Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:19][CH2:18][C:11]2([NH:15][C:14](=[O:16])[NH:13][C:12]2=[O:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CS(O[CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2[N:39]=[C:38]([C:40]#[N:41])[C:37]3[N:42]=[CH:43][N:44]([CH3:45])[C:36]=3[CH:35]=2)=[CH:30][C:29]=1[C:46]([F:49])([F:48])[F:47])(=O)=O.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCCC[N+](CCCC)(CCCC)CCCC.[I-]>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]2([NH:15][C:14](=[O:16])[N:13]([CH2:25][CH2:26][O:27][C:28]3[CH:33]=[CH:32][C:31]([C:34]4[N:39]=[C:38]([C:40]#[N:41])[C:37]5[N:42]=[CH:43][N:44]([CH3:45])[C:36]=5[CH:35]=4)=[CH:30][C:29]=3[C:46]([F:49])([F:47])[F:48])[C:12]2=[O:17])[CH2:18][CH2:19]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cn1cnc2c(C#N)nc(-c3ccc(OCCOS(C)(=O)=O)c(C(F)(F)F)c3)cc21
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)NC(=O)NC2=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: Cn1cnc2c(C#N)nc(-c3ccc(OCCN4C(=O)NC5(CCN(C(=O)OC(C)(C)C)CC5)C4=O)c(C(F)(F)F)c3)cc21
Temperature: 90 °C
Reaction time: 8 h
Yield: 55.8 %

Procedure:
A solution of 8-tert-butoxycarbonyl-1,3,8-triaza-spiro[4.5]decane-2,4-dione (75 mg) in DMF (1 mL) was added to a solution of 2-(4-(4-cyano-1-methyl-1H-imidazo[4,5-c]pyridin-6-yl)-2-(trifluoromethyl)phenoxy)ethyl methanesulfonate (90 mg) in DMF (1 mL), K2CO3 (83 mg) and TBAI (48 mg). The mixture was stirred overnight at 90° C. The solvent was removed under reduced pressure. The residue was partitioned between ethyl acetate (50 ml) and a saturated solution of Na2CO3 (20 ml). The organic layer was dried over sodium sulphate, filtered and concentrated under reduced pressure to afford 3-(2-(4-(4-cyano-1-methyl-1H-imidazo[4,5-c]pyridin-6-yl)-2-trifluoromethyl-phenoxy)-ethyl)-2,4-dioxo-1,3,8-triaza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester (70 mg). The crude product was dissolved in MeOH (2 mL) and a 5N solution of HCl in iPrOH (0.05 ml) was added. The mixture was stirred 2 hours at 60° C., then the solvent was evaporated under reduced pressure. The crude product was directly purified by preparative HPLC (HPLC:column XBridge MS C18 30×100 mm, 5 μm, Eluent:A:NH4HCO3, 10 mmol, pH=9.5/B:Acetonitrile, Focused gradient/8 minutes/50 mL/min) to afford 6-{4-[2-(2,4-dioxo-1,3,8-triaza-spiro[4.5]dec-3-yl)-ethoxy]-3-(trifluoromethyl)-phenyl}-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile (23 mg).
Reaction SMILES: C(Cl)(=O)C1C=CC=CC=1.[S-:10][C:11]#[N:12].[NH4+].[F:14][C:15]1[CH:16]=[C:17]([CH:19]=[C:20]([F:22])[CH:21]=1)[NH2:18].[OH-].[Na+].Cl.[OH-].[NH4+]>CC(C)=O.O>[F:14][C:15]1[CH:16]=[C:17]([NH:18][C:11]([NH2:12])=[S:10])[CH:19]=[C:20]([F:22])[CH:21]=1
Reactant: Nc1cc(F)cc(F)c1
Reactant: N#C[S-]
Agent: Cl
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: O=C(Cl)c1ccccc1
Solvent: CC(C)=O
Product: NC(=S)Nc1cc(F)cc(F)c1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 48.3 %

