Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:36]=[CH:35][C:7]([O:8][C:9]2[CH:10]=[CH:11][C:12]3[N:16]=[C:15]([CH2:17][O:18][C:19]4[CH:32]=[CH:31][C:22]([CH2:23][CH:24]5[S:28][C:27](=[O:29])[NH:26][C:25]5=[O:30])=[CH:21][CH:20]=4)[N:14]([CH3:33])[C:13]=3[CH:34]=2)=[CH:6][CH:5]=1.[C:37](Cl)(=[O:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.C(N(CC)CC)C>CN(C)C=O>[C:37]([NH:3][C:4]1[CH:36]=[CH:35][C:7]([O:8][C:9]2[CH:10]=[CH:11][C:12]3[N:16]=[C:15]([CH2:17][O:18][C:19]4[CH:32]=[CH:31][C:22]([CH2:23][CH:24]5[S:28][C:27](=[O:29])[NH:26][C:25]5=[O:30])=[CH:21][CH:20]=4)[N:14]([CH3:33])[C:13]=3[CH:34]=2)=[CH:6][CH:5]=1)(=[O:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(Oc3ccc(N)cc3)cc21
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(Oc3ccc(NC(=O)c4ccccc4)cc3)cc21
Yield: 58.4 %

Procedure:
In a similar manner to that described in Example 47, a reaction was carried out using 5-{4-[6-(4-aminophenoxy)-1-methyl-1H-benzimidazole-2-ylmethoxy]benzyl}thiazolidine-2,4-dione dihydrochloride (400 mg), benzoylchloride (126 mg), triethylamine (263 mg) and anhydrous N,N-dimethylformamide (8 ml) and the reaction mixture was purified to give the title compound (247 mg).
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[CH:4]=[CH:5][C:6]([OH:8])=O.[S:13]1[CH:17]=[CH:16][N:15]=[C:14]1[C:18]1[CH:19]=[C:20]([C@@H:24]([NH2:26])[CH3:25])[CH:21]=[CH:22][CH:23]=1>>[F:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[CH:4]=[CH:5][C:6]([NH:26][C@H:24]([C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([C:14]2[S:13][CH:17]=[CH:16][N:15]=2)[CH:19]=1)[CH3:25])=[O:8]
Reactant: C[C@H](N)c1cccc(-c2nccs2)c1
Reactant: O=C(O)C=Cc1ccccc1F
Product: C[C@H](NC(=O)C=Cc1ccccc1F)c1cccc(-c2nccs2)c1

Procedure:
The title compound was prepared from 2-fluorocinnamic acid and (S)-1-(3-thiazol-2-yl-phenyl)-ethylamine following the general procedures as described for Example 1.
Reaction SMILES: [O:1]([CH2:8][C@@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1C(OC(C)(C)C)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.[O:28]=[C:29]1[C:37](=[O:38])[C:36]2[C:31](=[CH:32][CH:33]=[C:34]([S:39](Cl)(=[O:41])=[O:40])[CH:35]=2)[NH:30]1>C(Cl)Cl.C1COCC1>[O:1]([CH2:8][C@@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[S:39]([C:34]1[CH:35]=[C:36]2[C:31](=[CH:32][CH:33]=1)[NH:30][C:29](=[O:28])[C:37]2=[O:38])(=[O:40])=[O:41])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1Nc2ccc(S(=O)(=O)Cl)cc2C1=O
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1COc1ccccc1
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1Nc2ccc(S(=O)(=O)N3CCC[C@H]3COc3ccccc3)cc2C1=O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 84.6 %

