Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]2[C:18]3[C:13](=[CH:14][C:15]([CH3:19])=[CH:16][CH:17]=3)[N:12]=[C:11]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[OH:26])[N:10]=2)[CH2:4]1.C(N(CC)CC)C.Cl[C:35]([O:37][C@@H:38]1[CH2:42][CH2:41][O:40][CH2:39]1)=[O:36]>>[O:40]1[CH2:41][CH2:42][C@@H:38]([O:37][C:35](=[O:36])[NH:1][CH2:2][C@H:3]2[CH2:8][CH2:7][CH2:6][N:5]([C:9]3[C:18]4[C:13](=[CH:14][C:15]([CH3:19])=[CH:16][CH:17]=4)[N:12]=[C:11]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[OH:26])[N:10]=3)[CH2:4]2)[CH2:39]1
Reactant: O=C(Cl)O[C@@H]1CCOC1
Reactant: Cc1ccc2c(N3CCC[C@H](CN)C3)nc(-c3ccccc3O)nc2c1
Solvent: CCN(CC)CC
Product: Cc1ccc2c(N3CCC[C@H](CNC(=O)O[C@@H]4CCOC4)C3)nc(-c3ccccc3O)nc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 2-(4-((R)-3-(aminomethyl)piperidin-1-yl)-7-methylquinazolin-2-yl)phenol (150 mg, 0.43 mmol) under an N2 atmosphere at 0° C. was added triethylamine (87 mg, 0.86 mmol) followed by the dropwise addition of (R)-tetrahydrofuran-3-yl chloroformate (65 mg, 0.43 mmol). The reaction was allowed to warm to room temperature and was stirred for 2 h. The mixture was partitioned between H2O and CH2Cl2 and separated, and the aqueous layer was extracted twice with CH2Cl2. The organic layers were combined, dried over Na2SO4, filtered, and concentrated. Purification via silica gel chromatography using 4:1 CH2Cl2:EtOAc afforded (R)-tetrahydrofuran-3-yl((R)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-yl)methylcarbamate. LC/MS: m/z 463.5 (M+H)+ at 2.34 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=[CH:11][C:12]2[CH:22]=[CH:21][CH:20]=[CH:19][C:13]=2/[C:14](/[NH:17][OH:18])=[N:15]\[H])=[N:2]1.C(N(C(C)C)CC)(C)C.[CH2:32]([CH:34](C(Cl)=O)[C:35](Cl)=[O:36])C.C(=O)([O-])[O-].[K+].[K+].[H-].C([Al+]CC(C)C)C(C)C.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>C1COCC1.O.CO>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:22]=[CH:21][CH:20]=[CH:19][C:13]=2[C:14]2[N:15]=[C:32]([CH2:34][CH2:35][OH:36])[O:18][N:17]=2)=[N:2]1
Reactant: [H]/N=C(/NO)c1ccccc1C=Cc1n[nH]c2ccccc12
Reactant: CCC(C(=O)Cl)C(=O)Cl
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: OCCc1nc(-c2ccccc2/C=C/c2n[nH]c3ccccc23)no1
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 45.7 %

