Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]4[C:33]5[C:28](=[CH:29][C:30]([OH:36])=[C:31]([O:34][CH3:35])[CH:32]=5)[N:27]=[CH:26][N:25]=4)=[C:19]([F:37])[CH:18]=3)=[O:15])[CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1.O[CH2:39][CH2:40][CH2:41][N:42]1[CH2:47][CH2:46][O:45][CH2:44][CH2:43]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>ClCCl>[F:37][C:19]1[CH:18]=[C:17]([NH:16][C:14]([C:11]2([C:9]([NH:8][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[O:10])[CH2:13][CH2:12]2)=[O:15])[CH:22]=[CH:21][C:20]=1[O:23][C:24]1[C:33]2[C:28](=[CH:29][C:30]([O:36][CH2:39][CH2:40][CH2:41][N:42]3[CH2:47][CH2:46][O:45][CH2:44][CH2:43]3)=[C:31]([O:34][CH3:35])[CH:32]=2)[N:27]=[CH:26][N:25]=1
Reactant: COc1cc2c(Oc3ccc(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CC4)cc3F)ncnc2cc1O
Reactant: OCCCN1CCOCC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc2c(Oc3ccc(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CC4)cc3F)ncnc2cc1OCCCN1CCOCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 47.5 %

Procedure:
To a mixture of cyclopropane-1,1-dicarboxylic acid [3-fluoro-4-(7-hydroxy-6-methoxy-quinazolin-4-yloxy)-phenyl]-amide (4-fluoro-phenyl)-amide (1.5 g, 2.96 mmol), 4-(3-hydroxypropyl)morpholine (0.623 mL, 4.5 mmol), triphenylphosphine (1.18 g, 4.5 mmol), and dichloromethane (50 mL) was added diisopropyl azodicarboxylate (0.886 mL, 4.5 mmol). The mixture was stirred at room temperature for 16 h, monitored by LCMS. After removal of solvent, the crude mixture was separated by flash column chromatography (silica), eluting with 5% methanol in dichloromethane to give N-[3-fluoro-4-({6-(methyloxy)-7-[(3-morpholin-4-ylpropyl)oxy]quinazolin-4-yl}oxy)phenyl]-N′-(4-fluorophenyl)cyclopropane-1,1-dicarbox-amide (890 mg, 47% yield). 1H NMR (400 MHz, DMSO-d6): d 10.36 (br s, 1H), 10.05 (br s, 1H), 8.55 (s, 1H), 7.83 (m, 1H), 7.64 (m, 2H), 7.57 (s, 1H), 7.44 (m, 3H), 7.18 (t, 2H), 4.27 (m, 2H), 3.99 (s, 3H), 3.61 (m, 6H), 2.40 (m, 4H), 2.01 (m, 2H), 1.47 (m, 4H). LC/MS Calcd for [M+H]+ 634.2, found 634.3.
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][NH:7]/[CH:8]=[C:9]2\[C:10](=[O:21])[NH:11][C:12](=[O:20])[C:13]3[C:18]\2=[CH:17][C:16]([I:19])=[CH:15][CH:14]=3)=[CH:4][C:3]=1[O:24][Si](C(C)C)(C(C)C)C(C)C.[C:35](O)(=[O:39])[C:36]#[C:37][CH3:38]>>[OH:24][C:3]1[CH:4]=[C:5]([CH2:6][NH:7]/[CH:8]=[C:9]2\[C:10](=[O:21])[NH:11][C:12](=[O:20])[C:13]3[C:18]\2=[CH:17][C:16]([I:19])=[CH:15][CH:14]=3)[CH:22]=[CH:23][C:2]=1[NH:1][C:35](=[O:39])[C:36]#[C:37][CH3:38]
Reactant: CC#CC(=O)O
Reactant: CC(C)[Si](Oc1cc(CN/C=C2\C(=O)NC(=O)c3ccc(I)cc32)ccc1N)(C(C)C)C(C)C
Product: CC#CC(=O)Nc1ccc(CN/C=C2\C(=O)NC(=O)c3ccc(I)cc32)cc1O

