Oc1cc(I)cc(OC(C)C)c1
Temperature: -78 °C
Yield: 79.2 %

Procedure:
To a solution of 1-bromo-3,5-bis(propan-2-yloxy)benzene (46) (2.0 g, 7.3 mmol) in THF (100 mL), cooled to −78° C., a 1.6 M n-BuLi solution in hexanes (9.16 mL, 14.7 mmol) was added dropwise. The temperature was maintained at −78° C. for 30 min, after which a solution of iodine (3.17 g, 29.3 mmol) in THF (15 mL) was added dropwise. The mixture was warmed to −35° C. and maintained at this temperature for 1.5 h. The reaction mixture was diluted with EtOAc (100 mL) and washed with water (2×50 mL) and brine (50 mL). The organic layer was separated, dried (Na2SO4) and concentrated. Purification by column chromatography on silica gel (Hexanes/EtOAc, 4:1) gave 1-iodo-3,5-bis(propan-2-yloxy)benzene (47) (1.85 g, 79%) as a viscous orange oil.
Reaction SMILES: I[C:2]1[CH:3]=[N:4][O:5][C:6]=1[CH3:7].[CH3:8][O:9][C:10]1[N:15]=[C:14]([CH3:16])[C:13](B(O)O)=[CH:12][CH:11]=1.C(=O)(O)[O-].[Na+].O>COCCOC>[CH3:16][C:14]1[C:13]([C:2]2[CH:3]=[N:4][O:5][C:6]=2[CH3:7])=[CH:12][CH:11]=[C:10]([O:9][CH3:8])[N:15]=1
Reactant: COc1ccc(B(O)O)c(C)n1
Reactant: Cc1oncc1I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1ccc(-c2cnoc2C)c(C)n1
Temperature: 25 °C
Yield: 40.2 %

Procedure:
A mixture of 4-iodo-5-methylisoxazole (18.2 g, 87 mmol), 6-methoxy-2-methylpyridine-3-boronic acid (14.6 g, 87 mmol), sodium bicarbonate (22.0 g, 262 mmol), water (150 mL) and DME (150 mL) was degassed three times with stirring by the application of a vacuum and then introduction of a nitrogen atmosphere. [1,1-Bis(diphenylphosphino)ferrocene]-dichloropalladium (II) (2.14 g, 2.6 mmol) was added in one portion. The reaction mixture was degassed as before. The reaction mixture was then stirred at 80° C. for 4 h, then it was cooled to ambient temperature. Three extractions with EtOAc, drying the combined organic layers over MgSO4, filtration and removal of solvent in vacuo afforded an oil. Flash chromatography (EtOAc:hexane::1:9) and removal of solvent in vacuo from the desired fractions gave the product (7.15 g): 1H-NMR(CDCl3, 300 MHz): δ 8.16 (s, 1H), 7.33 (d, 1H, J=8), 6.63 (d, 1H, J=8), 3.95 (s, 3H), 2.35 (s, 6H); APCI+-MS: 205 (M++H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Br:29][Si](C)(C)C.BrN1C(=O)CCC1=O>C1COCC1>[Br:29][CH:14]([CH:11]1[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10]1)[C:15]([O:17][CH3:18])=[O:16]
Reactant: COC(=O)CC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: C[Si](C)(C)Br
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C1CCC(=O)N1Br
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C(Br)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Commercially available methyl 2-(1-tert-butoxycarbonyl-4-piperidinyl)-acetate (Astatech, 2.57 g, 10.0 mmol) was dissolved in anhydrous THF (20 mL) under argon, cooled to −78° C., treated dropwise with a 1N solution of LHMDS in THF (20 mL), and stirred under positive Ar pressure for 30 mins. Bromotrimethylsilane (2.10 mL, 15.9 mmol) was added dropwise via dry syringe over 5 mins, then a solution of freshly recrystallized N-bromosuccinimide (2.14 g, 12.0 mmol) in anhydrous THF (20 mL) was added in one portion from an addition funnel. The reaction was kept at −78° C. for 2 hrs then warmed to ambient temperature. The crude reaction was concentrated in vacuo then partitioned between saturated aq. NaHCO3 and ethyl acetate. The aqueous layer was extracted twice with ethyl acetate, and the combined organic layers washed with brine, dried over Na2SO4, filtered, and filtrate concentrated in vacuo giving 4.7 g of orange slurry. This was purified by flash column chromatography on silica gel (0 to 10% EtOAc/DCM step gradient elution), and the combined TLC-pure fractions were concentrated and dried in vacuo giving the title compound as a viscous, pale yellow oil. 1H NMR (CHLOROFORM-d) δ: 4.05-4.26 (m, 2H), 4.02 (d, J=8.8 Hz, 1H), 3.79 (s, 3H), 2.70 (br. s., 2H), 1.97-2.10 (m, 4H), 1.57-1.68 (m, 2H), 1.45 (s, 9H), 1.13-1.32 (m, 3H).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[N:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1.CON(C)[C:19](=[O:38])[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]2[CH:37]=[CH:36][C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[N:29]=2)=[CH:22][CH:21]=1.C(O)(=O)C>O1CCCC1>[N:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:19]([C:20]2[CH:21]=[CH:22][C:23]([O:26][CH2:27][C:28]3[CH:37]=[CH:36][C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[N:29]=3)=[CH:24][CH:25]=2)=[O:38])=[CH:11][CH:10]=1
Reactant: CON(C)C(=O)c1ccc(OCc2ccc3ccccc3n2)cc1
Reactant: Cc1ccncc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: O=C(Cc1ccncc1)c1ccc(OCc2ccc3ccccc3n2)cc1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 80 %