Procedure:
(E)-2-[2-(1H-indazol-3-yl)vinyl]-N-hydroxybenzamidine (0.08 g, 0.29 mmol) obtained in Step 1 of Example 175 was dissolved in THF (5.0 mL) and the solution was added with diisopropylethylamine (0.12 mL, 0.66 mmol) and ethylmalonyl chloride (47 μL, 0.44 mmol), followed by stirring at 80° C. for 15 minutes. Then, potassium carbonate and methanol were added to the mixture and stirred for 30 minutes. The mixture was added with water, extracted with ethyl acetate, and the organic layer was concentrated and then dried. Further, the residue was dissolved in a mixed solvent of methylene chloride (1.0 mL) and THF (1.0 mL), cooled to −78° C. and diisobutylaluminum hydride (0.95 mol/L toluene solution, 0.58 mL, 0.55 mmol) was added. The mixture was warmed to room temperature and stirred for 3 hours. The reaction mixture was added with saturated aqueous Rochelle salt solution and extracted with ethyl acetate. After the organic layer was concentrated, the residue was triturated in ethyl acetate to obtain Compound 181 (44 mg, 35%).
Reaction SMILES: [CH2:1]([C:4]1[CH:24]=[C:23]([C:25]#[N:26])[CH:22]=[CH:21][C:5]=1[O:6][CH:7]([C:12]1[CH:17]=[CH:16][C:15]2[O:18][CH2:19][O:20][C:14]=2[CH:13]=1)[C:8]([O:10]C)=[O:9])[CH2:2][CH3:3].[OH-].[Na+].[CH:29](Cl)(Cl)Cl.CO.[OH-].[NH4+].Cl>CO>[CH3:29][C:7]([C:12]1[CH:17]=[CH:16][C:15]2[O:18][CH2:19][O:20][C:14]=2[CH:13]=1)([O:6][C:5]1[CH:21]=[CH:22][C:23]([C:25]#[N:26])=[CH:24][C:4]=1[CH2:1][CH2:2][CH3:3])[C:8]([OH:10])=[O:9]
Reactant: ClC(Cl)Cl
Reactant: CCCc1cc(C#N)ccc1OC(C(=O)OC)c1ccc2c(c1)OCO2
Agent: Cl
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CCCc1cc(C#N)ccc1OC(C)(C(=O)O)c1ccc2c(c1)OCO2
Reaction time: 8 h

Procedure:
To a solution of 3.5 g (8.64 mmol) of the product of Step C in 30 mL of methanol was added 2.07 mL (10.37 mmol) of 5.0N aqueous sodium hydroxide solution. After stirring overnight, TLC analysis (80:15:1 chloroform/methanol/ammonium hydroxide) indicated that the saponification was complete. The reaction mixture was acidified to pH 3 with 6N aqueous HCl and concentrated in vacuo.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[N:5]([CH2:6][CH2:7][OH:8])[N:4]([CH:9]2[CH:16]3[CH2:17][CH:12]4[CH2:13][CH:14]([CH2:18][CH:10]2[CH2:11]4)[CH2:15]3)[C:3]1=[O:19].[H-].[Na+].Cl[C:24]1[N:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=1.O>O1CCCC1.CN(C)C=O>[CH3:1][C:2]1([CH3:20])[N:5]([CH2:6][CH2:7][O:8][C:24]2[N:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=2)[N:4]([CH:9]2[CH:10]3[CH2:11][CH:12]4[CH2:13][CH:14]([CH2:15][CH:16]2[CH2:17]4)[CH2:18]3)[C:3]1=[O:19]
Reactant: CC1(C)C(=O)N(C2C3CC4CC(C3)CC2C4)N1CCO
Reactant: N#Cc1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC1(C)C(=O)N(C2C3CC4CC(C3)CC2C4)N1CCOc1ccc(C#N)cn1
Reaction time: 1 h
Yield: 100.1 %

Procedure:
Under an argon atmosphere, a mixed solution of 4,4-dimethyl-1-(2-hydroxyethyl)-2-(adamantan-2-yl)-1,2-diazetidin-3-one (27.8 mg, 0.100 mmol) in tetrahydrofuran-N,N-dimethylformamide (2:1, 1 mL) was added with sodium hydride (10.0 mg, 0.200 mmol) and 6-chloro-3-pyridine carbonitrile (27.7 mg, 0.200 mmol), and the resultant was stirred at the same temperature for 1 hour. The reaction solution was added with water and extracted with diethyl ether. The organic layer was dried over anhydrous sodium sulfate, concentrated in vacuo, the obtained residue was purified using Preparatory Thin-Layer chromatography (hexane:ethyl acetate=1:1), and the title compound (38.1 mg, quant.) was obtained as a white crystalline powder.
Reaction SMILES: Cl.[CH3:2][CH:3]1[CH2:8][N:7]([CH2:9][C:10]([OH:12])=O)[CH2:6][CH:5]([CH3:13])[O:4]1.[NH2:14][C@@H:15]([CH2:33][O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:16]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)=[CH:21][CH:20]=1)=[O:17]>>[CH2:35]([O:34][CH2:33][C@H:15]([NH:14][C:10](=[O:12])[CH2:9][N:7]1[CH2:6][CH:5]([CH3:13])[O:4][CH:3]([CH3:2])[CH2:8]1)[C:16]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)=[CH:21][CH:20]=1)=[O:17])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Reactant: CC1CN(CC(=O)O)CC(C)O1
Agent: Cl
Product: CC1CN(CC(=O)N[C@@H](COCc2ccccc2)C(=O)Nc2ccc(Oc3ccc(F)cc3)cc2)CC(C)O1
Yield: 25.9 %