Procedure:
Benzoyl chloride (5.44 g, 38.73 mmol) was added to a stirred solution of ammonium thiocyanate (3.83 g, 50.35 mmol) in acetone (80 mL) at 30° C. The mixture was stirred at reflux for 30 minutes, then cooled to 50° C., and a solution of 3,5-difluoroaniline (5.00 g, 38.73 mmol) in acetone (10 mL) was added in one portion. The mixture was stirred at reflux for 30 minutes. A solution of NaOH (5.42 g, 135.54 mmol) in water (65 mL) was added, and the mixture was stirred at reflux for 20 minutes and then cooled to 20° C. Concentrated HCl was added to adjust the acidity to pH=5, and then the mixture was adjusted to slightly alkaline by the addition of conc. ammonium hydroxide. After 30 minutes, the mixture was cooled to 10° C. and extracted with EtOAc, and the combined organic layer was washed with brine, filtered, and concentrated to afford N-(3,5-difluorophenyl) thiourea (3.52 g, 48%). ret. time 1.73; m/z 189.0 (MH+); 1H NMR (400 MHz, MeOH-d4) δ 6.72 (m, 1H), 7.16 (m, 2H).
Reaction SMILES: BrC1C=C(C=CC=1)OC(C)(CC1C=CC(OCCC2N=C(C3CCCCC3)OC=2C)=CC=1)C(O)=O.[S:36]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F-].[K+].[CH2:65]([O:67][C:68](=[O:100])[C:69]([CH3:99])([O:92][C:93]1[CH:98]=[CH:97][CH:96]=[CH:95][CH:94]=1)[CH2:70][C:71]1[CH:76]=[CH:75][C:74]([O:77][CH2:78][CH2:79][C:80]2[N:81]=[C:82]([CH:86]3[CH2:91][CH2:90][CH2:89][CH2:88][CH2:87]3)[O:83][C:84]=2[CH3:85])=[CH:73][CH:72]=1)[CH3:66]>C1COCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C>[CH2:65]([O:67][C:68](=[O:100])[C:69]([CH3:99])([O:92][C:93]1[CH:94]=[CH:95][CH:96]=[C:97]([C:38]2[CH:39]=[CH:40][S:36][CH:37]=2)[CH:98]=1)[CH2:70][C:71]1[CH:72]=[CH:73][C:74]([O:77][CH2:78][CH2:79][C:80]2[N:81]=[C:82]([CH:86]3[CH2:91][CH2:90][CH2:89][CH2:88][CH2:87]3)[O:83][C:84]=2[CH3:85])=[CH:75][CH:76]=1)[CH3:66]
Reactant: CCOC(=O)C(C)(Cc1ccc(OCCc2nc(C3CCCCC3)oc2C)cc1)Oc1ccccc1
Reactant: OB(O)c1ccsc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1oc(C2CCCCC2)nc1CCOc1ccc(CC(C)(Oc2cccc(Br)c2)C(=O)O)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)(Cc1ccc(OCCc2nc(C3CCCCC3)oc2C)cc1)Oc1cccc(-c2ccsc2)c1