Procedure:
Following the acetylation and desilylation procedure employed for the preparation of (2E)-N-[2-hydroxy-4-({[(Z)-(6-iodo-1,3-dioxo-2,3-dihydroisoquinolin-4(1H)-ylidene)methyl]aminomethyl)phenyl]-2-methylbut-2-enamide, (4Z)-4-[({4-amino-3-[(triisopropylsilyl)oxy]benzyl}amino)methylene]-6-iodoisoquinoline-1,3(2H,4H)-dione (65 mg, 0.11 mmol) is reacted with acid chloride derived from 2-butynoic acid (92 mg, 1.1 mmol). Following desilylation and precipitation, N-[2-hydroxy-4-({[(Z)-(6-iodo-1,3-dioxo-2,3-dihydroisoquinolin-4(1H)-ylidene)methyl]amino}methyl)phenyl]but-2-ynamide is obtained as a solid (20 mg, 36%).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[CH2:9][O:8][C:7](=[O:11])[C:6]=2[CH:5]=[CH:4][C:3]=1[C:12](=[O:21])[CH2:13][N:14]1[CH2:19][CH2:18][NH:17][CH2:16][C:15]1=[O:20].[CH3:22][C:23]1[C:31]2[CH2:30][O:29][C:28](=[O:32])[C:27]=2[CH:26]=[CH:25][C:24]=1[C@@H:33]1[CH2:35][O:34]1>CCO>[OH:34][C@H:33]([C:24]1[CH:25]=[CH:26][C:27]2[C:28](=[O:32])[O:29][CH2:30][C:31]=2[C:23]=1[CH3:22])[CH2:35][N:17]1[CH2:18][CH2:19][N:14]([CH2:13][C:12]([C:3]2[CH:4]=[CH:5][C:6]3[C:7](=[O:11])[O:8][CH2:9][C:10]=3[C:2]=2[CH3:1])=[O:21])[C:15](=[O:20])[CH2:16]1
Reactant: Cc1c([C@@H]2CO2)ccc2c1COC2=O
Reactant: Cc1c(C(=O)CN2CCNCC2=O)ccc2c1COC2=O
Solvent: CCO
Product: Cc1c(C(=O)CN2CCN(C[C@H](O)c3ccc4c(c3C)COC4=O)CC2=O)ccc2c1COC2=O
Temperature: 140 °C

Procedure:
A mixture of 1-[2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)-2-oxoethyl]piperazin-2-one (30 mg, 0.10 mmol) and 4-methyl-5-[(2R)-oxiran-2-yl]-2-benzofuran-1(3H)-one (40 mg, 0.21 mmol) in EtOH (2 mL) was heated to 140° C. in a microwave tube for 1 hour. The solution was concentrated to dryness, re-dissolved in MeOH, filtered and shot into Mass-directed HPLC for separation to give the title product. LC-MS (IE, m/z): 479 [M+1]+.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:23][CH3:24])[C:4]1[CH:9]=[CH:8][C:7]([C:10](=O)[C:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:12]N(C)C)=[CH:6][CH:5]=1.Cl.[NH2:26][C:27]([NH2:29])=[NH:28].C[O-].[Na+]>CO>[CH3:24][O:23][CH:3]([O:2][CH3:1])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:11]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][N:26]=[C:27]([NH2:29])[N:28]=2)=[CH:6][CH:5]=1
Reactant: N=C(N)N
Reactant: COC(OC)c1ccc(C(=O)C(=CN(C)C)c2ccccc2)cc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(OC)c1ccc(-c2nc(N)ncc2-c2ccccc2)cc1