Procedure:
To a solution of 9 (1.46 g, 5.2 mmol) in CH2Cl2 (5 mL) was added trifluoroacetic acid (5 mL) at 0° C. The mixture was stirred at 0° C. for 15 min. After evaporation of the solvent in vacuo, CH2Cl2 (15 mL) and triethylamine (2 mL) were added, then a solution of 6 (1.44 g, 5.9 mmol) in THF (25 mL) was added at 0° C. The reaction mixture was stirred overnight at room temperature. The solvent was evaporated in vacuo, then ethyl acetate (150 mL) was added, washed with water (50 mL×2) and saturated NaCl (50 mL), and dried over Na2SO4. After evaporation of the ethyl acetate, the crude product was purified with ether to afford 1.7 g (84%) of 10 as a yellow solid, mp 204.5-205.9° C. 1H NMR (300 MHz, CDCl3) δ 8.94 (s, 1H), 7.77 (dd, J=8.25 Hz, J=2.1 Hz, 1H), 7.67 (s, 1H), 7.02 (t, J=8.7 Hz, 2H), 6.84 (d, J=8.1 Hz, 1H), 6.69 (t, J=7.2 Hz, 1H), 6.63 (d, J=7.8 Hz, 2H), 3.89 (m, 1H), 3.75-3.66 (m, 2H), 3.23 (m, 1H), 2.96 (m, 1H), 1.72 (m, 2H), 1.54-1.42 (m, 2H). LRMS (FAB) m/e: 387.1 (M+H, 100). Anal. Calcd for C19.N2O5S: C, 59.06, H, 4.70; N, 7.25. Found: C, 58.99, H, 4.74, N, 7.11.
Reaction SMILES: [CH3:1]CN(CC)CC.[Br:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]([OH:17])=O)=[N:13][CH:14]=1.[NH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22].CCN=C=NCCCN(C)C>C(Cl)Cl.O.C(Cl)Cl>[Br:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]([NH:18][CH2:19][CH2:20][C:21]([O:23][CH3:1])=[O:22])=[O:17])=[N:13][CH:14]=1
Reactant: CCN(CC)CC
Reactant: NCCC(=O)O
Reactant: O=C(O)c1ccc(Br)cn1
Agent: CCN=C=NCCCN(C)C
Solvent: O
Solvent: ClCCl
Product: COC(=O)CCNC(=O)c1ccc(Br)cn1
Temperature: 25 °C

Procedure:
Neat Et3N (5.2 mL, 37.5 mmol) was added to a DCM mixture (50 mL) of 5-bromopicolinic acid (5.1 g, 25.0 mmol), beta-alanine mether ester hydrochloride (4.2 g, 30.0 mmol), and EDCI (5.8 g, 30 mmol) and the resulting mixture was stirred at room temperature. After 24 h the resulting mixture was poured into CH2Cl2/H2O (50 mL/50 mL). The aqueous layer was extracted with CH2Cl2 (50 mL). The combined organic layers were dried (Na2SO4), concentrated, and purified via column chromatography to yield the title compound.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][NH2:17])=[C:11]([O:18][CH3:19])[C:10]=1OC)C1C=CC=CC=1.[CH2:22]([OH:24])C>[Pd]>[NH2:17][CH2:16][CH2:15][C:12]1[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][C:11]=1[O:18][CH2:19][O:24][CH3:22]
Reactant: CCO
Reactant: COc1c(CCN)ccc(OCc2ccccc2)c1OC
Agent: [Pd]
Product: COCOc1cc(O)ccc1CCN
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 18.00 g of 2-(4-benzyloxy-2-methoxy-methoxyphenyl)ethylamine, 3.6 g of 10% palladium on carbon (Degussa Inc.:E101 NE/W) and 230 mL of ethanol was stirred under a hydrogen atmosphere at room temperature for 1 hour. After the catalyst was filtered off through a diatomaceous earth, the filtrate was concentrated under reduced pressure to give 12.65 g of 4-(2-aminoethyl)-3-methoxymethoxyphenol as a colorless solid.
Reaction SMILES: [NH:1]1[CH2:4][CH2:3][C:2]1=[O:5].[C:6]([O-:9])(=[O:8])[CH3:7].[Na+].C(OO)(=O)C>[Ru](Br)Br.C1C=CC=CC=1.C(O)(=O)C.C(OCC)(=O)C>[C:6]([O:9][CH:4]1[NH:1][C:2](=[O:5])[CH2:3]1)(=[O:8])[CH3:7]
Reactant: CC(=O)[O-]
Reactant: O=C1CCN1
Agent: Br[Ru]Br
Agent: CC(=O)OO
Agent: [Na+]
Solvent: CC(=O)O
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: CC(=O)OC1CC(=O)N1
Yield: 64.7 %

