Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C@H:8]([CH:12]([CH3:14])[CH3:13])[C@:7]([CH2:16][CH2:17][N:18]([CH2:20][CH2:21][CH2:22][N:23]([CH2:33][CH2:34][F:35])[CH2:24][C:25]([CH2:30][O:31][CH3:32])([CH3:29])[CH2:26][O:27][CH3:28])[CH3:19])([OH:15])[CH2:6][CH2:5]2.CCN(CC)CC.[C:43](Cl)(=[O:47])[CH:44]([CH3:46])[CH3:45]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C@H:8]([CH:12]([CH3:13])[CH3:14])[C@@:7]([O:15][C:43](=[O:47])[CH:44]([CH3:46])[CH3:45])([CH2:16][CH2:17][N:18]([CH2:20][CH2:21][CH2:22][N:23]([CH2:33][CH2:34][F:35])[CH2:24][C:25]([CH2:26][O:27][CH3:28])([CH3:29])[CH2:30][O:31][CH3:32])[CH3:19])[CH2:6][CH2:5]2
Reactant: COCC(C)(COC)CN(CCF)CCCN(C)CC[C@@]1(O)CCc2cc(F)ccc2[C@@H]1C(C)C
Reactant: CC(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCC(C)(COC)CN(CCF)CCCN(C)CC[C@@]1(OC(=O)C(C)C)CCc2cc(F)ccc2[C@@H]1C(C)C
Temperature: 0 °C
Reaction time: 0.42 h

Procedure:
To a solution of 398 mg of (1S,2S)-6-fluoro-2-[2-({3-[(2-fluoro-ethyl)-(3-methoxy-2-methoxymethyl-2-methyl-propyl)-amino]-propyl}-methyl-amino)-ethyl]-1-isopropyl-1,2,3,4-tetrahydro-naphthalen-2-ol and 0.44 mL of NEt3 in 8 mL of DCM 0.25 mL of isobutyrylchloride was added at 0° C. The mixture was stirred for 25 min at 0° C. and then for 3 h at rt. It was quenched with sat. aqueous NaHCO3 and extracted with DCM. The organic phase was dried over anh. Na2SO4 and concentrated in vacuo. The resulting crude was purified by CC using EtOAc/Hept 3/1 as eluant to yield 411 mg of isobutyric acid (1S,2S)-6-fluoro-2-[2-({3-[(2-fluoro-ethyl)-(3-methoxy-2-methoxymethyl-2-methyl-propyl)-amino]-propyl}-methyl-amino)-ethyl]-1-isopropyl-1,2,3,4-tetrahydro-naphthalen-2-yl ester as orange oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[CH3:9][O:10][CH2:11]Cl.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH3:9][O:10][CH2:11][O:8][C:4]1[CH:3]=[C:2]([Br:1])[CH:7]=[CH:6][CH:5]=1
Reactant: COCCl
Reactant: Oc1cccc(Br)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCOc1cccc(Br)c1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of 3-bromophenol (27.4 g, 158 mmol) in CH2Cl2 was added chloromethyl methyl ether (18 mL, 237 mmol). The reaction mixture was cooled to 0° C. and diisopropylethylamine (55 mL, 316 mmol) was added and the cold bath was removed. The reaction mixture was stirred for 3 hours at ambient temperature and then poured into 10% aqueous HCl. The layers were separated and the aqueous phase was extracted 4 times with CH2Cl2. The combined organic layers were washed once each with saturated aqueous NaHCO3, 15% aqueous NaOH, and brine, dried over MGSO4, filtered, and concentrated in vacuo to provide 3-methyloxymethoxybromobenzene as a yellow oil.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH:7]1([CH2:14][C:15]#[N:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=[CH:8]1>C(OCC)C>[CH:7]1([CH2:14][CH2:15][NH2:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=[CH:8]1
Reactant: N#CCC1C=CC=CC=C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: NCCC1C=CC=CC=C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 72.4 %