Procedure:
5 g of the product of step 3 and 3 g guanidine hydrochloride were dissolved in 100 mL methanol and 2.7 g of NaOMe was added. The mixture was heated to reflux for 17 h. The product was precipitated upon dilution of the mixture with water and was collected by filtration and washed twice with water.
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12][CH2:13][CH2:14][N:15]1[C:24]2[C:19](=[N:20][CH:21]=[C:22]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)[CH:23]=2)[C:18]([OH:33])=[C:17]([C:34]([NH:36][CH2:37][CH2:38][O:39][CH2:40][CH3:41])=[O:35])[C:16]1=[O:42].NN.O>C(O)C>[NH2:3][CH2:12][CH2:13][CH2:14][N:15]1[C:24]2[C:19](=[N:20][CH:21]=[C:22]([CH2:25][C:26]3[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=3)[CH:23]=2)[C:18]([OH:33])=[C:17]([C:34]([NH:36][CH2:37][CH2:38][O:39][CH2:40][CH3:41])=[O:35])[C:16]1=[O:42]
Reactant: CCOCCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCN2C(=O)c3ccccc3C2=O)c1=O
Agent: NN
Solvent: O
Solvent: CCO
Product: CCOCCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCN)c1=O
Temperature: 50 °C

Procedure:
A mixture of 1-[3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)propyl]-N-[2-(ethyloxy)ethyl]-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide (261 mg, 0.46 mmol) and anhydrous hydrazine (286 μL, 9.1 mmol) in ethanol (20 mL) was heated at 50° C. for 5 hours. Water (40 mL) was added and the resulting slurry was cooled to 0-5° C. and collected by filtration to provide the product as a white solid: 1H NMR (CDCl3) δ 10.52 (1H, b), 8.44 (1H, s), 7.93 (1H, s), 7.33-7.39 (2H, m), 7.09-7.16 (2H, m), 4.22 (2H, t, J=7 Hz), 4.13 (2H, s), 3.42-3.50 (6H, m), 2.61 (2H, t, J=7 Hz), 1.65-1.73 (2H, m), 1.11 (3H, t, J=7 Hz); ES+ MS: 443 (M+H+).
Reaction SMILES: [H-].[Na+].[CH2:3]([C@H:10]1[CH2:14][O:13][C:12](=[O:15])[NH:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Br[CH2:17][C:18]1[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][C:19]=1[I:28]>C1COCC1>[CH2:3]([C@H:10]1[CH2:14][O:13][C:12](=[O:15])[N:11]1[CH2:17][C:18]1[CH:23]=[C:22]([C:24]([F:25])([F:27])[F:26])[CH:21]=[CH:20][C:19]=1[I:28])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: FC(F)(F)c1ccc(I)c(CBr)c1
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1OC[C@H](Cc2ccccc2)N1Cc1cc(C(F)(F)F)ccc1I
Reaction time: 0.33 h