Procedure:
1.42 g (20 mmol) of azetidine-2-one was added with 1.81 g (22 mmol) of anhydrous sodium acetate, 6.4 g of acetic acid, 5.6 g of ethyl acetate and 0.678 g (2 mmol) of benzene ruthenium dibromide, cooled to 5°-10° C., then added dropwise with 16.5 g of acetic acid solution containing 22% peracetic acid over 1.5 hours while stirring. After the dropping, a further 15 hour stirring was conducted at the same temperature. The solvent was distilled off under reduced pressure, followed by purification by silica gel column chromatography (hexane/ethyl acetate=1/1 by volume) to obtain 1.67 g of 4-acetoxyazetidine-2-one (yield: 65%).
Reaction SMILES: Cl.[C:2]([CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][NH:5]1)#[CH:3].[OH-].[Na+].[CH3:12][C:13]1[S:14][C:15]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:16]([C:18](Cl)=[O:19])[N:17]=1>C1(C)C=CC=CC=1.CCOC(C)=O>[C:2]([CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][N:5]1[C:18]([C:16]1[N:17]=[C:13]([CH3:12])[S:14][C:15]=1[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:19])#[CH:3]
Reactant: C#CC1CCCCN1
Reactant: Cc1nc(C(=O)Cl)c(-c2ccccc2)s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C#CC1CCCCN1C(=O)c1nc(C)sc1-c1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a rapidly-stirred mixture of 2-ethynylpiperidine hydrochloride (330 mg, 2.27 mmol), toluene (5 mL), and 1N NaOH (4.7 mL), cooled at 0° C., was added a solution of 2-methyl-5-phenyl-1,3-thiazole-4-carbonyl chloride (539 mg, 2.27 mmol) in toluene (8 mL) dropwise over 20 mins. The mixture was stirred at 0° C. for 20 mins, then allowed to warm to ambient temperature. After 1 h, the solution was diluted with EtOAc and the layers separated. Brine was added to the aqueous layer and it was extracted with EtOAc. The combined organics were dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude material was purified by silica gel flash chromatography eluting with 0-50% EtOAc in hexanes to provide (2-ethynylpiperidin-1-yl)(2-methyl-5-phenyl-1,3-thiazol-4-yl)methanone as an orange foam. The compound gave a mass ion (ES+) of 311.2 for M+H+. 1H NMR δ (ppm) (CDCl3): 7.44-7.50 (2 H, m), 7.31-7.39 (3H, m), 5.78 (1H, s), 4.58 (1H, d, J=13.6 Hz), 3.33 (1H, d, J=11.2 Hz), 2.99-3.10 (1H, m), 2.73 (3H, s), 2.30 (1H, dd, J=22.0, 3.2 Hz), 1.55-2.04 (4H, m), 1.36-1.42 (1H, m), 1.20-1.28 (1H, m), 0.87-0.97 (1H, m).
Reaction SMILES: [CH2:1]([CH:3]1[CH2:8][C:7]([CH2:9][CH3:10])=[CH:6]O[CH:4]1OC)[CH3:2].[N+:13]([O-])([O-])=O.[NH4+]>O.C(O)(=O)C.[N+]([O-])(O)=O>[CH2:1]([C:3]1[CH:4]=[N:13][CH:6]=[C:7]([CH2:9][CH3:10])[CH:8]=1)[CH3:2]
Reactant: O=[N+]([O-])[O-]
Reactant: CCC1=COC(OC)C(CC)C1
Agent: [NH4+]
Solvent: O
Solvent: O=[N+]([O-])O
Solvent: CC(=O)O
Product: CCc1cncc(CC)c1
Reaction time: 0.25 h
Yield: 64 %

