Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]([CH3:32])[C:4](=[O:31])[C:5]2[N:6]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[Cl:30])[C:7]([N:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]3)=[N:8][C:9]=2[N:10]=1.[C:33]([O:37][CH2:38][CH3:39])(=[O:36])[CH2:34][OH:35].[H-].[Na+]>CN1CCCC1=O.C(OCC)(=O)C>[Cl:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[N:6]1[C:5]2[C:4](=[O:31])[N:3]([CH3:32])[C:2]([O:35][CH2:34][C:33]([O:37][CH2:38][CH3:39])=[O:36])=[N:10][C:9]=2[N:8]=[C:7]1[N:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])[CH2:13][CH2:12]1
Reactant: Cn1c(Cl)nc2nc(N3CCN(C(=O)OC(C)(C)C)CC3)n(-c3ccccc3Cl)c2c1=O
Reactant: CCOC(=O)CO
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CCOC(=O)COc1nc2nc(N3CCN(C(=O)OC(C)(C)C)CC3)n(-c3ccccc3Cl)c2c(=O)n1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 210.3 %

Procedure:
10 mg of t-butyl 4-[2-chloro-7-(2-chlorophenyl)-1-methyl-6-oxo-6,7-dihydro-1H-purin-8-yl]piperazine-1-carboxylate and 10 mg of ethyl glycolate were dissolved in 0.2 ml of N-methylpyrrolidone, and 10 mg of sodium hydride was added thereto. The mixture was stirred at room temperature for 2 hours. The reaction solution was dissolved in ethyl acetate, and the mixture was washed with 1N hydrochloric acid. Thus, 24 mg of t-butyl 4-[7-(2-chlorophenyl)-2-ethoxycarbonylmethoxy-1-methyl-6-oxo-6,7-dihydro-1H-purin-8-yl]piperazine-1-carboxylate was obtained. 8 mg of this compound was dissolved in trifluoroacetic acid, and the mixture was concentrated. The residue was purified by reverse-phase high performance liquid chromatography (using an acetonitrile-water mobile phase (containing 0.1% trifluoroacetic acid)) to give 2.11 mg of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C@:9]([CH3:16])([CH:11]([O:14][CH3:15])[O:12][CH3:13])[C@@H:8]3[O:17][C@@H:7]3[C:6]=2[CH:18]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][CH2:27][C:28]2[N:29]=[N:30][N:31]([CH3:33])[N:32]=2)=[CH:22][CH:21]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C@:9]([CH3:16])([CH:11]([O:14][CH3:15])[O:12][CH3:13])[C@H:8]([OH:17])[C@@H:7]([N:26]([C:23]3[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=3)[CH2:27][C:28]3[N:29]=[N:30][N:31]([CH3:33])[N:32]=3)[C:6]=2[CH:18]=1
Reactant: COC(OC)[C@@]1(C)Oc2ccc(Br)cc2[C@H]2O[C@H]21
Reactant: Cn1nnc(CNc2ccc(F)cc2)n1
Product: COC(OC)[C@@]1(C)Oc2ccc(Br)cc2[C@H](N(Cc2nnn(C)n2)c2ccc(F)cc2)[C@H]1O
Yield: 47.9 %

Procedure:
The same procedure as step 3 of example 1 was accomplished, except for using (2S,3R,4R)-6-bromo-2-methyl-2-dimethoxymethyl-3,4-epoxy-3,4-dihydro-2H-1-benzopyran (209 mg, 0.66 mmol) and N-(4-fluorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amine (138 mg, 0.66 mmol). The crude product was purified by silica gel column chromatography (developing solvent-n-hexane:ethyl acetate=6:1), to give desired compound (165 mg, yield: 51%).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[C:4]([CH3:11])[CH:3]=1.[Br:12]N1C(=O)CCC1=O.ClCCl>ClC(Cl)(Cl)Cl>[Br:1][C:2]1[S:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[C:4]([CH2:11][Br:12])[CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1sc(Br)cc1C
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1sc(Br)cc1CBr
Temperature: 90 °C
Reaction time: 18 h

Procedure:
In a 100 mL round bottom flask, methyl 5-bromo-3-methylthiophene-2-carboxylate (1.50 g, 6.38 mmol) was dissolved in tetrachloromethane (30 mL). To above solution was added 1-bromopyrrolidine-2,5-dione (1.14 g, 6.38 mmol, 1.0 eq) and diphenylperoxyanhydride (0.155 g, 0.638 mmol, 0.1 eq). The reaction was stirred at 90° C. for 18 hr. To above reaction was added dichloromethane (30 mL), washed with aqueous sodium bicarbonate, brine and water. The organic phase was dried over MgSO4, filtered and concentrated. The crude was used in next step without purification. LC-MS (IE, m/z): 337.4 [M+N]+.
Reaction SMILES: Br[CH:2]([CH3:16])[C:3]([C:5]1[CH:6]=[CH:7][C:8]2[O:12][C:11](=[O:13])[N:10]([CH3:14])[C:9]=2[CH:15]=1)=O.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][N:19]=1>>[CH3:16][C:2]1[N:19]2[CH:20]=[C:21]([CH3:24])[CH:22]=[CH:23][C:18]2=[N:17][C:3]=1[C:5]1[CH:6]=[CH:7][C:8]2[O:12][C:11](=[O:13])[N:10]([CH3:14])[C:9]=2[CH:15]=1
Reactant: Cc1ccc(N)nc1
Reactant: CC(Br)C(=O)c1ccc2oc(=O)n(C)c2c1
Product: Cc1ccc2nc(-c3ccc4oc(=O)n(C)c4c3)c(C)n2c1
Yield: 77.9 %