Procedure:
A stirred suspension of sodium hydride (60% in oil, 27 mg, 0.68 mmol) in THF (3 mL) was treated at 0° C. with (S)-4-benzyl-2-oxazolidinone (49 mg, 0.27 mmol) dissolved in THF (1 mL), under an atmosphere of N2. The reaction was stirred for 20 min and a solution of 2-(bromomethyl)-1-iodo-4-(trifluoromethyl)benzene (100 mg, 0.27 mmol) in THF (1 mL) was added dropwise. The reaction was stirred at room temperature for 18 h. The reaction was quenched with H2O (1 mL) and partitioned between EtOAc (80 mL) and H2O (25 mL). The aqueous phase was re-extracted with EtOAc (2×20 mL) and the combined organic extracts were washed with brine (30 mL), dried (MgSO4) and concentrated in vacuo to give the crude product. This was purified by flash silica-gel chromatography (0-30% EtOAc in hexanes gradient) to afford (4S)-4-benzyl-3-[2-iodo-5-(trifluoromethyl)benzyl]1,3-oxazolidin-2-one. Rf=0.45 (15% EtOAc/hexanes). LCMS 462 (M+1)+. 1H NMR (CDCl3, 500 MHz) δ 8.04 (d, J=8.2 Hz, 1H), 7.54 (br s, 1H), 7.33-7.27 (m, 5H), 7.11-7.10 (m, 2H), 7.32 (m, 1H), 4.80 (d, J=16.0 Hz, 1H), 4.49 (d, J=16.1 Hz), 4.28 (t, J=8.7 Hz, 1H), 4.25 (t, J=9.1, 4.8 Hz, 1H), 3.94 (m, 1H), 3.16 (dd, J=13.5, 4.8 Hz, 1H), 2.73 (dd, J=9.1, 4.4 Hz, 1H).
Reaction SMILES: [CH:1]([S:4]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([C:20]#[C:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:16]([NH2:19])=[N:17][CH:18]=2)=[CH:9][CH:8]=1)(=[O:6])=[O:5])([CH3:3])[CH3:2].C1COCC1>CO.[Pd]>[CH:1]([S:4]([C:7]1[CH:8]=[CH:9][C:10]([C:13]2[N:14]=[C:15]([CH2:20][CH2:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:16]([NH2:19])=[N:17][CH:18]=2)=[CH:11][CH:12]=1)(=[O:5])=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)S(=O)(=O)c1ccc(-c2cnc(N)c(C#Cc3ccccc3)n2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)S(=O)(=O)c1ccc(-c2cnc(N)c(CCc3ccccc3)n2)cc1
Reaction time: 1 h
Yield: 127.6 %

Procedure:
Pd/C5% (20 mg, 0.1879 mmol) was added to a suspension of 5-(4-isopropylsulfonylphenyl)-3-(2-phenylethynyl)pyrazin-2-amine (100 mg, 0.1602 mmol) in MeOH (5 mL)/THF (5 mL) and the reaction stirred under an atmosphere of H2 for 1 hour. The catalyst was removed by filtration and the filtrate concentrated in vacuo. The material was purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 μM, 100 Å column, gradient 10%-95% B (solvent A: 0.05% TFA in water; solvent B: CH3CN) over 16 minutes at 25 mL/min]. The fractions were collected, and freeze-dried to give the di-TFA salt of the title compound as a yellow solid (78 mg, 80% Yield). 1H NMR (400.0 MHz, DMSO) δ 1.17-1.20 (m, 6H), 2.99-3.03 (m, 2H), 3.10-3.14 (m, 2H), 3.43 (q, 1H), 7.19 (t, 1H), 7.33 (m, 4H), 7.87 (d, 2H), 8.22 (d, 2H) and 8.56 (s, 1H) ppm; (ES+) 382.0.
Reaction SMILES: C(OC1C=CC(C(OC2C=CC([CH2:22][CH:23]([NH:31][C:32](=[O:41])[C:33]3[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=3)[C:24]([O:26]C(C)(C)C)=[O:25])=CC=2OC)=O)=CC=1)CCCCCC.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:40][O:39][C:36]1[CH:35]=[CH:34][C:33]([C:32]([NH:31][CH:23]([CH3:22])[C:24]([OH:26])=[O:25])=[O:41])=[CH:38][CH:37]=1
Reactant: CCCCCCCOc1ccc(C(=O)Oc2ccc(CC(NC(=O)c3ccc(OC)cc3)C(=O)OC(C)(C)C)cc2OC)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(C(=O)NC(C)C(=O)O)cc1
Temperature: 30 °C
Reaction time: 8 h