Procedure:
170 parts of 3,5-diethyl-2,3-dihydro-2-methoxy-4H-pyran are dissolved in 25 parts of water, 300 parts of acetic acid and 2 parts of 60 percent strength nitric acid at 22° C. After 15 minutes, a solution of 88 parts of ammonium nitrate in 80 parts of water is added. The resulting solution is run into 800 parts of acetic acid at 110° C. in the course of 20 minutes, whilst stirring. The reaction mixture is left to cool, the acetic acid, water and methanol are distilled off, 200 parts of water are added to the residue and the solution is rendered alkaline with 25 percent strength ammonia solution. The 3,5-diethylpyridine is extracted with ether. Distillation gives 87 parts (64% of theory) of 3,5-diethylpyridine of boiling point 92° C./15 mm Hg.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:14]2[CH2:17][CH:16]([C:18]([NH:20][CH2:21][CH:22]([CH3:24])[CH3:23])=[O:19])[CH:15]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][N:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1.[H][H]>CCO.[Pd].CCOC(C)=O>[CH2:21]([NH:20][C:18]([CH:16]1[CH2:17][CH:14]([C:4]2[CH:5]=[CH:6][C:7]([CH2:8][N:9]3[CH2:13][CH2:12][CH2:11][CH2:10]3)=[C:2]([F:1])[CH:3]=2)[CH2:15]1)=[O:19])[CH:22]([CH3:24])[CH3:23]
Reactant: [H][H]
Reactant: CC(C)CNC(=O)C1C=C(c2ccc(CN3CCCC3)c(F)c2)C1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)CNC(=O)C1CC(c2ccc(CN3CCCC3)c(F)c2)C1
Yield: 54 %

Procedure:
Crude intermediate 16, 3-(3-fluoro-4-((pyrrolidin-1-yl)methyl)phenyl)-N-isobutylcyclobut-2-enecarboxamide prepared above was dissolved in EtOH (100 mL) and added to a hydrogenation bottle containing 10% palladium on carbon slurried in EtOH (˜5 mL). The mixture was shaken at room temperature under 45 psi of hydrogen for 2 h, filtered through diatomaceous earth with an EtOH rinse and concentrated to yield an orange oil. This was dissolved in EtOAc (150 mL) and washed with aqueous K2CO3 and brine, dried over MgSO4 and concentrated to afford 3.29 g of waxy orange solid. Flash chromatography on a 2.5″×4″ silica gel column eluting with 1000 mL EtOAc and 500 mL 10% MeOH/EtOAc afforded 1.90 g (54%) of the title compound as a yellow tinged solid: Rf=0.26 (20% MeOH/EtOAc).
Reaction SMILES: C([S:4][CH2:5][C:6]1[C@:7]2([CH2:24][CH2:23][C@H:22]3[C:12](=[CH:13][CH:14]=[C:15]4[C@:20]3([CH3:21])[C@@H:19]([O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])[CH2:18][C@H:17]([O:33][Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35])[CH2:16]4)[C@@H:9]2[CH2:10][CH:11]=1)[CH3:8])(=O)C.Br[CH2:42][CH2:43][C:44]([OH:47])([CH3:46])[CH3:45].CO.[OH-].[K+]>O1CCCC1>[Si:26]([O:25][C@@H:19]1[C@@:20]2([CH3:21])[C:15](=[CH:14][CH:13]=[C:12]3[C@@H:22]2[CH2:23][CH2:24][C@@:7]2([CH3:8])[C@H:9]3[CH2:10][CH:11]=[C:6]2[CH2:5][S:4][CH2:42][CH2:43][C:44]([OH:47])([CH3:46])[CH3:45])[CH2:16][C@@H:17]([O:33][Si:34]([C:37]([CH3:38])([CH3:39])[CH3:40])([CH3:36])[CH3:35])[CH2:18]1)([C:29]([CH3:31])([CH3:32])[CH3:30])([CH3:28])[CH3:27]
Reactant: CC(=O)SCC1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Reactant: CC(C)(O)CCBr
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(O)CCSCC1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Yield: 93 %

Procedure:
17-Acetylthiomethyl-1α,3β-bis(tert-butyldimethylsilyloxy)androsta-5,7,16-triene (67.7 mg, 0.112 mmol), 1-bromo-3-hydroxy-3-methylbutane (93.5 mg, 0.560 mmol), 1M potassium hydroxide methanol solution (1 ml) and tetrahydrofuran (1 ml) were subjected to reaction using a procedure similar to that of Example 31(1) (at room temperature for 30 min.), worked up and purified by preparative thin layer chromatography (2 sheets (each 0.5 mm thickness), hexane:ethyl acetate=3:1, developed once) to give the titled compound (67.4 mg, 93%) as a colorless oil.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[OH:13][C:14]([CH3:52])([CH3:51])[CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[C:28](=[O:29])[C:27]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([C:37]4[C:38]([C:43]#[N:44])=[CH:39][CH:40]=[CH:41][CH:42]=4)=[CH:33][CH:32]=3)=[C:26]([CH2:45][CH2:46][CH3:47])[N:25]3[N:48]=[CH:49][N:50]=[C:24]23)=[CH:19][CH:18]=1>O.C(OCC)(=O)C>[OH:13][C:14]([CH3:51])([CH3:52])[CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[C:28](=[O:29])[C:27]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=4[C:43]4[NH:3][C:4](=[O:7])[O:5][N:44]=4)=[CH:33][CH:32]=3)=[C:26]([CH2:45][CH2:46][CH3:47])[N:25]3[N:48]=[CH:49][N:50]=[C:24]23)=[CH:19][CH:18]=1
Reactant: O=C([O-])O
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(-c2ccc(OCC(C)(C)O)cc2)c2ncnn12
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(-c2ccc(OCC(C)(C)O)cc2)c2ncnn12
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 33.4 %