Procedure:
Proceeding as in Example 1, but substituting 2-(2,6-dimethylmorpholino)acetic acid hydrochloride and (S)-2-amino-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide, gave Compound 265, (2S)-3-(benzyloxy)-2-(2-(2,6-dimethylmorpholino)acetamido)-N-(4-(4-fluorophenoxy)phenyl)propanamide (11.1 mg, 25.9%); Major isomer: 1H-NMR (400 MHz, DMSO-D6): σ 10.20 (s, 1H), 7.98 (d, 1H), 7.60 (d, 2H), 7.27-7.32 (m, 5H), 7.19-7.23 (m, 2H), 6.98-7.04 (m, 4H), 4.69-4.71 (m, 1H), 4.52 (s, 2H), 3.71-3.77 (m, 2H), 3.54-3.5 (m, 2H), 2.93-3.03 (m, 2H), 2.74 (dd, 2H), 1.73-1.80 (m, 2H), 1.00 (dd, 6H). MS (EI) for C30H34FN3O5. found 536.6 (MH+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:19]=[C:18]([CH3:20])[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]([OH:21])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:28][O:29][CH2:30]Br.O>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:19]=[C:18]([CH3:20])[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]([O:21][CH2:28][O:29][CH3:30])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1c(C)cc(OCc2ccccc2)cc1O
Reactant: COCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(C)cc(OCc2ccccc2)cc1OCOC
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 86.1 %

Procedure:
To a solution of ethyl 4-(benzyloxy)-2-hydroxy-6-methylbenzoate (15.0 g, 52.4 mmol) in DMF (100 mL) were added potassium carbonate (14.5 g, 105 mmol) and bromomethyl methyl ether (6.40 mL, 78.5 mmol), and the mixture was stirred at room temperature for 20 min. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed twice with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=19:1 to 4:1) to give the title compound (14.9 g, yield 86%) as a yellow solid.
Reaction SMILES: [Br-:1].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.[C:34]([C:39]1[CH:40]=[C:41]([CH:46]=[CH:47][CH:48]=1)[C:42]([O:44][CH3:45])=[O:43])(=[O:38])[CH:35]([CH3:37])[CH3:36]>O1CCCC1>[CH3:45][O:44][C:42]([C:41]1[CH:40]=[C:39]([C:34](=[O:38])[C:35]([Br:1])([CH3:37])[CH3:36])[CH:48]=[CH:47][CH:46]=1)=[O:43]
Reactant: COC(=O)c1cccc(C(=O)C(C)C)c1
Reactant: [Br-]
Agent: C[N+](C)(C)c1ccccc1
Solvent: C1CCOC1
Product: COC(=O)c1cccc(C(=O)C(C)(C)Br)c1