Procedure:
To a suspension of lithium aluminum hydride (911 mg, 24.0 mmol, 1.4 eq.) in anhydrous diethyl ether (75 mL, 0.23 M) at 0° C. was slowly added, drop-wise over 15 minutes, a solution of #61 (2.25 g, 17.2 mmol, 1 eq.) in diethyl ether (15 mL). The reaction was warmed to room temperature. After 5 hours, the reaction was cooled to 0° C. and quenched by addition of water (1 mL), then filtered through a small pad of Celite and washed with methanol. The filtrate was dried over sodium sulfate, filtered, and concentrated in vacuo to provide #62 (1.683 g, 73%) as a golden oil. LC-MS: m/z 136.1 [M+H+], retention time=0.23 minutes; 1H NMR (400 MHz, CDCl3) δ 6.64-6.67 (m, 2H), 6.16-6.21 (m, 2H), 5.16-5.21 (m, 2H), 2.84-2.89 (m, 2H), 1.86-1.92 (m, 2H), 1.62-1.70 (m, 1H).
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH:18]=O)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2].[NH:30]1[CH2:33][CH:32]([CH2:34][N:35]([CH3:40])[CH:36]2[CH2:39][O:38][CH2:37]2)[CH2:31]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH2:18][N:30]4[CH2:31][CH:32]([CH2:34][N:35]([CH3:40])[CH:36]5[CH2:37][O:38][CH2:39]5)[CH2:33]4)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2]
Reactant: CN(CC1CNC1)C1COC1
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=O)n(C)c2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CC(CN(C)C4COC4)C3)n(C)c2n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 59.2 %

Procedure:
A mixture of 2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde (78 mg, 0.2 mmol), (azetidin-3-ylmethyl)methyloxetan-3-yl-amine (47 mg, 0.3 mmol), and 4 Å molecular sieves (250 mg) in 1,2-dichloroethane (2 mL) was stirred at RT for 6 h. Sodium triacetoxyborohydride (85 mg, 0.4 mmol) was added and the resulting reaction mixture was stirred at RT under nitrogen atmosphere for 16 h. The suspension was filtered through Celite and the filtrate was concentrated in vacuo. The crude residue was loaded on an Isolute® SCX-2 cartridge (5 g). The cartridge was washed with DCM/MeOH and the desired product was subsequently eluted using a mixture of 2M NH3 in MeOH and DCM. The residue was purified by column chromatography (Si—PPC, MeOH:DCM, gradient 0:100 to 8:92) to afford 421 as an off-white foam (63 mg, 59%). LCMS (Method I): RT 2.11 min, [M+H]+ 532. 1H NMR (400 MHz, CDCl3): δ 7.97-7.96 (1 H, m), 7.72-7.71 (1 H, m), 7.23 (2 H, t, J=3.78 Hz), 4.61 (2 H, t, J=6.53 Hz), 4.53 (2 H, t, J=6.23 Hz), 4.32 (4 H, s), 3.82-3.81 (9 H, m), 3.51-3.50 (3 H, m), 3.32 (2 H, q, J=7.48 Hz), 3.03-2.89 (2 H, m), 2.68-2.57 (1 H, m), 2.40 (2 H, d, J=7.26 Hz), 2.04 (3 H, s), 1.41 (3 H, t, J=7.47 Hz)
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:32])=[C:4]([CH:29]=[CH:30][CH:31]=1)[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:27][CH3:28])=[C:13]([O:16][CH:17]3[CH2:22][CH2:21][N:20]([C:23](=[O:26])[CH2:24]Cl)[CH2:19][CH2:18]3)[CH:14]=2)[N:9]=[CH:8][N:7]=1.[I-].[Na+].[NH:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1>>[Cl:1][C:2]1[C:3]([F:32])=[C:4]([CH:29]=[CH:30][CH:31]=1)[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:27][CH3:28])=[C:13]([O:16][CH:17]3[CH2:22][CH2:21][N:20]([C:23](=[O:26])[CH2:24][N:35]4[CH2:39][CH2:38][CH2:37][CH2:36]4)[CH2:19][CH2:18]3)[CH:14]=2)[N:9]=[CH:8][N:7]=1
Reactant: C1CCNC1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC1CCN(C(=O)CCl)CC1
Agent: [I-]
Agent: [Na+]
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC1CCN(C(=O)CN2CCCC2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A suspension of 4-(3-chloro-2-fluoroanilino)-6-[1-(chloroacetyl)piperidin-4-yloxy]-7-methoxyquinazoline (0.15 g) (starting material used in Example 17) and sodium iodide (0.02 g) in pyrrolidine (5 ml) was stirred at ambient temperature for 16 hours. The mixture was evaporated under vacuum and the residue dissolved in methylene chloride/methanol. This was adsorbed onto silica and purified by column chromatography eluting with increasingly polar mixtures of methylene chloride/methanol (100/0 to 92/8). The fractions containing the title product were combined and evaporated under vacuum and the residue triturated with diethyl ether, filtered and dried under vacuum to give the title product as a white crystalline solid. (0.085 g); 1H NMR Spectrum: (DMSO d6) 1.57-1.77 (m, 6H), 1.92-2.09 (m, 2H), 3.20-3.48 (m, 8H), 3.80-3.90 (m, 2H), 3.94 (s, 3H), 4.75 (m, 1H), 7.2-7.31 (m, 2H), 7.45-7.55 (m, 2H), 7.86 (s, 1H), 8.37 (s, 1H), 9.53 (s, 1H); Mass Spectrum: (M−H)+ 514.
Reaction SMILES: [F:1][C:2]([F:62])([F:61])[C:3]1[CH:4]=[C:5]([CH:54]=[C:55]([C:57]([F:60])([F:59])[F:58])[CH:56]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:16]=[N:17][N:18](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:19]=2)[CH2:10][C@H:9]1[CH2:39][C:40]1[CH:45]=[CH:44][C:43]([CH3:46])=[C:42]([O:47][CH2:48][O:49][CH2:50][CH2:51][O:52][CH3:53])[CH:41]=1)=[O:7].Cl.[OH-].[Na+].[Cl-].[Na+]>O1CCOCC1>[F:62][C:2]([F:1])([F:61])[C:3]1[CH:4]=[C:5]([CH:54]=[C:55]([C:57]([F:59])([F:58])[F:60])[CH:56]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:19]=[N:18][NH:17][CH:16]=2)[CH2:10][C@H:9]1[CH2:39][C:40]1[CH:45]=[CH:44][C:43]([CH3:46])=[C:42]([O:47][CH2:48][O:49][CH2:50][CH2:51][O:52][CH3:53])[CH:41]=1)=[O:7]
Reactant: COCCOCOc1cc(C[C@@H]2CN(Cc3cnn(C(c4ccccc4)(c4ccccc4)c4ccccc4)c3)CCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)ccc1C
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COCCOCOc1cc(C[C@@H]2CN(Cc3cn[nH]c3)CCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)ccc1C
Temperature: 40 °C
Reaction time: 7 h
Yield: 67.7 %