Procedure:
A mixture of hydroxylammonium chloride (0.28 g), sodium hydrogen carbonate (0.45 g) and dimethyl sulfoxide (2 mL) was stirred at 40° C. for 30 min, 4′-({4-[4-(2-hydroxy-2-methylpropoxy)phenyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (0.14 g) was added, and the mixture was stirred at 90° C. for 22 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (2 mL). N,N′-Carbonyldiimidazole (0.054 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.049 mL) were added, and the mixture was stirred at room temperature for 60 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was acidified with 1 M hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.052 g, 32%).
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH:12]=O)=[C:10]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].Cl.[NH2:19][OH:20].C(=O)([O-])[O-].[Na+].[Na+]>CO.O>[Cl:1][C:2]1[C:11]([CH:12]=[N:19][OH:20])=[C:10]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: NO
Reactant: COC(=O)c1ccc(S(C)(=O)=O)c(C=O)c1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)c1ccc(S(C)(=O)=O)c(C=NO)c1Cl
Temperature: 25 °C
Reaction time: 12 h
Yield: 91.4 %

Procedure:
15.00 g (54 mmol) of methyl 2-chloro-3-formyl-4-methylsulfonylbenzoate and 4.20 g (60 mmol) of hydroxylamine hydrochloride were taken up in 300 ml of methanol, and a solution of 3.18 g (30 mmol) of sodium carbonate in 80 ml of water was added dropwise. After the mixture had been stirred at room temperature for 12 hours, the methanol was distilled off and the residue was diluted with water and extracted with diethyl ether. The organic phase was dried and the solvent was removed. 14.40 g (91% of theory) of methyl 2-chloro-3-hydroxyiminomethyl-4-methylsulfonylbenzoate were obtained.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([CH2:12][CH2:13][C:14]([OH:16])=O)[NH:9][N:8]=1.Cl.[Cl:18][C:19]1[CH:20]=[C:21]([CH:30]=[CH:31][C:32]=1[Cl:33])[CH2:22][N:23]1[CH2:28][CH2:27][CH:26]([NH2:29])[CH2:25][CH2:24]1.C(N(CC)CC)C.[OH-].[Na+]>CC(N(C)C)=O.ClCCl>[Cl:18][C:19]1[CH:20]=[C:21]([CH:30]=[CH:31][C:32]=1[Cl:33])[CH2:22][N:23]1[CH2:24][CH2:25][CH:26]([NH:29][C:14](=[O:16])[CH2:13][CH2:12][C:10]2[NH:9][N:8]=[C:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[N:11]=2)[CH2:27][CH2:28]1
Reactant: O=C(O)CCc1nc(-c2ccccn2)n[nH]1
Reactant: NC1CCN(Cc2ccc(Cl)c(Cl)c2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CC(=O)N(C)C
Product: O=C(CCc1nc(-c2ccccn2)n[nH]1)NC1CCN(Cc2ccc(Cl)c(Cl)c2)CC1
Reaction time: 2 h
Yield: 4.4 %