Procedure:
Add palladium acetate (8 mg, 0.04 mmol) to a solution of 2-(3-Bromo-phenoxy)-3-(4-[2-(2-cyclohexyl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-methyl-propionic acid (0.204 g, 0.36 mmol), thiophene-3-boronic acid (91 mg, 0.71 mmol), triphenylphosphine (19 mg, 0.07 mmol), and potassium fluoride (51 mg, 1.07 mmol) in anhydrous THF (3 mL). Reflux the reaction mixture for 18 h under an atmosphere of nitrogen. Dilute the cooled reaction mixture with ethyl acetate and wash with water and brine. The organic layer was dried over Na2SO4, concentrated in vacuo, and purified by flash column chromatography (9% acetone in hexanes) to provide a mixture of the titled compound and 3-{4-[2-(2-Cyclohexyl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-methyl-2-phenoxy-propionic acid ethyl ester (70 mg, 34%). 1H NMR (400 MHz, CDCl3): δ 7.38-7.19 (m, 5H), 7.13 (d, 2H, J=8.60 Hz), 7.07 (m, 1H), 6.80 (2H, J=8.60 Hz), 6.73-6.70 (m, 1H), 4.19 (q, 2H, J=7.04 Hz), 4.12 (t, 2H, J=6.65 Hz), 3.27 (d, 1H, J=13.69 Hz), 3.11 (d, 1H, J=13.69 Hz), 2.85 (t, 2H, J=6.65 Hz), 2.70-2.63 (m, 1H), 2.22 (s, 3H), 2.01 (d, 2H, J=11.73 Hz), 1.79-1.76 (m, 2H), 1.67 (h, 1H, J=11.73 Hz), 1.59 (s, 3H), 1.56-1.46 (m, 2H), 1.41 (s, 3H), 1.37-1.23 (m, 2H), 1.20 (t, 3H, J=7.04 Hz). MS [EI+] 574 (M+H)+. Rf=0.08 in 9% ethyl acetate in hexanes.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:7]([N:21]2[CH2:32][CH2:31][N:30]3[C:23](=[CH:24][C:25]4[CH2:26][C:27]([CH3:34])([CH3:33])[CH2:28][C:29]=43)[C:22]2=[O:35])=[N:8][CH:9]=[CH:10][C:11]=1B1OC(C)(C)C(C)(C)O1)(=[O:3])[CH3:2].Br[C:37]1[CH:38]=[C:39]([NH:45][C:46]2[CH:59]=[C:49]3[CH2:50][N:51]([CH:54]([CH3:58])[CH2:55][O:56][CH3:57])[CH2:52][CH2:53][N:48]3[N:47]=2)[C:40](=[O:44])[N:41]([CH3:43])[CH:42]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C([O-])(=O)C.[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(#N)C.O>[C:1]([O:4][CH2:5][C:6]1[C:7]([N:21]2[CH2:32][CH2:31][N:30]3[C:23](=[CH:24][C:25]4[CH2:26][C:27]([CH3:34])([CH3:33])[CH2:28][C:29]=43)[C:22]2=[O:35])=[N:8][CH:9]=[CH:10][C:11]=1[C:37]1[CH:38]=[C:39]([NH:45][C:46]2[CH:59]=[C:49]3[CH2:50][N:51]([CH:54]([CH3:58])[CH2:55][O:56][CH3:57])[CH2:52][CH2:53][N:48]3[N:47]=2)[C:40](=[O:44])[N:41]([CH3:43])[CH:42]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Reactant: COCC(C)N1CCn2nc(Nc3cc(Br)cn(C)c3=O)cc2C1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: O
Product: COCC(C)N1CCn2nc(Nc3cc(-c4ccnc(N5CCn6c(cc7c6CC(C)(C)C7)C5=O)c4COC(C)=O)cn(C)c3=O)cc2C1
Temperature: 100 °C
Yield: 49.8 %