Procedure:
0.8 g of phenyltrimethylammonium tribromide was added to a mixture comprising 1.5 g of the crude product of methyl m-isobutyrylbenzoate obtained in the above step (3) and 20 ml of tetrahydrofuran, and followed by a reaction at room temperature overnight. After completion of the reaction, the precipitated crystal was separated by filtration, then tetrahydrofuran was distilled off. The residue was dissolved in ethyl acetate, then washed with a saturated sodium chloride aqueous solution, followed by drying over anhydrous sodium sulfate. Then, concentration under reduced pressure was carried out, and then, rough purification was carried out by silica gel column chromatography to obtain 0.27 g of crude 3′-methoxycarbonyl-2-bromo-2-methylpropiophenone. The NMR spectrum data of this product were as follows.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19](SCC)=[N:18][C:17]3=[O:24])=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[CH3:35][O:36][CH2:37][C@H:38]1[O:43][CH2:42][CH2:41][NH:40][CH2:39]1>>[F:34][C:2]([F:1])([F:33])[C:3]1[CH:28]=[C:27]([C:29]([F:30])([F:32])[F:31])[CH:26]=[CH:25][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19]([N:40]4[CH2:41][CH2:42][O:43][C@H:38]([CH2:37][O:36][CH3:35])[CH2:39]4)=[N:18][C:17]3=[O:24])=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: COC[C@@H]1CNCCO1
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1
Product: COC[C@@H]1CN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(C(F)(F)F)cc4C(F)(F)F)c3)S2)CCO1

Procedure:
5-({1-[2,4-Bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-[2-(S)-(methoxymethyl)morpholin-4-yl]-1,3-thiazol-4(5H)-one was prepared from 5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and (2S)-2-Methoxymethyl-morpholine following General Procedure C.
Reaction SMILES: [CH2:1]([N:9]1[CH:13]=[C:12]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[C:20]([C:23]4[CH:28]=[CH:27][C:26]([N:29]5[CH2:34][CH2:33][N:32](C(OC(C)(C)C)=O)[CH2:31][CH2:30]5)=[CH:25][CH:24]=4)[CH:21]=3)[N:16]([S:42]([C:45]3[CH:51]=[CH:50][C:48]([CH3:49])=[CH:47][CH:46]=3)(=[O:44])=[O:43])[CH:15]=2)[CH:11]=[N:10]1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH2:1]([N:9]1[CH:13]=[C:12]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[C:20]([C:23]4[CH:24]=[CH:25][C:26]([N:29]5[CH2:30][CH2:31][NH:32][CH2:33][CH2:34]5)=[CH:27][CH:28]=4)[CH:21]=3)[N:16]([S:42]([C:45]3[CH:46]=[CH:47][C:48]([CH3:49])=[CH:50][CH:51]=3)(=[O:44])=[O:43])[CH:15]=2)[CH:11]=[N:10]1)[CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(CCc4ccccc4)c3)c3cc(-c4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)cc4)cnc32)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(CCc4ccccc4)c3)c3cc(-c4ccc(N5CCNCC5)cc4)cnc32)cc1
Yield: 102.2 %

Procedure:
Using similar reaction conditions as described in step-ii of example-7, tert-butyl 4-(4-(3-(1-phenethyl-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazine-1-carboxylate (200 mg, 0.284 mmol) was deprotected in TFA/DCM (2/5 ml) to afford 175 mg (86.2% yield) of the titled compound. MS: m/z=603.2 (M+1).
Reaction SMILES: [C:1]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1/[CH:20]=[CH:21]/[P:22](=[O:29])([O:26]CC)[O:23]CC)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].Br[Si](C)(C)C.CC(C)=O.O>C(Cl)Cl.[2H]C([2H])(Cl)Cl>[C:1]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH:20]=[CH:21][P:22](=[O:23])([OH:29])[OH:26])#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCCCCCCC#Cc1ccccc1/C=C/P(=O)(OCC)OCC
Agent: C[Si](C)(C)Br
Agent: [2H]C([2H])(Cl)Cl
Solvent: ClCCl
Solvent: CC(C)=O
Solvent: O
Product: CCCCCCCCCCCC#Cc1ccccc1C=CP(=O)(O)O
Reaction time: 30 h
Yield: 76.8 %