Procedure:
To a solution of Lithium diisopropyl amide (1.0M) in tetrahydrofuran was added 4-picoline dropwise (7.55 ml, 5 eq.) at 0° C. under N2. After 30 min the anion was cooled to −78° C. In a separate round bottom flask N-Methoxy-N-methyl-4-(quinolin-2-ylmethoxy)-benzamide (5.0, 15.5 mmole) was dissolved in tetrahydrofuran (77 ml, 0.2M) and cooled to −78° C. under N2. 1.2 eq. of the 4-picoline anion was added dropwise to the amide solution. After 45 min, 1 eq. more of the 4-picoline anion was added. After an addition 30 min, acetic acid (40 ml) was added dropwise and the reaction was slowly warmed to ambient temperature. The solid product (acetate salt) was filtered and partitioned between saturated sodium bicarbonate and dichloromethane. The layers were separated, dried magnesium sulfate filtered and concentrated to provide the title compound as a tan solid (4.41 g, 80%). 1H NMR (400 MHz, CDCl3) δ 8.52 (d, J=5.8 Hz, 2 H), 8.19 (d, J=8.7 Hz, 1 H), 8.07 (d, J=8.7 Hz, 1H), 7.93 (m, 2 H), 7.82 (d, J=8.3 Hz, 1 H), 7.75 (m, 1 H), 7.61 (d, J=8.3 Hz, 1 H), 7.54 (dt, J=7.9, 1.0 Hz, 1 H), 7.23 (m, 2 H) 7.07 (m, 2H), 5.42 (s, 2H), 4.19 (s, 2H); MS: (M+H m/z=355.2).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10](Br)[CH:9]=1)(=[O:3])[CH3:2].[CH3:27][O:28][C:29]1[N:34]=[CH:33][C:32](B(O)O)=[CH:31][N:30]=1>>[C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:32]2[CH:31]=[N:30][C:29]([O:28][CH3:27])=[N:34][CH:33]=2)[CH:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cccc(Br)c1
Reactant: COc1ncc(B(O)O)cn1
Product: COc1ncc(-c2cccc(O[C@@H]3SC[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)c2)cn1

Procedure:
By carrying out the operation analogously to example 3, starting from 3-bromophenyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation VII, and 2-methoxy-5-pyrimidineboronic acid, the expected product is obtained and is reacted further without additional purification in order to obtain the nonacetylated xyloside.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)[CH2:23][C:24]1[CH:25]=[N:26][NH:27][CH:28]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[CH2:39][C:40]1[CH:41]=[N:42][N:43]([CH2:45][CH3:46])[CH:44]=1>>[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([CH2:23][C:24]1[CH:25]=[N:26][N:27]([CH2:39][C:40]2[CH:41]=[N:42][N:43]([CH2:45][CH3:46])[CH:44]=2)[CH:28]=1)[C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)c1ccc(N(Cc2cn[nH]c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Reactant: CCn1cc(CCl)cn1
Agent: Cl
Product: CCn1cc(Cn2cc(CN(C(=O)C3CCCc4c(OCc5ccccc5)cccc43)c3ccc(C(C)C)nc3)cn2)cn1
Yield: 65.3 %

