Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][CH2:12][C:13]1[CH:14]=[C:15]([CH:31]=[CH:32][CH:33]=1)[CH2:16][CH2:17][NH:18][C:19]1[C:20](=[O:30])[N:21]([CH2:26][C:27]([OH:29])=O)[C:22]([CH3:25])=[CH:23][N:24]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:34][C:35]1[C:43]2[C:38](=[CH:39][CH:40]=[C:41]([CH2:44][NH2:45])[CH:42]=2)[NH:37][CH:36]=1.C1C=CC2N(O)N=NC=2C=1.Cl.CN1CCOCC1>CN(C)C=O>[CH3:25][C:22]1[N:21]([CH2:26][C:27]([NH:45][CH2:44][C:41]2[CH:42]=[C:43]3[C:38](=[CH:39][CH:40]=2)[NH:37][CH:36]=[C:35]3[CH3:34])=[O:29])[C:20](=[O:30])[C:19]([NH:18][CH2:17][CH2:16][C:15]2[CH:14]=[C:13]([CH:33]=[CH:32][CH:31]=2)[CH2:12][O:11][CH2:10][CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[N:24][CH:23]=1
Reactant: Cc1cnc(NCCc2cccc(COCCNC(=O)OC(C)(C)C)c2)c(=O)n1CC(=O)O
Reactant: Cc1c[nH]c2ccc(CN)cc12
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: Cc1c[nH]c2ccc(CNC(=O)Cn3c(C)cnc(NCCc4cccc(COCCNC(=O)OC(C)(C)C)c4)c3=O)cc12
Yield: 96.1 %

Procedure:
A mixture of 2-[3-{[3-({2-[(tert-butoxycarbonyl)amino]ethoxy}methyl)phenethyl]amino)6-methyl-2-oxo-1(2H)-pyrazinyl]acetic acid (preparation 107) (174 mg, 0.38 mmol), (3-methyl-1H-indol-5-yl)methylamine (preparation 36) (67 mg, 0.42 mmol), HOBT (77 mg, 0.57 mmol), WSCDI.HCl (91 mg, 0.47 mmol) and N-methylmorpholine (124 ml, 1.13 mmol) in N,N-dimethylformamide (5 ml), was stirred at room temperature for 20 hrs. The reaction mixture was partitioned between ethyl acetate and water and the .phases separated. The organic layer was dried over MgSO4 and evaporated under reduced pressure to give the title compound as a white solid, (220 mg, 96%).
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].O[CH2:8][CH2:9][CH2:10][CH2:11][S:12][C:13]1[C:17]([CH:18]2[CH:23]3[CH2:24][CH2:25][N:20]([CH2:21][CH2:22]3)[CH2:19]2)=[N:16][S:15][N:14]=1.BrCCCC[OH:31]>>[C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[CH2:11]([S:12][C:13]1[C:17]([CH:18]2[CH:23]3[CH2:24][CH2:25][N:20]([CH2:21][CH2:22]3)[CH2:19]2)=[N:16][S:15][N:14]=1)[C:10](=[O:31])[CH2:9][CH3:8]
Reactant: OCCCCBr
Reactant: OCCCCSc1nsnc1C1CN2CCC1CC2
Agent: O=C(O)C(=O)O
Product: CCC(=O)CSc1nsnc1C1CN2CCC1CC2

Procedure:
3-(3-(4-Hydroxybutylthio)-1,2,5-thiadiazol-4-yl)-1-azabicyclo[2.2.2]octane oxalate (Compound 219) M.p. 160°-161° C., from 1-bromo-4-hydroxybutane.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[NH:9][C:8](=[O:16])[C:7]2=[CH:17][S:18][CH:19]=[C:6]12)=[O:4].[NH:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[N:20]1([CH2:2][C:3]([N:5]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[NH:9][C:8](=[O:16])[C:7]3=[CH:17][S:18][CH:19]=[C:6]23)=[O:4])[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: C1CCNC1
Reactant: O=C1Nc2ccccc2N(C(=O)CCl)c2cscc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: O=C1Nc2ccccc2N(C(=O)CN2CCCC2)c2cscc21
Yield: 65.9 %