Procedure:
To a solution of (2R)-1-[3,5-bis(trifluoromethyl)-benzoyl]-2-[3-[(2-methoxyethoxy)methoxy]-4-methylbenzyl]-4-[(1-trityl-1H-pyrazol-4-yl)methyl]piperazine (1.184 g) in 1,4-dioxane (118 ml) was added 1N hydrochloric acid (71 ml) and the resulting mixture was stirred at 40° C. for 7 hours. After cooling, the pH of the mixture was adjusted to 7 with 4N sodium hydroxide solution and sodium chloride was added to the mixture. The organic layer was separated, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel with a mixture of methylene chloride and methanol (30:1) as eluent to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-[3-[(2-methoxyethoxy)methoxy]-4-methylbenzyl]-4-[(1H-pyrazol-4-yl)-methyl]piperazine (575 mg).
Reaction SMILES: [C:1]([O:10][CH2:11][C:12]([O:14][CH2:15][C:16]([OH:18])=O)=[O:13])(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C(Cl)(=O)C([Cl:22])=O>CCCCCC>[C:1]([O:10][CH2:11][C:12]([O:14][CH2:15][C:16]([Cl:22])=[O:18])=[O:13])(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCCCCCCC(=O)OCC(=O)OCC(=O)O
Solvent: CCCCCC
Product: CCCCCCCC(=O)OCC(=O)OCC(=O)Cl
Temperature: 25 °C
Reaction time: 6 h