Procedure:
A 50-mL round bottomed flask equipped with a reflux condenser was charged with {3-[(acetyloxy)methyl]-2-{4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.02,6]dodeca-2(6),7-dien-10-yl}pyridin-4-yl}boronic acid 199e (238 mg, 0.60 mmol), 300c (240 mg, 0.80 mmol), K3PO4 (254 mg, 1.2 mmol), sodium acetate (98 mg, 1.6 mmol), Pd(dppf)Cl2 (22 mg, 0.030 mmol), and acetonitrile/water (12/0.5 mL). The system was subjected to three cycles of vacuum/nitrogen flush and heated at 100° C. under N2 protection for 1 h. Analysis of the reaction mixture by LCMS showed complete conversion to the desired product. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure. The residue was partitioned between dichloromethane (30 mL) and water (30 mL). The water layer was extracted with dichloromethane (2×30 mL). The combined organic extract was dried over Na2SO4, filtered, and concentrated under reduced pressure. The dark residue was purified by silica-gel column chromatography eluting with dichloromethane/methanol (80/1 to 30/1) to afford 300d (200 mg, 50%) as yellow solid. MS-ESI: [M+H]+ 669.4
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C@@H:5]1[NH:9][C:8](=[O:10])[N:7]([C:11]2[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=2)[C:14]([OH:16])=[O:15])[C:6]1=[O:20].[C:21](=O)([O:29]C1C=CC([N+]([O-])=O)=CC=1)[O:22][CH:23]([O:25][C:26](=[O:28])[CH3:27])[CH3:24].C(N(CC)CC)C>CN(C=O)C>[C:26]([O:25][CH:23]([O:22][C:21]([NH:1][CH2:2][CH2:3][CH2:4][C@@H:5]1[NH:9][C:8](=[O:10])[N:7]([C:11]2[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=2)[C:14]([OH:16])=[O:15])[C:6]1=[O:20])=[O:29])[CH3:24])(=[O:28])[CH3:27]
Reactant: NCCC[C@@H]1NC(=O)N(c2cccc(C(=O)O)c2)C1=O
Reactant: CC(=O)OC(C)OC(=O)Oc1ccc([N+](=O)[O-])cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)OC(C)OC(=O)NCCC[C@@H]1NC(=O)N(c2cccc(C(=O)O)c2)C1=O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
2.50 g (7.97 mmol) of 3-(5-(S)-3-aminopropyl-2,4-dioxoimidazolidin-3-yl)benzoic acid and 2.15 g (7.97 mmol) of 1-acetoxyethyl p-nitrophenyl carbonate are dissolved in 50 ml of DMF, treated with 3.33 ml (24 mmol) of triethylamine and stirred at room temperature for 3 d. The mixture is concentrated in vacuo and the residue is chromatographed on silica gel (dichloromethane/methanol/glacial acetic acid).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH2:10][C:9](=[O:12])[N:8]([CH2:13][CH2:14][N:15]3[CH2:20][CH2:19][CH:18]([NH:21]C(=O)OC(C)(C)C)[CH2:17][C:16]3=[O:29])[C:7]=2[CH:30]=1)#[N:2].FC(F)(F)C(O)=O.NC1CCN(CCN2C3C=C(OC)C=CC=3COC2=O)CC1>>[NH2:21][CH:18]1[CH2:19][CH2:20][N:15]([CH2:14][CH2:13][N:8]2[C:7]3[CH:30]=[C:3]([C:1]#[N:2])[CH:4]=[CH:5][C:6]=3[O:11][CH2:10][C:9]2=[O:12])[C:16](=[O:29])[CH2:17]1
Reactant: CC(C)(C)OC(=O)NC1CCN(CCN2C(=O)COc3ccc(C#N)cc32)C(=O)C1
Agent: COc1ccc2c(c1)N(CCN1CCC(N)CC1)C(=O)OC2
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc2c(c1)N(CCN1CCC(N)CC1=O)C(=O)CO2

Procedure:
tert-Butyl {1-[2-(6-cyano-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)ethyl]-2-oxopiperidin-4-yl}carbamate (Intermediate 117, 225 mg, 0.54 mmol) was reacted as described for Intermediate 106. The crude trifluoro acetate of the title compound was obtained as a red oil, 232 mg (quantitative), and used without further purification for the next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]2[C:7]([CH2:10][C:11]([OH:13])=[O:12])=[CH:8][O:9][C:5]=2[CH:4]=1.OS(O)(=O)=O.[CH3:21]O>>[CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]2[C:7]([CH2:10][C:11]([O:13][CH3:21])=[O:12])=[CH:8][O:9][C:5]=2[CH:4]=1
Reactant: CO
Reactant: COc1ccc2c(CC(=O)O)coc2c1
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1coc2cc(OC)ccc12
Yield: 98 %