Procedure:
Diethyl E-2-[2-(1-tridecynyl)phenyl]ethenylphosphonate (0.521 g, 1.25 mmol) prepared according to Example 13 was dissolved in CH2Cl2 : CD2Cl2 (1:1, 9 ml ) and stirred while bromotrimethylsilane (0.38 g, 2.48 mmol) was added. The reaction was monitored by 1H and 31P NMR. Additional bromotrimethylsilane (0.1 ml, 0.76 mmol) was added after 6.5 hours. After stirring for 30 hours, the solvent was removed under reduced pressure. Acetone (5 ml) was added, along with water (0.15 ml, 8.3 mmol). The reaction mixture was stirred for about 42 hours, then stripped. NMR indicated that the reaction was incomplete. Acetone (3 ml) and water (0.2 ml, 11.1 mmol) were added back and the reaction was stirred overnight. The solvent was then removed, and the residue was recrystallized from heptane, as a white crystalline solid, 0.348 g, 0.96 mmol, 76.8% yield; mp 82°-83° C.; 1H NMR (CDCl3) ∂0.85 (t, J=6.7 Hz, 3H), 1.10 to 1.45 (m, 16H), 1.59 (m, 2H), 2.43 (t, J=7.1 Hz, 2H), 6.44 (t, J=18.5 Hz, 1H), 7.26 (m, 2H), 7.41 (m, 1H), 7.54 (m, 1H), 8.04 (dd, J=24.2, 17.6 Hz, 1H), 10.46 (br s, 2H); FAB mass spectrum m/z 363 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:16])=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[N:7]([CH2:12][C:13]#[N:14])[C:6]=2[CH:15]=1.[C:17]1(=O)[O:22][C:20](=[O:21])[CH:19]2[CH2:23][CH2:24][CH:25]=[CH:26][CH:18]12.C(O)(=O)C>O>[C:13]([CH2:12][N:7]1[C:6]2[CH:15]=[C:2]([N:1]3[C:20](=[O:21])[C:19]4[CH2:23][CH2:24][CH2:25][CH2:26][C:18]=4[C:17]3=[O:22])[C:3]([F:16])=[CH:4][C:5]=2[O:10][CH2:9][C:8]1=[O:11])#[N:14]
Reactant: N#CCN1C(=O)COc2cc(F)c(N)cc21
Reactant: O=C1OC(=O)C2CCC=CC12
Solvent: O
Solvent: CC(=O)O
Product: N#CCN1C(=O)COc2cc(F)c(N3C(=O)C4=C(CCCC4)C3=O)cc21
Yield: 73.5 %

Procedure:
6-amino-4-cyanomethyl-7-fluoro-2H-1,4-benzoxazin-3(4H)-one (0.5 g), tetrahydrophthalic anhydride (0.38 g) and acetic acid (10 ml) were mixed with each other, then the mixture was refluxed under heating for 3 hours. After the liquor was allowed to cool, it was added to water (40 ml), and separating crystals were collected by filtration, and then the crystals were dissolved in dichloromethane (30 ml). The dichloromethane solution was washed with a saturated solution of sodium bicarbonate, and water, in that order, and then dehydrated with anhydrous sodium sulfate, and subsequently concentrated. Separated crystals were washed with a small amount of ether to give the desired 2-[4-cyanomethyl-7-fluoro-2H-1,4-benzoxazin-3(4H)-on 6-yl]-4,5,6,7-tetrahydro-2H-isoindole-1,3-dione (0.59 g). mp. 227°-229° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13](=[O:20])[NH:12][N:11]=2)[S:7][CH:8]=1)([O-])=O.[Cl-].[NH4+]>C(O)C.O.[Fe]>[NH2:1][C:4]1[CH:5]=[C:6]([CH2:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13](=[O:20])[NH:12][N:11]=2)[S:7][CH:8]=1
Reactant: O=c1[nH]nc(Cc2cc([N+](=O)[O-])cs2)c2ccccc12
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Nc1csc(Cc2n[nH]c(=O)c3ccccc23)c1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
To a suspension of 4-(4-nitro-thiophen-2-ylmethyl)-2H-phthalazin-1-one (27) (0.90 g, 5.71 mmol) in ethanol (25 mL) under a nitrogen blanket was added dropwise a solution of ammonium chloride (0.31 g, 5.7 mmol) in water 18 mL). After stirring the resultant solution for 5 minutes, iron powder (0.64 g, 11.5 mmol) was added in one portion. The yellow mixture was stirred at 80° C. for 3 hours. The reaction mixture was filtered hot through celite which was washed with ethyl acetate (80 mL). The concentrated in vacuo and then diluted with ethyl acetate (20 mL) washed with brine (20 mL), dried over magnesium, sulphate and dried in vacuo to afford the title cpd as a bright yellow powder. Single peak in LC-MS analysis, (0.68 g, 84% purity and required no further purification; m/z (LC-MS, ESP), RT=2.94 (M+H) 258.
Reaction SMILES: [CH:1]1(B(O)O)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[Na+].[Na+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.[CH2:42]([O:44][C:45]1[CH:54]=[C:53](I)[CH:52]=[CH:51][C:46]=1[C:47]([O:49][CH3:50])=[O:48])[CH3:43]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O.C1(C)C=CC=CC=1>[CH:1]1([C:53]2[CH:52]=[CH:51][C:46]([C:47]([O:49][CH3:50])=[O:48])=[C:45]([O:44][CH2:42][CH3:43])[CH:54]=2)[CH2:3][CH2:2]1
Reactant: OB(O)C1CC1
Reactant: CCOc1cc(I)ccc1C(=O)OC
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCOc1cc(C2CC2)ccc1C(=O)OC
Temperature: 100 °C
Reaction time: 18 h
Yield: 100.1 %