Procedure:
5.6 g (0.022 mole) octanoyl-oxyacetyl-oxyacetic acid, 50 ml hexane were placed in a 250 ml round bottom flask. 2.9 ml (0.03 mole) oxalyl chloride was added in one portion and the reaction stirred at room temperature for 6 hours. The reaction was then heated to 80° C., a distillation head attached with condenser and receiver, and the excess oxalyl chloride and solvent removed at reduced pressure. There remained 4.5 g of light yellow oil. IR spectrum reveals no free --OH and a broad V--C=O absorbance, with maxima at 1815, 1780 and 1755 cm-1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[CH:20][CH:19]=[CH:18][C:4]=1[O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:8]([C:9]([OH:11])=O)[C:7]=1[C:15]([OH:17])=O.Cl.[NH2:23][CH:24]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:25]1=[O:26]>N1C=CC=CC=1>[O:26]=[C:25]1[CH:24]([N:23]2[C:15](=[O:17])[C:7]3[C:8](=[CH:12][CH:13]=[CH:14][C:6]=3[O:5][C:4]3[CH:18]=[CH:19][CH:20]=[CH:21][C:3]=3[O:2][CH3:1])[C:9]2=[O:11])[CH2:30][CH2:29][C:28](=[O:31])[NH:27]1
Reactant: NC1CCC(=O)NC1=O
Reactant: COc1ccccc1Oc1cccc(C(=O)O)c1C(=O)O
Agent: Cl
Solvent: c1ccncc1
Product: COc1ccccc1Oc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Yield: 88 %

Procedure:
A mixture of 3-(2-methoxy-phenoxy)-phthalic acid (0.51 g, 1.8 mmol) and rac-α-aminoglutarimide hydrochloride (0.29 g, 1.8 mmol) in pyridine (10 mL) was heated to reflux for 16 h. The mixture was cooled and evaporated under vacuum. The residue was dissolved in ethyl acetate (100 mL) and washed with dilute aqueous HO (2×100 mL) and water (100 mL), and was evaporated. The residue was chromatographed using a CH2Cl2-methanol gradient, eluting the title compound at 95:5 CH2Cl2-methanol, 0.59 g, in 88% yield; mp 223-225° C.; HPLC, Waters Symmetry C-18, 3.9×150 mm, 5 μm, 1 mL/min, 240 nm, 40/60 CH3CN/0.1% H3PO4, 6.06 (99.46%); 1H NMR (DMSO-d6) δ 2.06-2.11 (m, 1H), 2.53-2.64 (m, 2H), 2.83-2.90 (m, 1H), 3.75 (s, 1H), 5.15 (dd, J=12.4 Hz, J=5.3 Hz, 1H), 6.85 (d, J=8.5 Hz, 1H), 7.06 (t, J=7.3 Hz, 1H), 7.21-7.37 (m, 3H), 7.54 (d, J=7.2 Hz, 1H), 7.72 (t, J=7.9 Hz, 1H), 11.13 (s, 1H); 13C NMR (DMSO-d6) δ 21.9, 31.0, 48.9, 55.7, 113.7, 116.5, 116.7, 120.7, 121.5, 122.3, 127.2, 133.3, 137.0, 141.3, 151.2, 154.7, 165.0, 166.6, 170.0, 172.8; Anal. Calcd for C20H16N2O6: C, 63.16; H, 4.24; N. 7.37. Found: C, 63.00; H, 4.24; N, 7.29.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:13][CH:12]=1.Cl.O>N1C=CC=CC=1>[C:1]([O:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:15][CH:16]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Oc1ccc(-c2ccccc2)cc1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: O=C(Oc1ccc(-c2ccccc2)cc1)c1ccccc1
Yield: 94 %

Procedure:
128 ml benzoyl chloride is dripped into a solution of 170 g 4-hydroxybiphenyl in 500 ml pyridine, at 20° C.; subsequently, the reaction mixture is heated under reflux for 30 min. After cooling, the reaction mixture is mixed with a solution of 500 ml concentrated hydrochloric acid and 750 ml water. The remaining precipitate is filtered off, washed neutral with water, dried and recrystallized from n-butanol (melting point: 150° C.); yield: 94%.
Reaction SMILES: C1(C)C=CC=CC=1.Cl.[CH3:9][C:10]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][C:11]=1[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20](=[N:24][O:25][CH3:26])[C:21]([NH2:23])=[O:22]>O>[CH3:9][C:10]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][C:11]=1[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1/[C:20](=[N:24]\[O:25][CH3:26])/[C:21]([NH2:23])=[O:22]
Reactant: CON=C(C(N)=O)c1ccccc1COc1cc(C)ccc1C
Agent: Cl
Solvent: Cc1ccccc1
Solvent: O
Product: CO/N=C(/C(N)=O)c1ccccc1COc1cc(C)ccc1C
Temperature: 85 °C
Reaction time: 2 h
Yield: 81.6 %