Procedure:
A mixture of (6-methoxy-benzofuran-3-yl)-acetic acid (2 g, 9.7 mmol) and H2SO4 (0.3 mL) in methanol (40 mL) was refluxed for 8 h and then concentrated. An aqueous NaHCO3 solution was added, followed by extraction with CH2Cl2. The combined organic layers were dried over anhydrous MgSO4 and evaporated to give a brown oil, which was purified on a silica gel column eluting with EtOAc/hexane (1:10) to give methyl 2-(6-methoxybenzofuran-3-yl)acetate (2.1 g, 98%)
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2([CH2:16][CH2:17][N:18]3[CH:23]4[CH2:24][CH2:25][CH:19]3[CH2:20][CH:21]([N:26]3[C:30]5[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=5[N:28]=[C:27]3[CH3:35])[CH2:22]4)[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][C:5]=1[F:36].C(N(CC)CC)C.[CH3:44][C:45]([CH3:50])([CH3:49])[C:46](Cl)=[O:47]>ClCCl>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2([CH2:16][CH2:17][N:18]3[C@H:23]4[CH2:24][CH2:25][C@@H:19]3[CH2:20][CH:21]([N:26]3[C:30]5[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=5[N:28]=[C:27]3[CH3:35])[CH2:22]4)[CH2:15][CH2:14][N:13]([C:46](=[O:47])[C:45]([CH3:50])([CH3:49])[CH3:44])[CH2:12][CH2:11]2)=[CH:6][C:5]=1[F:36]
Reactant: Cc1nc2ccccc2n1C1CC2CCC(C1)N2CCC1(c2ccc(Cl)c(F)c2)CCNCC1
Reactant: CC(C)(C)C(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC1(c2ccc(Cl)c(F)c2)CCN(C(=O)C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.9 %

Procedure:
A mixture of 1-(8-{2-[4-(4-chloro-3-fluorophenyl)piperidin-4-yl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-1H-benzimidazole dihydrochloride (0.20 g, 0.39 mmol), triethylamine (0.11 mL, 0.78 mmol) and trimethylacetyl chloride (0.053 mL, 0.43 mmol) in dichloromethane (4 mL) was stirred at rt for 1 h before the reaction mixture was quenched with saturated sodium bicarbonate solution. The organic layer was separated, dried, concentrated and purified by chromatography on silica gel eluting with a dichloromethane to 1:9 methanol:dichloromethane gradient to give 1-((1R,5S)-8-{2-[4-(4-chloro-3-fluorophenyl)-1-(2,2-dimethylpropanoyl)piperidin-4-yl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-1H-benzimidazole as a white foam (0.11 g, 51%). 1H NMR (400 MHz, CDCl3) δ 7.67 (m, 1H), 7.40 (m, 1H), 7.29 (m, 1H), 7.03-7.19 (m, 4H), 4.72 (m, 1H), 3.90 (m, 2H), 3.33 (m, 4H), 2.59 (s, 3H), 2.42 (m, 2H), 1.78-2.13 (m, 14H), 1.27 (s, 9H). HRMS C33H42ClFN4O m/z 565.3109 (M+H)Cal., 565.3134 (M+H)Obs..
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[CH:11]=[O:12].[Br:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1B(O)O>>[Br:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:2]1[CH:10]=[CH:9][C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[CH:11]=[O:12]
Reactant: OB(O)c1ccccc1Br
Reactant: O=Cc1c(Br)ccc2c1OCO2
Product: O=Cc1c(-c2ccccc2Br)ccc2c1OCO2