Procedure:
1.9 g of 4-chloroacetyl-9,10-dihydro-4H-thieno[3,4-b][1,5]benzodiazepin-10-one, 0.55 g of pyrrolidine, 0.85 g of ground sodium carbonate and 15 ml of absolute ethanol are heated at the boil for 2 hours, and the resulting hot solution is filtered and concentrated in vacuo. The obtained residue is dissolved in methylene chloride; the organic solution is washed at pH 7 with water and then concentrated; 1.4 g of 9,10-dihydro-4-(pyrrolidinoacetyl)-4H-thieno[3,4-b][1,5]benzodiazepin-10-one are thus obtained.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:6]=1[C:7](O)=[O:8])(=[O:3])[CH3:2].P(Cl)(Cl)(Cl)(Cl)[Cl:16]>C1C=CC=CC=1>[C:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:6]=1[C:7]([Cl:16])=[O:8])(=[O:3])[CH3:2]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: CC(=O)Oc1ccc(Cl)cc1C(=O)O
Solvent: c1ccccc1
Product: CC(=O)Oc1ccc(Cl)cc1C(=O)Cl

Procedure:
To a suspension of 21.4 g (0.1 mole) of 2-acetoxy-5-chlorobenzoic acid in 100 ml of refluxing benzene is added in portions over 1 hour 20.8 g (0.1 mole) of phosphorous pentachloride. The clear solution is refluxed for 1 hour, then concentrated to dryness. The residue is distilled, bp 112° C at 0.1 mm to give a clear oil which solidified on standing, mp 35°-8° C. ##STR6##
Reaction SMILES: [Br:1][C:2]1[CH:12]=[C:11]2[C:5]([CH:6]3[CH2:14][CH:8]([NH:9][C:10]2=O)[CH2:7]3)=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:16].CCN(C(C)C)C(C)C>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:12]=[C:11]2[C:5]([CH:6]3[CH2:14][CH:8]([N:9]=[C:10]2[Cl:16])[CH2:7]3)=[CH:4][CH:3]=1
Reactant: O=C1NC2CC(C2)c2ccc(Br)cc21
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: ClC1=NC2CC(C2)c2ccc(Br)cc21
Temperature: 85 °C
Reaction time: 5 h
Yield: 108.6 %

Procedure:
Into a 5000-mL 3-necked round-bottom flask was placed 5-bromo-9-azatricyclo[8.1.1.0[2,7]]dodeca-2,4,6-trien-8-one (223 g, 884.55 mmol, 1.00 equiv), PhCH3 (3500 mL), PCl5 (560 g, 2.69 mol, 3.00 equiv), and DIPEA (275 g, 3.00 equiv). The resulting solution was stirred at 85° C. for 5 h and quenched by the addition of 300 g of DIPEA. The solids were filtered out and the filtrate was concentrated under vacuum to afford 260 g (crude) of 5-bromo-8-chloro-9-azatricyclo[8.1.1.0[2,7]]dodeca-2,4,6,8-tetraene as a black oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:33])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[C:8]2[CH:7]=[C:6]([C:20]#[C:21][C:22]3[CH:32]=[CH:31][C:25]([C:26]([O:28]CC)=[O:27])=[CH:24][CH:23]=3)[CH:5]=[CH:4][C:3]1=2.[OH-].[Na+].Cl>CCO.C1COCC1>[CH3:1][C:2]1([CH3:33])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[C:8]2[CH:7]=[C:6]([C:20]#[C:21][C:22]3[CH:23]=[CH:24][C:25]([C:26]([OH:28])=[O:27])=[CH:31][CH:32]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ccc(OC)cc2)=CCC3(C)C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1ccc(C2=CCC(C)(C)c3ccc(C#Cc4ccc(C(=O)O)cc4)cc32)cc1
Temperature: 50 °C