Procedure:
A crude solution of 4-(3-(tert-butoxy)-2-(4-methoxybenzamido)-3-oxopropyl)-2-methoxyphenyl 4-(heptyloxy)benzoate in DCM (1 mL) was treated with TFA (0.1 mL) and stirred overnight at 30° C. The solvent was evaporated and the residue was purified by preparative HPLC to give 16.9 mg (48%) of 3-(4-(4-(heptyloxy)benzoyl)oxy)-3-methoxyphenyl)-2-(4-methoxybenzamido)propanoic acid 2. LCMS-ESI (m/z) calculated for C32H37NO8: 563. Found 564 [M+H]+, tR=11.01 min (Method 2). 1H NMR (400 MHz, DMSO) δ 12.79 (s, 1H), 8.57 (d, J=8.1 Hz, 1H), 8.00 (d, J=9.0 Hz, 2H), 7.82 (d, J=8.9 Hz, 2H), 7.13 (d, J=1.7 Hz, 1H), 7.11-7.03 (m, 3H), 6.99 (d, J=8.9 Hz, 2H), 6.92 (dd, J=8.1, 1.7 Hz, 1H), 4.61 (ddd, J=10.8, 8.1, 4.4 Hz, 1H), 4.07 (t, J=6.5 Hz, 2H), 3.80 (s, 3H), 3.69 (s, 3H), 3.20 (dd, J=13.8, 4.2 Hz, 1H), 3.08 (dd, J=13.7, 10.7 Hz, 1H), 1.84-1.66 (m, 2H), 1.51-1.17 (m, 8H), 0.87 (t, J=6.9 Hz, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C@H:7]([CH2:11][C:12]([O:14]CC)=[O:13])[CH2:6][CH2:5]2.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:24][CH2:25][O:26][C:27]1[CH:39]=[CH:38][C:30]2[C:31]([C:34](F)(F)F)=[N:32][O:33][C:29]=2[C:28]=1[CH2:40][CH2:41][CH3:42]>CN(C=O)C.O>[CH3:34][C:31]1[C:30]2[CH:38]=[CH:39][C:27]([O:26][CH2:25][CH2:24][O:1][C:2]3[CH:3]=[C:4]4[C:8](=[CH:9][CH:10]=3)[C@H:7]([CH2:11][C:12]([OH:14])=[O:13])[CH2:6][CH2:5]4)=[C:28]([CH2:40][CH2:41][CH3:42])[C:29]=2[O:33][N:32]=1
Reactant: CCCc1c(OCCBr)ccc2c(C(F)(F)F)noc12
Reactant: CCOC(=O)C[C@@H]1CCc2cc(O)ccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCc1c(OCCOc2ccc3c(c2)CC[C@H]3CC(=O)O)ccc2c(C)noc12
Temperature: 60 °C
Reaction time: 10 h

Procedure:
Ethyl [(1S)-5-hydroxy-2,3-dihydro-1H-inden-1-yl]acetate (Example 6) (62.4 mg, 0.28 mmol) was dissolved in DMF (5 mL), and Cs2CO3 (111 mg, 0.34 mmol), and 3 drops of water were added. 6-(2-bromoethoxy)-7-propyl-3-(trifluoromethyl)-1,2-benzisoxazole (100 mg, 0.28 mmol) was added and the reaction mixture was stirred for 10 h at 60° C. The solvent was removed under reduced pressure, and the crude product was taken up in EtOAc, filtered through silica gel, and the filtrate was concentrated under reduced pressure. The crude product was dissolved in THF (2 mL), and LiOH (0.5 M aqueous solution, 0.9 mL) and MeOH (4 drops) were added. After stirring for 18 h at 50° C. the reaction mixture was concentrated under reduced pressure. Water and HCl (1 N aqueous solution) were added until the mixture was acidic which was followed by extraction using EtOAc. The product was purified by silica gel filtration (gradient 1:6 EtOAc/Hexane to 100% EtOAc), yielding 12 mg (9% over 2 steps) of the title compound as white crystals. 1H NMR (300 MHz, CD3OD): δ 0.91 (t, 3H), 1.70 (m, 3H), 2.33 (m, 2H), 2.68 (m, 2H), 2.87 (m, 3H), 3.46 (m, 1H), 4.33 (m, 2H), 4.48 (m, 2H), 6.73 (dd, 1H), 6.82 (d, 1H), 7.11 (d, 1H), 7.34 (d, 1H), 7.67 (d, 1H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].O.[CH2:8]([C:17]1[C:26]([CH3:27])=[C:25]([O:28]C(=O)C)[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=1)/[CH:9]=[CH:10]/[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].Cl>CO>[CH2:8]([C:17]1[CH:26]([CH3:27])[C:25](=[O:28])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=1)/[CH:9]=[CH:10]/[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCC/C=C/Cc1nc2ccccc2c(OC(C)=O)c1C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CCCCCC/C=C/CC1=Nc2ccccc2C(=O)C1C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 89.4 %