Procedure:
Toluene (4 ml) and conc. hydrochloric acid (0.8 ml) were added to 2-[2-(2,5-dimethylphenoxymethyl)phenyl]-2-methoxyiminoacetamide (E/Z=15/85) (1.25 g, 4.0 mmol), and the mixture was stirred at 85° C. for 2 hours. After the reaction, water (80 ml) was added. The mixture was extracted with toluene (80 ml), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give crystals. The crystals were recrystallized from n-hexane/ethyl acetate to give (E)-2-[2-(2,5-dimethylphenoxymethyl)phenyl]-2-methoxyiminoacetamide (1.02 g, Yield: 81.6%) as colorless crystals.
Reaction SMILES: [CH3:1][C@H:2]([C:15]([OH:17])=[O:16])[C:3]1[CH:4]=[CH:5][C:6]2[CH:7]=[C:8]([O:13][CH3:14])[CH:9]=[CH:10][C:11]=2[CH:12]=1.[NH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25].[NH2:27][CH:28]([CH2:31][OH:32])[CH2:29][OH:30].[C:33]1(=[O:39])[O:38][C:36](=[O:37])[CH2:35][CH2:34]1.ClCCl>CN(C1C=CN=CC=1)C.C(Cl)CCl>[CH3:1][C@H:2]([C:15]([OH:17])=[O:16])[C:3]1[CH:4]=[CH:5][C:6]2[CH:7]=[C:8]([O:13][CH3:14])[CH:9]=[CH:10][C:11]=2[CH:12]=1.[NH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25].[NH2:27][CH:28]([CH2:31][OH:32])[CH2:29][OH:30].[CH2:35]([C:36]([O-:13])=[O:37])[CH2:34][C:33]([O-:38])=[O:39]
Reactant: O=C1CCC(=O)O1
Agent: CN(C)c1ccncc1
Agent: COc1ccc2cc([C@H](C)C(=O)O)ccc2c1
Agent: NC(CO)CO
Solvent: ClCCl
Solvent: ClCCCl
Product: O=C([O-])CCC(=O)[O-]
Yield: 1363.6 %

Procedure:
The desired solid support 8a was prepared according to reported procedures (References for succinilation: Rajeev et al., Org. Lett., 2003, 5, 3005 and for conjugation to CPG: Kumar et al., Nucleosides Nucleotides, 1996, 15, 879). A mixture of compound 7a (1.00 g, 1.39 mmol), succinic anhydride (0.17 g, 1.69 mmol, purchased from Aldrich) and DMAP (0.21 g, 1.72 mmol) were suspended in 7 mL of anhydrous ethylene dichloride for 24 h. Reaction mixture was diluted to 50 mL by adding dichloromethane and washed with dilute aqueous citric acid solution (20 mL), dried over anhydrous Na2SO4 and evaporated to dryness. The residue obtained was further dried over P2O5 under vacuum to afford an almost pure but crude monosuccinate as a white solid (1.10 g, 96.5%). The product obtained was directly used for subsequent reaction without further purification. 1H NMR (400 MHz, [D6]DMSO, 25° C.): δ7.94-7.91 (t, J(H,H)=5.19, 5.49 Hz, 1H, exchangeable with D2O), 7.83-7.81 (d, J(H,H)=7.94 Hz, 1H, exchangeable with D2O), 7.76-7.68 (m, 3H), 7.42-7.10 (m, 12H), 6.88-6.86 (d, 4H), 4.18-4.12 (m, 2H), 4.07-3.98 (m, 2H), 3.83 (s, 3H), 3.71-3.66 (m, 7H), 3.00-2.91 (m, 4H), 2.40 (s, 4H), 2.04-2.00 (t, J(H,H)=7.32 Hz, 2H), 1.44-1.22 (m, 7H), 1.19-1.15 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([Br:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[CH:10](=O)/[CH:11]=[CH:12]/[CH3:13].N>Cl>[Br:9][C:7]1[CH:6]=[C:5]2[C:3](=[C:2]([F:1])[CH:8]=1)[N:4]=[C:12]([CH3:13])[CH:11]=[CH:10]2
Reactant: Nc1ccc(Br)cc1F
Reactant: C/C=C/C=O
Agent: Cl
Agent: N
Product: Cc1ccc2cc(Br)cc(F)c2n1
Yield: 46.8 %