Procedure:
To a solution of ethyl 4-[(5,6-dihydro-5,5-dimethyl-8-(4-methoxyphenyl)-2-naphthalenyl)ethynyl]benzoate (Compound 8) 80.0 mg (0.183 mmol) in 3 ml of EtOH and 2 ml of THF was added 40.0 mg (1.00 mmol, 1.0 ml) of NaOH (1.0M aqueous solution). The solution was heated to 50° C. for 2 hours, cooled to room temperature, and acidified with 10% HCl. Extraction with EtOAc, followed by drying over Na2SO4, and removal of the solvents under reduced pressure afforded the title compound as a colorless solid. 1H NMR (DMSO): δ7.90 (2H, d, J=8.3 Hz), 7.60 (2H, d, J=8.3 Hz), 7.45 (2H, s), 7.24 (2H, d, J=8.6 Hz), 7.02-6.89 (3H, m), 5.98 (1H, t, J=4.4 Hz), 3.79 (3H, s), 2.31 (2H, d, J=4.7 Hz), 1.29 (6H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][N:3]=1.OO.C([O-])([O-])=[O:15].[Na+].[Na+]>FC(F)(F)C(O)=O>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:5]=[CH:4][N+:3]=1[O-:15]
Reactant: O=C([O-])[O-]
Reactant: FC(F)(F)c1ccnc(Cl)c1
Agent: OO
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: [O-][n+]1ccc(C(F)(F)F)cc1Cl
Temperature: 50 °C

Procedure:
To a solution of 2-chloro-4-trifluoromethylpyridine (1.81 g, 10 mmol) in trifluoroacetic acid (12 mL) was added 30% hydrogen peroxide (8 mL), and the mixture was stirred at 50° C. over a weekend. The reaction mixture was poured into ice-cold water, neutralized with solid Na2CO3 with stirring, and extracted with ethyl acetate three times. The combined organic layer was dried over anhydrous Na2SO4, filtered, concentrated, and dried to give 1.67 g of analytically pure 2-chloro-4-trifluoromethylpyridine N-oxide as a brown oil. 1H NMR (CDCl3): δ 8.45 (d, J=6.9 Hz, 1H), 7.77 (d, J=2.4 Hz, 1H), 7.47 (dd, J=6.9, 2.4 Hz, 1H). GC/MS: 197 [M]+.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:16][C:10]2([O:13][CH2:12][C:11]2([CH3:15])[CH3:14])[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.C(N(C(C)C)CC)(C)C.ClC1[CH:39]=[C:38]([NH:40][C:41]2[NH:42][N:43]=[C:44]([CH3:46])[CH:45]=2)[N:37]=[C:36]([S:47][C:48]2[CH:53]=[CH:52][C:51]([NH:54][C:55](=[O:58])[CH2:56][CH3:57])=[CH:50][CH:49]=2)[N:35]=1>C(Cl)Cl.CCCCO.[Cl-].[Na+].O.C(OCC)(=O)C>[CH3:15][C:11]1([CH3:14])[C:10]2([CH2:9][N:8]([C:6]3[CH:39]=[C:38]([NH:40][C:41]4[NH:42][N:43]=[C:44]([CH3:46])[CH:45]=4)[N:37]=[C:36]([S:47][C:48]4[CH:53]=[CH:52][C:51]([NH:54][C:55](=[O:58])[CH2:56][CH3:57])=[CH:50][CH:49]=4)[N:35]=3)[CH2:16]2)[O:13][CH2:12]1
Reactant: CCC(=O)Nc1ccc(Sc2nc(Cl)cc(Nc3cc(C)n[nH]3)n2)cc1
Reactant: CC(C)(C)OC(=O)N1CC2(C1)OCC2(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CCC(=O)Nc1ccc(Sc2nc(Nc3cc(C)n[nH]3)cc(N3CC4(C3)OCC4(C)C)n2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 21.7 %