Procedure:
A solution of 300 mg (2.17 mmols) of potassium carbonate and 3 ml of water was added to a solution of 705 mg (2.17 mmols) of 2-(trans-2-nonenyl)-3-methyl-4-acetoxyquinoline, 10 ml of water and 50 ml of methanol and stirred at room temperature for 10 minutes. This solution was neutralized with 1N hydrochloric acid, after which the solvent was distilled off under reduced pressure, followed by addition of 50 ml of chloroform, washing with water and drying with sodium sulfate. The solvent was distilled off under reduced pressure and the resultant residue was purified by silica gel column chromatography (Wako Gel C 200) (solvent: n-hexane : ethyl acetate=1:2) to obtain 550 mg (yield 90%) of 2-(trans-2-nonenyl)-3-methyl-4-quinolone.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([S:9]([N:12]2[C:16]([C:17]3[C:18]([C:23]#[N:24])=[N:19][CH:20]=[CH:21][CH:22]=3)=[C:15]([F:25])[C:14]([CH2:26][N:27](C)[C:28](=O)OC(C)(C)C)=[CH:13]2)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1)#[N:2].C(OCC)(=O)C.[ClH:42]>C(OCC)(=O)C.CC(O)C>[ClH:42].[C:1]([C:3]1[CH:4]=[C:5]([S:9]([N:12]2[CH:13]=[C:14]([CH2:26][NH:27][CH3:28])[C:15]([F:25])=[C:16]2[C:17]2[C:18]([C:23]#[N:24])=[N:19][CH:20]=[CH:21][CH:22]=2)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: CN(Cc1cn(S(=O)(=O)c2cccc(C#N)c2)c(-c2cccnc2C#N)c1F)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: CNCc1cn(S(=O)(=O)c2cccc(C#N)c2)c(-c2cccnc2C#N)c1F
Temperature: 25 °C
Reaction time: 17 h
Yield: 79 %

Procedure:
To a solution of tert-butyl {[1-[(3-cyanophenyl)sulfonyl]-5-(2-cyanopyridin-3-yl)-4-fluoro-1H-pyrrol-3-yl]methyl}methylcarbamate (401 mg) in ethyl acetate (3 mL) and 2-propanol (2 mL) was added 4 mol/L hydrogen chloride-ethyl acetate solution (6 mL), and the mixture was stirred at room temperature for 17 hr. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from a mixed solvent of ethanol and water to give the title compound as a white solid (yield 276 mg, 79%).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[C:6]1([C:12]2[C:18]3[CH:19]=[C:20]([Cl:23])[CH:21]=[CH:22][C:17]=3[N:16]3[C:24]([C:27]([NH2:29])=O)=[N:25][N:26]=[C:15]3[CH2:14][N:13]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>CN(C)C=O>[C:6]1([C:12]2[C:18]3[CH:19]=[C:20]([Cl:23])[CH:21]=[CH:22][C:17]=3[N:16]3[C:24]([C:27]#[N:29])=[N:25][N:26]=[C:15]3[CH2:14][N:13]=2)[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: NC(=O)c1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: N#Cc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2