Procedure:
The process described in Method B was followed. 5-Bromo-1,3-benzodioxole-4-carbaldehyde (1.15 g, 5.00 mmol) and 2-bromophenylboronic acid (1.10 g, 5.50 mmol) were used to obtain the title compound. The crude product was purified by column chromatography with a mixture of hexane:ethyl acetate (9:1) as the eluent.
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[CH:4]=[CH:5][C:6]2[N:12]=[C:11]([NH:13][N:14]=[C:15]([C:25]([OH:27])=[O:26])[CH2:16][CH2:17][N:18]([CH2:22][CH2:23][CH3:24])[CH2:19][CH2:20][CH3:21])[CH2:10][N:9]=[C:8]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[F:34])[C:7]=2[CH:35]=1.[N+](=[CH2:40])=[N-]>>[F:37][C:2]([F:1])([F:36])[C:3]1[CH:4]=[CH:5][C:6]2[N:12]=[C:11]([NH:13][N:14]=[C:15]([C:25]([O:27][CH3:40])=[O:26])[CH2:16][CH2:17][N:18]([CH2:19][CH2:20][CH3:21])[CH2:22][CH2:23][CH3:24])[CH2:10][N:9]=[C:8]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[F:34])[C:7]=2[CH:35]=1
Reactant: CCCN(CCC)CCC(=NNC1=Nc2ccc(C(F)(F)F)cc2C(c2ccccc2F)=NC1)C(=O)O
Reactant: C=[N+]=[N-]
Product: CCCN(CCC)CCC(=NNC1=Nc2ccc(C(F)(F)F)cc2C(c2ccccc2F)=NC1)C(=O)OC

Procedure:
In the manner given in Example 14, 7-(trifluoromethyl)-2-[[1-carboxy-3-(dipropylamino)propylidene]-hydrazino]-5-(o-fluorophenyl)-3H-1,4-benzodiazepine can be treated with ethereal diazomethane to give 7-(trifluoromethyl)-2-[[1-(methoxycarbonyl)-3-(dipropylamino)propylidene]hydrazino]-5-(o-fluorophenyl)-3H-1,4-benzodiazepine.
Reaction SMILES: N#N.[O:3]1[CH:7]=[CH:6][N:5]=[C:4]1[CH:8]([OH:10])[CH3:9].[Si:11](Cl)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12].N1C=CN=C1.[NH4+].[Cl-]>C1COCC1>[C:14]([Si:11]([CH3:13])([CH3:12])[O:10][CH:8]([C:4]1[O:3][CH:7]=[CH:6][N:5]=1)[CH3:9])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(O)c1ncco1
Agent: N#N
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(O[Si](C)(C)C(C)(C)C)c1ncco1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), 1-oxazol-2-yl-ethanol (348 mg, 3.08 mmol) was dissolved in dry THF (15 mL). tert-Butyldimethylsilyl chloride (580 mg, 3.85 mmol) was added at rt followed by imidazole (262 mg, 3.85 mmol). The reaction mixture was stirred at rt for 16 h. Sat. aq. NH4Cl (20 mL) was added, the layers separated and the aq. layer extracted with EA (2×20 mL). The combined org. extracts were dried over MgSO4, filtered, and the solvent removed under reduced pressure. Purification of the residue by FC (1:4 Et2O-hexane) gave the title compound as a colorless oil. TLC:rf (1:4 Et2O-hexane)=0.39. LC-MS-conditions 02: tR=1.08 min, [M+H]+=228.48
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH2:12][CH2:11][CH2:10][CH2:9][CH:8]=2)[CH2:3][CH2:2]1.[P:13]([O-:28])([O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[O:1]1[CH2:6][CH2:5][N:4]([C:7]2([P:13]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)(=[O:28])[O:14][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH2:3][CH2:2]1
Reactant: [O-]P(Oc1ccccc1)Oc1ccccc1
Reactant: C1=C(N2CCOCC2)CCCC1
Product: O=P(Oc1ccccc1)(Oc1ccccc1)C1(N2CCOCC2)CCCCC1

Procedure:
To 1-morpholinocyclohexene (21.5 g; 0.13 mol) was added diphenyl phosphite (30 g; 0.13 mol) drop-wise during 20 minutes. The mixture which began to deposit a solid was heated at 100° for 30 minutes following the addition. After cooling, the resulting solid was recrystallized from benzene/hexane to yield pure diphenyl 1-morpholinocyclohexane-1-phosphonate, 37 g (70%), mp 103°-6°. NMR and IR spectra support the structure. Analysis: Calculated for C22H28NO4P; N, 3.49%; P, 7.73%. Found: N, 3.40% P, 7.70%. ##STR10##
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Br:13]N1C(=O)CCC1=O>>[Br:13][CH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1c(C)cccc1C
Reactant: O=C1CCC(=O)N1Br
Product: COC(=O)c1c(C)cccc1CBr