Procedure:
To a solution of 3,3-Dimethyl-1-oxa-6-aza-spiro[3.3]heptane-6-carboxylic acid tert-butyl ester (60 mg, 0.27 mmol) in DCM (3 ml) at 0° C. was added trifluoroacetic acid and the reaction stirred at room temperature for 1 hr. The reaction was concentrated to give an oil which was used crude in the next step. The oily residue was dissolved in n-BuOH (3 ml) and diisopropylethylamine (171 mg, 1.35 mmol, 0.24 ml) and N-{4-[4-Chloro-6-(5-methyl-2H-pyrazol-3-ylamino)-pyrimidin-2-ylsulfanyl]-phenyl}-propionamide (93 mg, 0.24 mmol) was added. The mixture was heated to 100° C. and stirred for 18 hrs. The reaction was allowed to cool to room temperature and diluted with brine (20 ml) and ethyl acetate (20 ml). The organic layer was dried (Na2SO4) and concentrated to give an oil. The oil was purified by flash column chromatography eluting with 2.5% MeOH in ethyl acetate to give the title compound as a pale orange solid 25 mg, 20%. 1H NMR (d6-DMSO, 400 MHz) 1.08 (3H, m), 1.20 (6H, s), 1.98 (3H, s), 2.34 (2H, q), 3.78 (2H, d), 4.14-4.15 (4H, m), 5.35 (1H, s), 5.61 (1H, brs), 7.47 (2H, d), 7.70 (2H, d), 9.24 (1H, s), 10.07 (1H, s), 11.43 (1H, s). ES+480.
Reaction SMILES: C([CH:4]1[CH:9]([CH:10]=[C:11]([Cl:13])[Cl:12])[C:8]([CH2:15][CH3:16])([CH3:14])[O:7][C:5]1=[O:6])(=O)C.Cl[O-]>O1CCOCC1>[Cl:13][C:11]([Cl:12])=[CH:10][CH:9]1[C:8]([CH2:15][CH3:16])([CH3:14])[O:7][C:5](=[O:6])[CH2:4]1
Reactant: CCC1(C)OC(=O)C(C(C)=O)C1C=C(Cl)Cl
Agent: [O-]Cl
Solvent: C1COCCO1
Product: CCC1(C)OC(=O)CC1C=C(Cl)Cl
Yield: 74.9 %

Procedure:
26.4 g (0.1 mol) of 2-acetyl-3-(2',2'-dichlorovinyl)-4-ethyl-γ-valerolactone were dissolved in 100 ml of dioxane. Technical grade hypochlorite solution was then added dropwise at 20-30° C. in an amount such that a total of 0.5 mol of hypochlorite had been added. The mixture was heated to the boil for a further 3-4 hours, any hypochlorite still present was destroyed with sodium bisulphite solution and the mixture was adjusted to pH 1 with 25% strength sulphuric acid. It was then extracted with methylene chloride and the organic phase was subjected to fractional distillation. 16.7 g (75% of theory) of 3-(2',2'-dichlorovinyl)-4-ethyl-γ-valerolactone of boiling point 160°-165° C./20 mm Hg were obtained. Refractive index: nD20 :1.5012.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[CH3:16][O:17][C:18]1[CH:31]=[CH:30][C:29]2[NH:28][C:27](=O)[C:26]3[C@@H:25]([CH3:33])[CH2:24][C:23]([O:34][CH3:35])=[CH:22][C:21]=3[C:20]=2[CH:19]=1.C(C1C=CC=C(C(C)(C)C)N=1)(C)(C)C.P([O-])([O-])([O-])=O>ClCCl>[F:1][C:2]([F:15])([F:14])[S:3]([O:6][C:27]1[N:28]=[C:29]2[C:20](=[C:21]3[C:26]=1[C@@H:25]([CH3:33])[CH2:24][C:23]([O:34][CH3:35])=[CH:22]3)[CH:19]=[C:18]([O:17][CH3:16])[CH:31]=[CH:30]2)(=[O:5])=[O:4]
Reactant: COC1=Cc2c(c(=O)[nH]c3ccc(OC)cc23)[C@@H](C)C1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: CC(C)(C)c1cccc(C(C)(C)C)n1
Agent: O=P([O-])([O-])[O-]
Solvent: ClCCl
Product: COC1=Cc2c(c(OS(=O)(=O)C(F)(F)F)nc3ccc(OC)cc23)[C@@H](C)C1
Temperature: 23 °C
Reaction time: 0.25 h
Yield: 86.6 %