Procedure:
4 ml of phosphorus oxychloride is added to a solution of 1.69 g (0.005 mole) of 6-phenyl-8-chloro-4H-s-triazolo[4,3-a ] [1,4]benzodiazepine-1-carboxamide in 5ml of dimethylformamide, and stirring maintained for 10 minutes at 80°. The reaction mixture is then poured on ice and extracted with ethylene chloride. The extract is washed with water and saturated sodium chloride solution, dried over magnesium sulphate and concentrated by evaporation. The residue is chromatographed on silica gel with the use of benzene and benzene/ethyl acetate mixtures as eluant. The fractions containing the desired nitrile [Rf = 0.5 in the eluant system benzene/chloroform/ethyl acetate (4:4:2)] are combined and concentrated by evaporation. The residue is crystallised from ethyl acetate/petroleum ether to obtain 6-phenyl-8-chloro-4H-s-triazolo [4,3-a][1,4]benzodiazepine-1-carbonitrile, M.P. 191°-192°.
Reaction SMILES: [CH3:1][C:2]([CH3:32])([CH3:31])[C:3]([N:5]1[C:9]([CH2:16][CH2:17][NH:18][S:19]([CH:22]=[CH2:23])(=[O:21])=[O:20])([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[S:8][C:7]([NH:24][C:25](=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27])=[N:6]1)=[O:4].[CH2:33]([NH2:35])[CH3:34]>C(#N)C>[CH3:1][C:2]([CH3:32])([CH3:31])[C:3]([N:5]1[C:9]([CH2:16][CH2:17][NH:18][S:19]([CH2:22][CH2:23][NH:35][CH2:33][CH3:34])(=[O:21])=[O:20])([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[S:8][C:7]([NH:24][C:25](=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27])=[N:6]1)=[O:4]
Reactant: C=CS(=O)(=O)NCCC1(c2ccccc2)SC(NC(=O)C(C)(C)C)=NN1C(=O)C(C)(C)C
Reactant: CCN
Solvent: CC#N
Product: CCNCCS(=O)(=O)NCCC1(c2ccccc2)SC(NC(=O)C(C)(C)C)=NN1C(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 86.5 %

Procedure:
N-[4-(2,2-Dimethylpropionyl)-5-(2-ethenesulfonylaminoethyl)-5-phenyl-4,5-dihydro-1,3,4-thiadiazol-2-yl]-2,2-dimethylpropanamide (0.16 g, 0.33 mmol) obtained in Step 4 mentioned above was dissolved in acetonitrile (10 mL), and 70% aqueous ethylamine (1.0 mL, 12 mmol) was added, then the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative silica gel thin layer chromatography (chloroform/methanol/concentrated aqueous ammonia=100/10/1) to give N-{4-(2,2-dimethylpropionyl)-5-[2-(2-ethylaminoethanesulfonyl-amino)ethyl]-5-phenyl-4,5-dihydro-1,3,4-thiadiazol-2-yl}-2,2-dimethylpropanamide} (0.15 g, 86%).
Reaction SMILES: [F:1][CH2:2][C:3]([N:11]1[C:15](=[O:16])[C:14]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:13]2[C:12]1=[O:21])([CH2:6][CH2:7][CH2:8][CH2:9]I)[C:4]#[N:5].CN(C=O)C.[C:27]1(=[O:37])[NH:31][C:30](=[O:32])[C:29]2=[CH:33][CH:34]=[CH:35][CH:36]=[C:28]12.[K]>CC(C)=O>[F:1][CH2:2][C:3]([N:11]1[C:15](=[O:16])[C:14]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:13]2[C:12]1=[O:21])([CH2:6][CH2:7][CH2:8][CH2:9][N:31]1[C:30](=[O:32])[C:29]2=[CH:33][CH:34]=[CH:35][CH:36]=[C:28]2[C:27]1=[O:37])[C:4]#[N:5]
Reactant: N#CC(CF)(CCCCI)N1C(=O)c2ccccc2C1=O
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: N#CC(CF)(CCCCN1C(=O)c2ccccc2C1=O)N1C(=O)c2ccccc2C1=O
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A mixture of 2-fluoromethyl-2-phthalimido-6-iodo-hexanenitrile (9.0 g, 22.5 mmol), dry DMF (30 ml), and potassium phthalimide (4.2 g, 1 equivalent) is stirred and heated at 80° C. for 4 hours. The DMF is removed under reduced pressure (0.1 mm Hg), and the residue is taken up in chloroform. The chloroform mixture is filtered, and the filtrate is washed with 2 N NaOH, 2 N HCl, and water. Evaporation of solvent gives a residue which, when dissolved in the minimum amount of acetone, crystallizes upon addition of ether. After standing at 5° C. overnight, the colourless crystals are collected (7.0 g), mp (Kofler) 136° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[S:13][C:12]([CH2:14][NH:15][OH:16])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.C[Si]([N:21]=[C:22]=[O:23])(C)C.[Cl-].[NH4+]>O1CCOCC1>[OH:16][N:15]([CH2:14][C:12]1[S:13][C:9]([S:8][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[CH:10][CH:11]=1)[C:22]([NH2:21])=[O:23]
Reactant: ONCc1ccc(Sc2ccc(Cl)cc2)s1
Reactant: C[Si](C)(C)N=C=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1COCCO1
Product: NC(=O)N(O)Cc1ccc(Sc2ccc(Cl)cc2)s1
Reaction time: 2 h