Procedure:
2-Fluoro-4-bromoaniline (10 g, 0.053 mol) was slurried in 6M HCl (100 ml). The mixture was heated to reflux and crotonaldehyde (14.9 g, 0.212 mol) was added dropwise over 1 hour. The resulting mixture was heated for an additional 90 minutes, then cooled down to room temperature and neutralized by careful addition of concentrated ammonia solution. The mixture was extracted with ethyl acetate and the organic layer was washed with water and brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography, eluting with 15-10% ethyl acetate/petrol. The product containing fractions were combined and concentrated to ca 60 ml. The product was then isolated by filtration. The filter cake was washed with petrol and air dried to afford the title compound as a solid (5.96 g, 47% yield). 1H NMR (CDCl3, 400 MHz) 2.80 (3H, s), 7.38 (1H, d), 7.53 (1H, d), 7.76 (1H, s), 8.00 (1H, d); MS (ES+) 240/242.
Reaction SMILES: C([N:3]1[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][O:11][CH3:12])[CH2:5][CH2:4]1)=O.[ClH:13].O1CCOCC1>CO>[ClH:13].[ClH:13].[CH3:12][O:11][CH2:10][CH2:9][N:6]1[CH2:7][CH2:8][NH:3][CH2:4][CH2:5]1
Reactant: COCCN1CCN(C=O)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: COCCN1CCNCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 57.2 g of 1-formyl-4-methoxyethylpiperazine in 100 mL of methanol was added dropwise 180 mL of 4N-hydrochloric acid/1,4-dioxane over 1.5 hours. The mixture was stirred at room temperature for 1 hour, and the resulting crystals were filtered, washed with isopropyl ether and dried in vacuo to give 68.8 g of the title compound.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]3[CH:14]=[CH:15][C:16]([C:18]#[C:19][CH2:20]OS(C)(=O)=O)=[CH:17][C:12]=3[S:11][N:10]=2)=[CH:5][CH:4]=1.[NH:28]1[CH2:31][CH2:30][CH2:29]1>>[N:28]1([CH2:20][C:19]#[C:18][C:16]2[CH:15]=[CH:14][C:13]3[C:9]([C:6]4[CH:7]=[CH:8][C:3]([C:2]([F:27])([F:26])[F:1])=[CH:4][CH:5]=4)=[N:10][S:11][C:12]=3[CH:17]=2)[CH2:31][CH2:30][CH2:29]1
Reactant: CS(=O)(=O)OCC#Cc1ccc2c(-c3ccc(C(F)(F)F)cc3)nsc2c1
Reactant: C1CNC1
Product: FC(F)(F)c1ccc(-c2nsc3cc(C#CCN4CCC4)ccc23)cc1

Procedure:
In analogy to example 17.1, Methanesulfonic acid 3-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-prop-2-ynyl ester and azetidine were converted to yield 6-(3-Azetidin-1-yl-prop-1-ynyl)-3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazole as light brown oil, MS: 373 (MH+).
Reaction SMILES: C[C:2]1(C)[O:6][C:5](=[CH:7][C:8]([N:10]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[C:16]([CH3:21])[CH:15]=2)[O:11][CH3:12])=[O:9])[C:4](=[O:22])[O:3]1>CO>[CH3:2][O:3][C:4](=[O:22])[C:5]([OH:6])=[CH:7][C:8](=[O:9])[N:10]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[C:16]([CH3:21])[CH:15]=1)[O:11][CH3:12]
Reactant: CON(Cc1ccc(F)c(C)c1)C(=O)C=C1OC(C)(C)OC1=O
Solvent: CO
Product: COC(=O)C(O)=CC(=O)N(Cc1ccc(F)c(C)c1)OC
Yield: 32 %