Procedure:
3-[3-(2-Pyridinyl)-1,2,4-triazol-5-yl]propanoic acid (0.218 g) in 1 ml dimethylacetamide) and N,N′-carbonyldiimidazole (0.250 g) in dichloromethane was stirred under nitrogen for 30 minutes. 1-(3,4-Dichlorobenzyl)-4-piperidinamine hydrochloride (0.316 g), and triethylamine (0.218 g) was then added and allowed to stir for 2 hours under nitrogen. 1M sodium hydroxide was added to the reaction with the resulting solution being washed three times with dichloromethane. The aqueous phase was acidified with glacial acetic acid, with the water/acetic acid being removed under reduced pressure. Water was then added and extracted three times with dichloromethane. The pooled organic phases were extracted once with water and the water removed under reduced pressure to leave a white solid. This was then triturated with diethyl ether/dichloromethane, filtered and was purified by RPHPLC (75%-5%, 0.1% ammonium acetate/acetonitrile), solvent removed to leave N-[1-(3,4-dichlorobenzyl)-4-piperidinyl]-3-[3-(2-pyridinyl)-1H-1,2,4-triazol-5-yl]propanamide (0.02 g).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH3:8])[CH:3]=1.[CH2:9]1[C:14](=O)[N:13](Br)[C:11](=O)[CH2:10]1.CC(N=NC(C#N)(C)C)(C#N)C.C(NCC)C>C(Cl)(Cl)(Cl)Cl>[CH2:11]([N:13]([CH2:14][CH3:9])[CH2:8][C:4]1[CH:3]=[C:2]([I:1])[CH:7]=[CH:6][N:5]=1)[CH3:10]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(I)ccn1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCNCC
Product: CCN(CC)Cc1cc(I)ccn1
Temperature: 0 °C
Reaction time: 6 h

Procedure:
Combine 4-iodo-2-methyl-pyridine (1.1 g, 5 mmol), NBS (0.98 g, 1.1 equiv.) and carbon tetrachloride (50 mL) in a round bottomed flask under nitrogen. Add AIBN (82 mg, 0.1 equiv.) and heat reaction overnight at reflux. Filter the reaction, washing with hexanes. Concentrate filtrate to approximately 10-20 mL volume. Redissolve in THF (20 mL) and cool to 0° C. under nitrogen. Add diethylamine (1.04 mL, 2 equiv.) dropwise via syringe and stir one hour at 0° C. Remove cooling bath and let warm to room temperature. After 6 hours total, concentrate to dryness and purify by silica gel (1:1 Hexanes:Ethyl Acetate→Ethyl Acetate) to give a tan liquid (0.51 g, 35% over 2 steps). MS (ES), m/z 291.0 (M+1).
Reaction SMILES: C(O)C.[CH2:4]([N:7]1[C:13]2[CH:14]=[CH:15][C:16](Br)=[CH:17][C:12]=2[CH:11]=[C:10]([C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([CH2:28][N:29]([CH3:36])[CH:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)=[CH:24][CH:23]=2)=[O:20])[CH2:9][CH2:8]1)[CH:5]=[CH2:6].B([O-])([O-])O[C:39]1[CH:44]=[CH:43][C:42]([O:45][CH2:46][CH2:47][O:48][CH2:49][CH2:50][CH2:51][CH3:52])=[CH:41][CH:40]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH2:4]([N:7]1[C:13]2[CH:14]=[CH:15][C:16]([C:39]3[CH:44]=[CH:43][C:42]([O:45][CH2:46][CH2:47][O:48][CH2:49][CH2:50][CH2:51][CH3:52])=[CH:41][CH:40]=3)=[CH:17][C:12]=2[CH:11]=[C:10]([C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([CH2:28][N:29]([CH3:36])[CH:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)=[CH:24][CH:23]=2)=[O:20])[CH2:9][CH2:8]1)[CH:5]=[CH2:6]
Reactant: C=CCN1CCC(C(=O)Nc2ccc(CN(C)C3CCOCC3)cc2)=Cc2cc(Br)ccc21
Reactant: CCCCOCCOc1ccc(OB([O-])[O-])cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: C=CCN1CCC(C(=O)Nc2ccc(CN(C)C3CCOCC3)cc2)=Cc2cc(-c3ccc(OCCOCCCC)cc3)ccc21
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 14.4 %