Procedure:
Trifluoromethanesulfonic anhydride (3.80 mL, 22.4 mmol, 1.10 equiv) was added via syringe to a suspension of (S)-7,8-dihydro-2,9-dimethoxy-7-methyl-6(5H)-phenanthridinone (10, 5.52 g, 20.3 mmol, 1 equiv) and 2.6-di-t-butylpyridine (6.10 mL, 27.1 mmol, 1.33 equiv) in dichloromethane (400 mL) at -78° C. The cold suspension was allowed to warm to 23° C. over 30) min and was stirred at that temperature for 15 min. Solids were observed to dissolve as the reaction proceeded. The reaction mixture was poured into aqueous phosphate buffer solution (pH 7, 0.05M in sodium hydrogen phosphate and 0.05M in potassium dihydrogen phosphate, 200 mL). The aqueous layer was separated and further extracted with two 200-mL portions of dichloromethane. The combined organic layers were dried over sodium sulfate and were concentrated in vacuo. The residue was purified by flash column chromatography (40% dichloromethane-hexanes) to provide (S)-7,8-dihydro-2,9-dimethoxy-7-methyl-6-phenanthridinol trifluoromethanesulfonate (ester) (12) as an off-white solid (mp 129.5°-130.5° C., 7.09 g, 86%). ##STR23##
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=3)=[N:11][N:10]=2)=[CH:5][CH:4]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:34]1[CH:35]=[CH:36][N:37]=[C:38]2[C:43]=1[N:42]=[CH:41][C:40]([O:44][CH3:45])=[CH:39]2>CN(C=O)C.O>[CH3:45][O:44][C:40]1[CH:39]=[C:38]2[C:43]([C:34]([O:26][C:23]3[CH:22]=[CH:21][C:20]([NH:19][C:12]4[C:13]5[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=5)[C:9]([C:6]5[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=5)=[N:10][N:11]=4)=[CH:25][CH:24]=3)=[CH:35][CH:36]=[N:37]2)=[N:42][CH:41]=1
Reactant: COc1cnc2c(Cl)ccnc2c1
Reactant: COc1ccc(-c2nnc(Nc3ccc(O)cc3)c3ccccc23)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(-c2nnc(Nc3ccc(Oc4ccnc5cc(OC)cnc45)cc3)c3ccccc23)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A 5 mL microwave tube was charged with 4-(4-(4-methoxyphenyl)phthalazin-1-ylamino)phenol and 3 equivalents of cesium carbonate (342 mg, 1.048 mmol) in 1.8 mL of DMF. The mixture was stirred at RT for 10 min. Following addition of 8-chloro-3-methoxy-1,5-naphthyridine (88 mg, 0.454 mmol), the vessel was capped and irradiated at 150° C. for 15 min in the microwave, at which time the reaction was determined complete by LC/MS. The mixture was cooled to ambient temperature and diluted with water. The solids were filtered and washed with water. The solids were triturated with methanol, filtered to remove remaining impurities, washed with additional methanol and dried under vacuum to afford N-(4-(7-methoxy-1,5-naphthyridin-4-yloxy)phenyl)-4-(4-methoxyphenyl)phthalazin-1-amine as a light orange solid. MS [M+H]=502; Calc'd 501.54 for C30H25N5O3.
Reaction SMILES: Br[C:2]1[C:10]([Cl:11])=[CH:9][C:5]2[NH:6][CH:7]=[N:8][C:4]=2[CH:3]=1.O.[CH3:13][N:14]1C(=O)CCC1>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.[C-]#N.[C-]#N.[Zn+2]>[Cl:11][C:10]1[C:2]([C:13]#[N:14])=[CH:3][C:4]2[N:8]=[CH:7][NH:6][C:5]=2[CH:9]=1
Reactant: CN1CCCC1=O
Reactant: Clc1cc2[nH]cnc2cc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Product: N#Cc1cc2nc[nH]c2cc1Cl
Temperature: 120 °C
Reaction time: 18 h