Procedure:
By the reaction and treatment in the same manner as in Example 271 using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.78 g) and 4-chloromethyl-1-ethylpyrazole (0.43 g) as starting materials, 5-benzyloxy-N-({1-[(1-ethylpyrazol-4-yl)methyl]pyrazol-4-yl}methyl)-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.58 g) was obtained.
Reaction SMILES: [C@@H:1]1([NH:10][C:11]2[C:12]3[CH:19]=[CH:18][N:17]([C@@H:20]4[CH2:24][C@@H:23]([CH2:25][OH:26])[C@@H:22]([OH:27])[C@H:21]4[OH:28])[C:13]=3[N:14]=[CH:15][N:16]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[Si:29](Cl)([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30].N1C=CN=C1>CN(C=O)C>[Si:29]([O:26][CH2:25][C@@H:23]1[CH2:24][C@@H:20]([N:17]2[C:13]3[N:14]=[CH:15][N:16]=[C:11]([NH:10][C@@H:1]4[C:9]5[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=5)[CH2:3][CH2:2]4)[C:12]=3[CH:19]=[CH:18]2)[C@H:21]([OH:28])[C@@H:22]1[OH:27])([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30]
Reactant: OC[C@@H]1C[C@@H](n2ccc3c(N[C@H]4CCc5ccccc54)ncnc32)[C@H](O)[C@@H]1O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@@H](n2ccc3c(N[C@H]4CCc5ccccc54)ncnc32)[C@H](O)[C@@H]1O
Reaction time: 1 h

Procedure:
A solution of (1R,2S,3R,5S)-3-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}-5-(hydroxymethyl)cyclopentane-1,2-diol (166 mg, 0.436 mmol, as prepared in Example 15a), tert-butyldimethylsilyl chloride (69.0 mg, 0.458 mmol), 1H-imidazole (44.6 mg, 0.654 mmol) in DMF (2.00 mL) was stirred under an atmosphere of nitrogen. After 2 h additional tert-butyldimethylsilyl chloride (6.00 mg, 0.0365 mmol) was added and the solution was stirred for 1 hour. The reaction was quenched with water and extracted with EtOAc. The combined organics were washed with water and saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue filtered through a plug of silica gel eluting with 60% EtOAc in hexanes to afford the title compound as an off white solid (179 mg, 83%). LC/MS: Rt=1.51 min, ES+ 495 (FA standard).
Reaction SMILES: [CH3:1][C:2]([CH3:20])([CH3:19])[CH2:3][O:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH:15]=O)[CH:13]=2)[N:8]=[CH:7][C:6]=1[C:17]#[N:18].COC1C=CC(/C=[C:36]2/[C:37]([NH:39][C:40]([S:42]/2)=[NH:41])=[O:38])=CC=1OC1CCCC1.C([O-])(=O)C.[Na+]>C(O)(=O)C>[NH2:41][C:40]1[S:42]/[C:36](=[CH:15]\[C:12]2[CH:13]=[C:14]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:17]#[N:18])=[C:5]3[O:4][CH2:3][C:2]([CH3:20])([CH3:19])[CH3:1])/[C:37](=[O:38])[N:39]=1
Reactant: COc1ccc(/C=C2\SC(=N)NC2=O)cc1OC1CCCC1
Reactant: CC(C)(C)COc1c(C#N)cnc2ccc(C=O)cc12
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)(C)COc1c(C#N)cnc2ccc(/C=C3\SC(N)=NC3=O)cc12

Procedure:
Similar procedure as described in example 28c was used, starting from 4-(2,2-dimethyl-propoxy)-6-formyl-quinoline-3-carbonitrile (example 67b), pseudothiohydantoin, sodium acetate and acetic acid to give 6-[2-amino-4-oxo-4H-thiazol-(5Z)-ylidenemethyl]-4-(2,2-dimethyl-propoxy)-quinoline-3-carbonitrile. LC-MS m/e 367 (MH+).