Procedure:
In toluene (15 ml), ethanol (1.5 ml) and water (1.5 ml) were suspended 1-allyl-7-bromo-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (262 mg), 4-butoxyethoxyphenyl borate (169 mg) and potassium carbonate (196 mg), and the suspension was stirred under argon atmosphere for 30 minutes. Then, to the mixture was added tetrakistriphenylphosphinepalladium (45 mg), and the mixture was heated under argon atmosphere at 100° C. for 6 hours. After allowing to cool, water was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with magnesium sulfate. The solvent was evaporated under reduced pressure and the resulting residue was separated and purified with silica gel column chromatography (methanol:ethyl acetate=1:16), which was recrystallized from hexane-ethyl acetate to give 1-allyl-7-(4-butoxyethoxyphenyl)-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 50) (46 mg) as yellow crystals.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][S:5][CH:6]=1.[CH3:7][O:8][C:9]1[N:14]=[C:13]([O:15][CH3:16])[C:12](B(O)O)=[CH:11][N:10]=1.C([O-])(O)=O.[Na+]>COCCOC.O>[S:5]1[CH:6]=[C:2]([C:12]2[C:13]([O:15][CH3:16])=[N:14][C:9]([O:8][CH3:7])=[N:10][CH:11]=2)[CH:3]=[N:4]1
Reactant: COc1ncc(B(O)O)c(OC)n1
Reactant: Brc1cnsc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1ncc(-c2cnsc2)c(OC)n1
Temperature: 90 °C
Reaction time: 0.5 h

Procedure:
4-bromoisothiazole (commercially available from Aurora, 500 mg, 3.05 mmol) was dissolved in degassed 1,2-Dimethoxyethane (DME) (5 ml). Pd(Ph3)4 (176 mg, 0.152 mmol) was added thereto. The reaction mixture was stirred at room temperature for 15 min. [2,4-bis(methyloxy)-5-pyrimidinyl]boronic acid (commercially available from Aldrich, 1178 mg, 6.40 mmol) and 5 mL of degassed 1M/H2O solution of NaHCO3 were added to the reaction mixture under N2 atm. After 2 h 30 min stirring at 90° C. the mixture was diluted with water and extracted with DCM. The collected organic phases were evaporated. The residue was purified by flash chromatography eluting with cyclohexane/EtOAc 5:1. 686 mg of the title compound were isolated as a yellow solid.
Reaction SMILES: [CH2:1]([O:3][S:4]([CH2:7]P(OCC)(OCC)=O)(=[O:6])=[O:5])[CH3:2].C([Li])CCC.[Cl:21][C:22]1[N:30]=[CH:29][N:28]=[C:27]2[C:23]=1[N:24]=[CH:25][N:26]2[CH:31]1[CH:35]2[O:36][C:37]([CH3:40])([CH3:39])[O:38][CH:34]2[CH:33]([CH:41]=O)[O:32]1>C1COCC1.CCCCCC>[Cl:21][C:22]1[N:30]=[CH:29][N:28]=[C:27]2[C:23]=1[N:24]=[CH:25][N:26]2[C@H:31]1[C@@H:35]2[O:36][C:37]([CH3:40])([CH3:39])[O:38][C@@H:34]2[C@@H:33]([CH:41]=[CH:7][S:4]([O:3][CH2:1][CH3:2])(=[O:5])=[O:6])[O:32]1
Reactant: CCOP(=O)(CS(=O)(=O)OCC)OCC
Reactant: CC1(C)OC2C(C=O)OC(n3cnc4c(Cl)ncnc43)C2O1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOS(=O)(=O)C=C[C@H]1O[C@@H](n2cnc3c(Cl)ncnc32)[C@@H]2OC(C)(C)O[C@@H]21
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 80.5 %

Procedure:
To a solution of (diethoxy-phosphoryl)-methanesulfonic acid ethyl ester (7.991 g, 0.03070 mol) in THF (100 mL), at −78° C. under an atmosphere of nitrogen, was added dropwise 2.5M n-butyllithium in hexane (13 mL), and the solution was stirred for 30 minutes. Freshly prepared 6-(6-chloro-purin-9-yl)-2,2-dimethyl-tetrahydro-furo[3,4-d][1,3]-dioxole-4-carbaldehyde (13.10 g, 0.03026 mol) in THF (100 mL) was added over 15 min at −78° C. The reaction was allowed to slowly warm to −10° C. over 4 hours with stirring. The reaction was quenched with water (400 mL) and 5M ammonium chloride in water (100 mL) and extracted with methylene chloride (600 mL). The organic phase was concentrated in vacuo and the residue was purified by flash chromatography (30 to 100% EtOAc:hexanes) to yield the product as a foam (10.5 g, 81%).