Procedure:
A mixture of 248 (550 mg, 2.38 mmol), Pd(PPh3)4 (275 mg, 0.238 mmol), and Zn(CN)2 (279 mg, 2.38 mmol) in NMP (10 mL) was stirred under nitrogen atmosphere at 120° C. for 18 h. The reaction mixture was poured into water (50 mL), extracted with EtOAc (3×20 mL), and concentrated to dryness in vacuo. The crude was purified by SiO2 chromatography eluting with DCM:MeOH (12:1) to afford 217 mg (51.5%) of 6-chloro-1H-benzo[d]imidazole-5-carbonitrile (250) as yellow solid (217 mg, 51.5%): MS (ESI) m/z=178.2 (M+1).
Reaction SMILES: [CH:1](N(C(C)C)CC)([CH3:3])[CH3:2].[C:10]([C:13]1[CH:18]=[CH:17][C:16]([S:19][C:20]2[CH:21]=[C:22]([C:26]3([O:31][CH3:32])[CH2:30][CH2:29][NH:28][CH2:27]3)[CH:23]=[CH:24][CH:25]=2)=[CH:15][CH:14]=1)(=[O:12])[CH3:11].C(Br)C#C>>[C:10]([C:13]1[CH:14]=[CH:15][C:16]([S:19][C:20]2[CH:21]=[C:22]([C:26]3([O:31][CH3:32])[CH2:30][CH2:29][N:28]([CH2:3][C:1]#[CH:2])[CH2:27]3)[CH:23]=[CH:24][CH:25]=2)=[CH:17][CH:18]=1)(=[O:12])[CH3:11]
Reactant: CCN(C(C)C)C(C)C
Reactant: COC1(c2cccc(Sc3ccc(C(C)=O)cc3)c2)CCNC1
Agent: C#CCBr
Product: C#CCN1CCC(OC)(c2cccc(Sc3ccc(C(C)=O)cc3)c2)C1
Yield: 14 %

Procedure:
Using an analogous procedure to that described in Example 3 except that diisopropylethylamine was used in place of potassium carbonate, 3-[3-(4-acetylphenylthio)phenyl]-3-methoxypyrrolidine was reacted with 2-propynyl bromide to give 3-[3-(4-acetylphenylthio)phenyl]-3-methoxy-1-(prop-2-ynyl)pyrrolidine as a gum in 14% yield.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[C:14]([CH3:16])[Se:15][C:11]=2[C:10]([C:17]2[O:18][C:19]([C:22](OC)=[O:23])=[CH:20][CH:21]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1C2C=C[Se]C=2C(C2OC(C(OC)=O)=CC=2)=N1)C1C=CC=CC=1.C(N1C2C=C[Se]C=2C(C2OC(CO)=CC=2)=N1)C1C=CC=CC=1>>[CH2:1]([N:8]1[C:12]2[CH:13]=[C:14]([CH3:16])[Se:15][C:11]=2[C:10]([C:17]2[O:18][C:19]([CH2:22][OH:23])=[CH:20][CH:21]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(-c2nn(Cc3ccccc3)c3cc(C)[se]c23)o1
Agent: COC(=O)c1ccc(-c2nn(Cc3ccccc3)c3cc[se]c23)o1
Agent: OCc1ccc(-c2nn(Cc3ccccc3)c3cc[se]c23)o1
Product: Cc1cc2c([se]1)c(-c1ccc(CO)o1)nn2Cc1ccccc1