Procedure:
Reaction of methyl 2,6-dimethylbenzoate with N-bromosuccinimide as described in Example 1a provides methyl 2-bromomethyl-6-methylbenzoate as an oil.
Reaction SMILES: O1CCCCC1[O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]#[CH:15].C(Cl)(Cl)Cl>CO>[CH2:8]([OH:7])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]#[CH:15]
Reactant: C#CCCCCCCOC1CCCCO1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: C#CCCCCCCO
Yield: 88.9 %

Procedure:
A suspension of lithium acetylide ethylenediamine complex (Aldrich, 11.3 g, 122.5 mmol) and dimethyl sulfoxide (50 ml) was cooled to 5-10° C., and added dropwise with 1-bromo-6-tetrahydropyranyloxyhexane (Sigma, 25 g, 94.3 mmol) over two hours. Then, the reaction mixture was stirred at room temperature for two hours. The reaction mixture was added with water (10 ml), stirred for ten minutes, then poured into water (150 ml), and extracted with ether (300 ml). The ether layer was washed with water, dried over magnesium sulfate, and concentrated under reduced pressure to afford 18.1 g of 8-(tetrahydropyranyloxy)-1-octyne as oil (yield; 91.2%). Dowex 50WX8 (H+ type, 18 g) was added to a mixture of 8-(tetrahydropyranyloxy)-1-octyne (18 g, 85.6 mmol), chloroform (40 ml) and methanol (140 ml), and heated for 1 hour under reflux. After the resin was separated by filtration, the filtrate was concentrated, and the resulting residue was purified by silica gel column chromatography (eluent; hexane-ethyl acetate mixed solvent) to afford 9.6 g of 7-octyn-1-ol (yield; 88.6%).
Reaction SMILES: [C:1]([C:4]1(C(OC)=O)[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1)(=[O:3])[CH3:2].S(=O)(=O)(O)O>>[C:1]([CH:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: COC(=O)C1(C(C)=O)CCOCC1
Agent: O=S(=O)(O)O
Product: CC(=O)C1CCOCC1
Yield: 97.5 %

Procedure:
In a flask made of glass having an inner volume of 10 ml and equipped with a stirring device, a thermometer and a reflux condenser were charged 0.38 g (2.0 mmol) of 4-acetyl-4-methoxycarbonyltetrahydropyran with a purity of 99% and synthesized in the same manner as in Reference example 1 and 1.08 ml (10 mmol) of 9 mol/l sulfuric acid, and the mixture was reacted at 120° C. for 1.5 hours with stirring. After completion of the reaction, when the reaction mixture was analyzed by gas chromatography (Internal standard method), 0.25 g (Reaction yield: 96%) of 4-acetyltetrahydropyran was found to be formed.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C@@H:7]([CH3:21])[CH2:8][N:9]2[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=O)=[CH:4][CH:3]=1.COC1C=CC(P2(=S)SP(C3C=CC(OC)=CC=3)(=S)[S:31]2)=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C@@H:7]([CH3:21])[CH2:8][N:9]2[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[S:31])=[CH:4][CH:3]=1
Reactant: C[C@H]1CN(C(=O)c2ccccc2F)c2cc(Br)ccc2N1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: C[C@H]1CN(C(=S)c2ccccc2F)c2cc(Br)ccc2N1
Temperature: 100 °C
Reaction time: 0.21 h
Yield: 133.7 %