Procedure:
Cyclopropylboronic acid (1.90 g), a 2 M aqueous sodium carbonate solution (22 mL), tris(dibenzylideneacetone)dipalladium(0) (944 mg), and dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (907 mg) were added at room temperature to a toluene (80 mL) solution of methyl 2-ethoxy-4-iodobenzoate (4.51 g), and the mixture was stirred at 100° C. for 18 hours in an argon atmosphere. Water was added to the reaction mixture at room temperature, and the mixture was filtered through celite. Then, the filtrate was subjected to extraction with ethyl acetate. The obtained organic layer was washed with water and saturated saline in this order and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (3.25 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([F:20])[CH:11]=2)=[NH:9])=[N:6][CH:7]=1.Cl.[CH3:22][C:23]1[N:24]=[C:25](N)[S:26][C:27]=1[CH3:28]>CC1C=CC=CC=1C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5](/[C:8](/[C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:17])[F:18])[CH:13]=[C:12]([F:20])[CH:11]=2)=[N:9]/[C:25]2[S:26][C:27]([CH3:28])=[C:23]([CH3:22])[N:24]=2)=[N:6][CH:7]=1
Reactant: Cc1nc(N)sc1C
Reactant: N=C(c1cc(F)cc(C(F)(F)F)c1)c1ccc(Cl)cn1
Agent: Cl
Solvent: Cc1ccccc1C
Product: Cc1nc(/N=C(\c2cc(F)cc(C(F)(F)F)c2)c2ccc(Cl)cn2)sc1C
Temperature: 25 °C
Yield: 44 %

Procedure:
A solution of (5-chloropyridin-2-yl)(3-fluoro-5-(trifluoromethyl)phenyl)methanimine (1.7 g, 5.6 mmol) and 4,5-dimethylthiazol-2-amine HCl salt (900 mg, 5 mmol) in o-xylene (10 mL) was heated at 150° C. for 18 h, then allowed to cool to room temperature. The solvent was removed under reduced pressure and the residue purified by ISCO chromatography (80 g column) using hexanes/EtOAc (0-40%) over 25 min to give (E)-N-((5-chloropyridin-2-yl)(3-fluoro-5-(trifluoromethyl)phenyl)methylene)-4,5-dimethylthiazol-2-amine as a beige solid (910 mg, 44% yield). LCMS RT=4.00 min [M+H] 413.87 (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H2O over 4 minutes containing 0.1% TFA; 4 mL/min, monitoring at 220 nm).
Reaction SMILES: C(NC(C)C)(C)C.I[C:9]1[S:10][CH:11]=[CH:12][N:13]=1.[CH3:14][Si:15]([C:18]#[CH:19])([CH3:17])[CH3:16]>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[CH3:14][Si:15]([C:18]#[C:19][C:9]1[S:10][CH:11]=[CH:12][N:13]=1)([CH3:17])[CH3:16]
Reactant: Ic1nccs1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: C[Si](C)(C)C#Cc1nccs1
Temperature: 50 °C