Procedure:
Compound 56 (0.800 g, 0.002 mole) was used to replace compound 55 in the preparation of compound 57 to afford compound 58. Yield: 0.612 g (82.5%); white needle crystals; mp 147-148° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]([OH:7])=O.[NH2:8][C:9]1[N:14]=[N:13][C:12]([N:15]2[CH2:20][CH2:19][N:18]([C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:29]([F:32])([F:31])[F:30])=[O:22])[CH2:17][CH2:16]2)=[CH:11][CH:10]=1>>[CH3:1][O:2][CH2:3][CH2:4][C:5]([NH:8][C:9]1[N:14]=[N:13][C:12]([N:15]2[CH2:16][CH2:17][N:18]([C:21](=[O:22])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:29]([F:32])([F:31])[F:30])[CH2:19][CH2:20]2)=[CH:11][CH:10]=1)=[O:7]
Reactant: COCCC(=O)O
Reactant: Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1
Product: COCCC(=O)Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 2, making variations only as required to use 3-methoxypropionic acid in place of benzyloxyacetic acid to react with [4-(6-aminopyridazin-3-yl)piperazin-1-yl](2-trifluoromethylphenyl)methanone, the title compound was obtained as a white powder (11% yield). 1H NMR (300 MHz, CDCl3) δ 9.44, 8.31, 7.74, 7.63, 7.55, 7.36, 7.02, 4.02-3.98, 3.94-3.89, 3.73, 3.70-3.61, 3.57-3.54, 3.43, 3.33-3.31, 2.73. MS (ES+) m/z 438.1 (M+1).
Reaction SMILES: Cl.C([O:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14]([NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]4[O:27][CH2:28][O:29][C:22]=34)=[N:15][CH:16]=[N:17]2)=[CH:12][C:11]=1[O:30][CH3:31])C1C=CC=CC=1.C([O-])=O.[NH4+].O>[Pd].CN(C=O)C>[OH:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14]([NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]4[O:27][CH2:28][O:29][C:22]=34)=[N:15][CH:16]=[N:17]2)=[CH:12][C:11]=1[O:30][CH3:31]
Reactant: COc1cc2c(Nc3cccc4c3OCO4)ncnc2cc1OCc1ccccc1
Agent: [Pd]
Agent: Cl
Agent: O=C[O-]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(Nc3cccc4c3OCO4)ncnc2cc1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.5 %

Procedure:
A mixture of 7-benzyloxy-6-methoxy-4-(2,3-methylenedioxyanilino)quinazoline hydrochloride (21 g), ammonium formate (30.2 g), 10% palladium-on-charcoal catalyst (4.8 g), water (26 ml) and DMF (350 ml) was stirred at ambient temperature for 2 hours. The mixture was filtered and the filtrate was evaporated. The residual oil was triturated under diethyl ether. The solid so obtained was triturated under water, collected by filtration, washed with water and with diethyl ether and dried under vacuum over phosphorus pentoxide. The material so obtained was purified by column chromatography on silica using a 9:1 mixture of methylene chloride and methanol as eluent. There was thus obtained the title compound (15 g); NMR Spectrum: (DMSOd6) 3.95 (s, 3H), 6.0 (s, 2H), 6.85 (m, 2H), 6.95 (d, 1H), 7.05 (s, 1H), 7.8 (s, 1H), 8.3 (s, 1H), 9.4 (s, 1H), 10.3 (s, 1H); Mass Spectrum: M+H+ 312.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[CH:4]=1.C1COCC1>CC(O)(C)C>[CH3:1][O:2][C:3]1[CH2:4][C:5]([O:9][CH3:10])=[CH:6][CH2:7][CH:8]=1
Reactant: COc1cccc(OC)c1
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Product: COC1=CCC=C(OC)C1
Reaction time: 3 h
Yield: 93.6 %