Procedure:
A screw-cap vial equipped with a magnetic stir bar was charge with (S)-(7-bromo-3-methyl-3,4-dihydroquinoxaline-1(2H)-yl)(2-fluorophenyl)methanone (0.050 g, 0.143 mmol), toluene (1 mL), and 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane-2,4-dithione (Lawesson's Reagent) (0.035 g, 0.086 mmol). The head space was flushed with nitrogen, the vial capped, and the mixture heated to 100° C. After about 10-15 min, the reaction mixture turned yellow. After 45 min, heating was discontinued. After cooling, the reaction mixture was loaded directly onto a preparative thin layer chromatography plate (1000 micron), and eluted with 4:1 hexanes-ethyl acetate. The non-polar, yellow band was isolated and afforded (S)-(7-bromo-3-methyl-3,4-dihydroquinoxaline-1(2H)-yl)(2-fluorophenyl)methanethione (0.042 g, 80%) as a bright yellow solid. MS (ESI, pos. ion) m/z 365, 367 [M+1].
Reaction SMILES: [CH3:1][C:2](=[N:4][OH:5])[CH3:3].CC(C)([O-])C.[K+].[C:12]([C:20]1[C:21](Cl)=[C:22]2[CH:28]=[N:27][N:26]([CH2:29][CH3:30])[C:23]2=[N:24][CH:25]=1)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>O1CCCC1>[C:12]([C:20]1[C:21]([O:5][N:4]=[C:2]([CH3:3])[CH3:1])=[C:22]2[CH:28]=[N:27][N:26]([CH2:29][CH3:30])[C:23]2=[N:24][CH:25]=1)(=[O:19])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CCn1ncc2c(Cl)c(C(=O)c3ccccc3)cnc21
Reactant: CC(C)=NO
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCn1ncc2c(ON=C(C)C)c(C(=O)c3ccccc3)cnc21
Yield: 72.7 %

Procedure:
In 25 ml of dry tetrahydrofuran (THF hereafter) was dissolved 1.6 g of acetone oxime, followed by 2.46 g of potassium t-butoxide. After stirring 0.5 hour 5.0 g of 5-benzoyl-4-chloro-1-ethyl-1H-pyrazolo[3,4-b]pyridine in 50 ml of THF was added to the solution. After an additional 0.5 hour the reaction was quenched with ammonium chloride solution and the product was extracted with ether. Evaporation of the organic phase and recrystallization of the residue from ethanol gave 4.1 g of product, mp 115°-116° C.
Reaction SMILES: [N:1]1([C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.N1C=CC=CC=1.[Cl-].[N:28]1[CH:33]=[CH:32][CH:31]=[N:30][C:29]=1[NH:34][S:35]([C:38]1[CH:43]=[CH:42][C:41]([NH:44][CH:45]=[S:46])=[CH:40][CH:39]=1)(=[O:37])=[O:36].CO>ClCCl>[N:28]1[CH:33]=[CH:32][CH:31]=[N:30][C:29]=1[NH:34][S:35]([C:38]1[CH:43]=[CH:42][C:41]([NH:44][C:45]([N:4]2[CH2:5][CH2:6][N:1]([C:7]3[C:16]4[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=4)[N:10]=[CH:9][N:8]=3)[CH2:2][CH2:3]2)=[S:46])=[CH:40][CH:39]=1)(=[O:37])=[O:36]
Reactant: COc1cc2ncnc(N3CCNCC3)c2cc1OC
Reactant: O=S(=O)(Nc1ncccn1)c1ccc(NC=S)cc1
Agent: [Cl-]
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CO
Product: COc1cc2ncnc(N3CCN(C(=S)Nc4ccc(S(=O)(=O)Nc5ncccn5)cc4)CC3)c2cc1OC
Reaction time: 8 h

Procedure:
To a solution of 4-(I-piperazinyl)-6,7-dimethoxy quinazoline (200 mg, 0.73 mmol) and pyridine (0.5 mL, 6.4 mmol) in dichloromethane (20 mL) was added a solution of product 1d in dichloromethane (20 mL) and this was stirred overnight. Methanol was added to quench excess thiophosgene, and the residue after removal of solvent was purified by silica gel column chromatography eluting with 5% methanol/dichloromethane and further recrystallized from dichloromethane/hexane to give 80 mg (20%).