Procedure:
To a solution of N-[5-(4-chlorophenylthio)thien-2-ylmethyl]hydroxylamine (6.65 g) in dioxan (100 ml) at room temperature under nitrogen, was added trimethylsilylisocyanate (4.25 g) and the resulting solution stirred for 2 hours, poured onto saturated aqueous ammonium chloride, extracted with ether (2×100 ml), dried over MgSO4 and evaporated under reduced pressure to give a yellow oil. The oil was flash chromatographed on a Sorbsil C60-40/60H column using ether to give a white solid. Recrystallised from ether/petroleum ether (40°-60° C.) to give a white crystalline solid m.p. 158°-160° C.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:5]=[C:6]([CH2:10][NH2:11])[CH:7]=[CH:8][CH:9]=1.[NH2:14][C:15]1[N:20]=[C:19]([C:21](O)=[O:22])[CH:18]=[CH:17][N:16]=1>>[NH2:14][C:15]1[N:20]=[C:19]([C:21]([NH:11][CH2:10][C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([O:3][C:2]([F:12])([F:13])[F:1])[CH:5]=2)=[O:22])[CH:18]=[CH:17][N:16]=1
Reactant: Nc1nccc(C(=O)O)n1
Reactant: NCc1cccc(OC(F)(F)F)c1
Product: Nc1nccc(C(=O)NCc2cccc(OC(F)(F)F)c2)n1
Yield: 37 %

Procedure:
The title compound is prepared in 37% yield (82 mg, a white solid) from (3-(trifluoromethoxy)phenyl)methanamine (137 mg, 0.72 mmol) and 2-aminopyrimidine-4-carboxylic acid (100 mg, 0.72 mmol) by the similar manner in Step-1 of Example 8.
Reaction SMILES: O[CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][CH2:5][CH2:4][CH2:3]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[O:6]1[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH:2]=[CH:3][CH2:4][CH2:5]1
Reactant: OC1CCCOc2ccccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: C1=Cc2ccccc2OCC1
Yield: 93.2 %

Procedure:
800 ml of toluene are poured over 53 g (0.323 mole) of 5-hydroxy-2,3,4,5-tetrahydro-1-benzoxepin and, with addition of 3.7 g of p-toluenesulfonic acid monohydrate, the mixture is refluxed with a water trap for 1.5 hours. The cold organic phase is washed with saturated sodium bicarbonate solution, water and sodium chloride solution, and the solvent is evaporated off in vacuo. Kugelrohr distillation at 30°-35° C./0.008 torr results in 44 g of oil. p 1H NMR (60 MHz/CDCl3): δ=7.23-6.70 (m, 4H); δ=6.30 (m, 1H); δ=6.07-5.70 (m, 1H); δ=4.20 (t, J=5 Hz, 2H); δ=2.63 (m, 2H).