Procedure:
A solution containing 1,3-dimethoxybenzene (10 g), dry THF (15 mL) and tBuOH (15 mL) was added to distilled ammonia (ca 250 mL). To the reaction mixture was added lithium wire (1.5 g) in small portions, and the deep blue colored solution was stirred for 3 hours. The reaction mixture was decolorized by dropwise addition of methanol. Ammonia was evaporated at room temperature. To the residue, ammonium chloride solution was added, then the product was extracted with hexane (3×120 mL). The combined extracts were washed with water and dried over anhydrous sodium sulfate. Removal of the solvent under reduced pressure gave the title compound as a clear liquid (9.5 g). 1H NMR (CDCl3): δ 2.7–2.9 (m, 4H, 2×CH2), 3.58 (s, 6H, 2×OCH3), 4.66 (t, 2H, olefinic).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5]([CH3:19])([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]#[C:14][Si](C)(C)C)[CH:8]=1)[CH3:6])[CH3:2].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH2:1]([O:3][C:4](=[O:20])[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]#[CH:14])[CH:8]=1)([CH3:6])[CH3:19])[CH3:2]
Reactant: CCOC(=O)C(C)(C)c1cccc(C#C[Si](C)(C)C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: C#Cc1cccc(C(C)(C)C(=O)OCC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.2 %

Procedure:
A solution of 2-methyl-2-(3-trimethylsilanylethynyl-phenyl)-propionic acid ethyl ester (Intermediate 131, 0.74 g, 2.56 mmol) in ethanol (10 mL) was treated with potassium carbonate (0.2 g, 1.45 mmol). The resulting reaction mixture was stirred at ambient temperature overnight. The volatiles were evaporated in vacuo and the residue was diluted with water and extracted with diethyl ether. The organic phase was washed with water and brine, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to a residue that was subjected to flash column chromatography over silica gel (230-400 mesh) using 1-5% ethyl acetate in hexane as the eluent to afford the title product (0.4 g, 72%).
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@H:8]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([CH2:33][CH:34]=O)=[CH:29][CH:28]=3)[CH:20]=2)[O:7][C@@H:6]1[CH2:36][O:37][C:38](=[O:40])[CH3:39])(=[O:3])[CH3:2].N1C=CC=CC=1.Cl.[CH3:48][O:49][NH2:50]>C(O)C>[C:1]([O:4][C@H:5]1[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@H:8]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([CH2:26][C:27]3[CH:28]=[CH:29][C:30]([CH2:33][CH:34]=[N:50][O:49][CH3:48])=[CH:31][CH:32]=3)[CH:20]=2)[O:7][C@@H:6]1[CH2:36][O:37][C:38](=[O:40])[CH3:39])(=[O:3])[CH3:2]
Reactant: CON
Reactant: CC(=O)OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(CC=O)cc3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: CON=CCc1ccc(Cc2cc([C@@H]3O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)ccc2Cl)cc1
Yield: 21.7 %

Procedure:
To a solution of (2R,3 R,4R,5S,65)-2-(acetoxymethyl)-6-(4-chloro-3-(4-(2-oxoethyl)benzyl)phenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (0.35 mg, 0.61 mmol), in ethanol (10 mL) under nitrogen atmosphere, were added pyridine (0.24 mL, 3.04 mmol), and O-methylhydroxylamine hydrochloride (151 mg, 1.82 mmol). The reaction mixture was refluxed for 2 h. After completion of the reaction as confirmed by TLC, the solvent was evaporated. The crude compound was diluted with ethyl acetate (25 mL). The organic layer was washed with water (3×10 mL), dried over Na2SO4 and concentrated in vacuo to afford crude product which was purified by column chromatography (silica gel, 1.0:9.0 Acetone:Pet. Ether) to afford the title compound (80 mg, 22%).