Procedure:
2-(2,2-Dimethyl-5-oxo-[1,3]-dioxolan-4-ylidene)-N-(4-fluoro-3-methylbenzyl)-N-methoxy-acetamide, prepared using the methods described in the previous examples, was treated with methanol as described in the preparation of Compound 44-C and gave the title ester as white crystals (32% yield); mp 60–62° C. 1HNMR 400 MHz (CDCl3) δ (ppm): 2.27 (3H, broad s, CH3), 3.70 (3H, s, OCH3), 3.90 (3H, s, OCH3), 4.76 (2H, s, NCH2), 6.46 (1H, s, CH), 6.96 (1H, m, aromatic), 7.12 (2H, m, aromatics). Anal. calcd for C14H16FNO5: C, 56.56; H, 5.42; N, 4.71. Found: C, 56.36; H, 5.44; N, 4.54.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[C:12]([N:14]3[CH:23]([CH3:24])[CH2:22][C:21]4[C:16](=[CH:17][C:18](B5OC(C)(C)C(C)(C)O5)=[CH:19][CH:20]=4)[CH2:15]3)[N:11]=[C:10]([NH2:34])[N:9]=2)[CH2:4][CH2:3]1.I[C:36]1[CH:41]=[CH:40][N:39]=[C:38]([C:42]([O:44]C)=[O:43])[CH:37]=1>>[NH2:34][C:10]1[N:11]=[C:12]([N:14]2[CH:23]([CH3:24])[CH2:22][C:21]3[C:16](=[CH:17][C:18]([C:36]4[CH:41]=[CH:40][N:39]=[C:38]([C:42]([OH:44])=[O:43])[CH:37]=4)=[CH:19][CH:20]=3)[CH2:15]2)[CH:13]=[C:8]([N:5]2[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]2)[N:9]=1
Reactant: COC(=O)c1cc(I)ccn1
Reactant: CC1Cc2ccc(B3OC(C)(C)C(C)(C)O3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Product: CC1Cc2ccc(-c3ccnc(C(=O)O)c3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 50A, Step 1 starting from 4-(4-methylpiperazin-1-yl)-6-[3-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl]pyrimidin-2-amine and methyl 4-iodopyridine-2-carboxylate (Combi-Blocks, Cat. No. CA-4128). LCMS (M+H)+: m/z=460.2.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=3)=[CH:9][N:8]([CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[C:4]=2[N:5]=[CH:6][N:7]=1.C[N:25]([CH3:28])C=O>>[NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:12]=[CH:13][C:14]([O:17][C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=4[C:28]#[N:25])=[CH:15][CH:16]=3)=[CH:9][N:8]([CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CN(C)C=O
Reactant: Nc1ncnc2c1c(-c1ccc(O)cc1)cn2C1CCOCC1
Product: N#Cc1ccccc1Oc1ccc(-c2cn(C3CCOCC3)c3ncnc(N)c23)cc1
Temperature: 120 °C
Reaction time: 6 h

Procedure:
A warm solution of 4-[4-amino-7-(4-tetrahydropyranyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]phenol (0.082 g) in dimethylformamide (3.4 ml) was added to a The vial was flushed with nitrogen then sealed. The mixture was shaken at 120° C. for 6 hours and then left to cool to ambient temperature over 16 hours. The mixture was diluted with water (11 ml) and then extracted with ethyl acetate to give 2-[4-(4-amino-7-(4-tetrahydropyranyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenoxy]benzonitrile, m.p. 125° C. (softens).
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12].[F:16][C:17]1[CH:22]=[C:21]([F:23])[CH:20]=[C:19](F)[C:18]=1[N+:25]([O-:27])=[O:26]>CS(C)=O>[F:16][C:17]1[C:18]([N+:25]([O-:27])=[O:26])=[C:19]([CH:20]=[C:21]([F:23])[CH:22]=1)[NH:1][C:2]1[S:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)c1c(N)sc2ccccc12
Reactant: O=[N+]([O-])c1c(F)cc(F)cc1F
Solvent: CS(C)=O
Product: CCOC(=O)c1c(Nc2cc(F)cc(F)c2[N+](=O)[O-])sc2ccccc12

Procedure:
In the same manner as in Starting Material Synthesis Example 4 and using ethyl 2-aminobenzo[b]thiophene-3-carboxylate, 2,4,6-trifluoronitrobenzene and dimethyl sulfoxide, ethyl 2-(3,5-difluoro-2-nitroanilino)benzo[b]thiophene-3-carboxylate is obtained.