Procedure:
Copper(I)iodide (38 mg, 0.20 mmol), dichlorobis(triphenylphosphine)palladium(II) (250 mg, 0.40 mmol) and N,N-diisopropylamine (1.40 g, 14 mmol) were added to a solution of 2-iodothiazole (1.50 g, 7.0 mmol; prepared as described in J. Org. Chem. 1988, 53, 2489) and dry tetrahydrofuran (50 mL). The reaction mixture was degassed and trimethylsilylacetylene (1.40 g, 14 mmol) was added in two portions under nitrogen atmosphere. The reaction was heated to 50° C. for 12 h. The formed precipitate and separated palladium were removed by filtration through a short path of silica gel. The filtrate was concentrated in vacuo and the residue was purified by column chromatography (silica gel Fluka 60: hexane/ethyl acetate 98:2-90:10) yielding 2-(trimethylsilylethynyl)thiazole as yellow oil.
Reaction SMILES: [NH2:1][CH:2]1[C:8](=[O:9])[N:7]([CH3:10])[C:6]2[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=2[C:4]2[CH:15]=[CH:16][CH:17]=[CH:18][C:3]1=2.[CH3:19][CH:20]([C:24]([NH:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=1)=[O:25])[C:21](O)=[O:22]>>[CH3:19][CH:20]([C:24]([NH:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:35])([F:36])[F:37])[CH:29]=1)=[O:25])[C:21]([NH:1][CH:2]1[C:8](=[O:9])[N:7]([CH3:10])[C:6]2[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=2[C:4]2[CH:15]=[CH:16][CH:17]=[CH:18][C:3]1=2)=[O:22]
Reactant: CN1C(=O)C(N)c2ccccc2-c2ccccc21
Reactant: CC(C(=O)O)C(=O)NCc1cccc(C(F)(F)F)c1
Product: CC(C(=O)NCc1cccc(C(F)(F)F)c1)C(=O)NC1C(=O)N(C)c2ccccc2-c2ccccc21

Procedure:
The title compound, MS: m/e=496.3 (M+H+), was prepared in analogy to example 16 from 7-amino-5-methyl-5H,7H-dibenzo[b,d]azepin-6-one and 2-methyl-N-(3-trifluoromethyl-benzyl)-malonamic acid.
Reaction SMILES: [CH:1]([N:4]1[C:8]2[CH:9]=[N:10][CH:11]=[CH:12][C:7]=2[NH:6][C:5]1=O)([CH3:3])[CH3:2].[NH4+].[OH-].O=P(Cl)(Cl)[Cl:18]>>[Cl:18][C:5]1[N:4]([CH:1]([CH3:3])[CH3:2])[C:8]2[CH:9]=[N:10][CH:11]=[CH:12][C:7]=2[N:6]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(C)n1c(=O)[nH]c2ccncc21
Agent: [NH4+]
Agent: [OH-]
Product: CC(C)n1c(Cl)nc2ccncc21
Temperature: 0 °C

Procedure:
A mixture of 3-isopropyl-1H-imidazo[4,5-c]pyridin-2(3H)-one (0.5 g, 2.82 mmol.) in POCl3 (5 mL) was refluxed for 16 hrs. Then the reaction mixture was poured into ice water and basified with NH4OH to pH=7˜8. The mixture was extracted with ethyl acetate. The organic layer was dried over Na2SO4 and evaporated to afford crude 2-chloro-3-isopropyl-3H-imidazo[4,5-c]pyridine which was used directly for the next step (150 mg, 27%).