Procedure:
5-(3,6-Dimethylimidazo[1,2-a]pyridin-2-yl)-3-methyl-2-benzoxazolinone (1.85 g) was prepared in substantially the same manner as that of Example 30 from 5-(2-bromopropionyl)-3-methyl-2-benzoxazolinone (2.3 g) and 2-amino-5-methylpyridine (2.6 g). mp. 247°-249° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH:5]([CH3:12])[CH:6]([NH:8][CH:9]1[CH2:11][CH2:10]1)[CH3:7])[CH3:2].[Cl:14][C:15]1[N:20]=[C:19](Cl)[C:18]([N+:22]([O-:24])=[O:23])=[CH:17][N:16]=1.C(=O)(O)[O-].[K+]>O.C(OCC)C>[CH2:1]([O:3][C:4](=[O:13])[CH:5]([CH3:12])[CH:6]([N:8]([C:17]1[C:18]([N+:22]([O-:24])=[O:23])=[CH:19][N:20]=[C:15]([Cl:14])[N:16]=1)[CH:9]1[CH2:11][CH2:10]1)[CH3:7])[CH3:2]
Reactant: CCOC(=O)C(C)C(C)NC1CC1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: CCOCC
Product: CCOC(=O)C(C)C(C)N(c1nc(Cl)ncc1[N+](=O)[O-])C1CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.7 %

Procedure:
A solution of 0.93 g (0.005 mole) of (rac)-3-cyclopropylamino-2-methyl-butanoic acid ethyl ester in 20 mL of water was added dropwise to a solution of 0.97 g (0.005 mole) of 2,4-dichloro-5-nitro-pyrimidine in 20 mL of ethyl ether. At 0 degrees, 1.0 g (0.010 mole) of potassium bicarbonate was added. The mixture was stirred at ambient temperature for 3 hours. The layers were then separated, and the aqueous layer extracted twice with 30 mL of ether. The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with hexanes-ethyl acetate (100:0-80:20) gave 1.4 g of (rac)-3-[(2-chloro-5-nitro-pyrimidin-4-yl)-cyclopropyl-amino]-2-methyl-butanoic acid ethyl ester (IV-46).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([SH:19])[CH:13]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.[CH2:31](Br)[C:32]#[CH:33]>O>[Cl:1][C:2]1[C:3]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([S:19][CH2:33][C:32]#[CH:31])[CH:13]=2)=[N:4][CH:5]=[C:6]([C:8]([F:10])([F:11])[F:9])[CH:7]=1
Reactant: C#CCBr
Reactant: FC(F)(F)c1cnc(-c2ccc(Cl)c(S)c2)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C#CCSc1cc(-c2ncc(C(F)(F)F)cc2Cl)ccc1Cl
Reaction time: 16 h

Procedure:
2.0 g of 3-chloro-2-(4-chloro-3-mercaptophenyl)-5-trifluoromethylpyridine (prepared as in Example 33) and 2.1 g of potassium carbonate were introduced into 50 ml of anhydrous dimethylformamide amide at 23° C. After a dropwise addition of 0.73 g of propargyl bromide, the mixture was stirred for 16 h and then poured into 300 ml of water. After 30 minutes, the crystals which had formed were removed, washed with water and dried.
Reaction SMILES: C(OC([N:8]1[CH2:15][CH:14]2[O:16][CH:10]([CH2:11][N:12]([CH2:17][CH2:18][N:19]([CH2:25][CH2:26][O:27][C:28]3[CH:33]=[CH:32][C:31]([C:34]#[N:35])=[CH:30][CH:29]=3)[C:20]([N:22]([CH3:24])[CH3:23])=[O:21])[CH2:13]2)[CH2:9]1)=O)(C)(C)C>Cl.O1CCOCC1>[C:34]([C:31]1[CH:30]=[CH:29][C:28]([O:27][CH2:26][CH2:25][N:19]([CH2:18][CH2:17][N:12]2[CH2:11][CH:10]3[O:16][CH:14]([CH2:15][NH:8][CH2:9]3)[CH2:13]2)[C:20]([N:22]([CH3:24])[CH3:23])=[O:21])=[CH:33][CH:32]=1)#[N:35]
Reactant: CN(C)C(=O)N(CCOc1ccc(C#N)cc1)CCN1CC2CN(C(=O)OC(C)(C)C)CC(C1)O2
Agent: Cl
Solvent: C1COCCO1
Product: CN(C)C(=O)N(CCOc1ccc(C#N)cc1)CCN1CC2CNCC(C1)O2
Reaction time: 0.5 h
Yield: 25.2 %

Procedure:
7-(2-{1-[2-(4-Cyanophenoxy)ethyl]-3,3-dimethylureido}ethyl)-9-oxa-3,7-di-azabicyclo[3.3.1]nonane-3-carboxylic acid tert-butyl ester (6.5 g; see Example 5 below) was taken in HCl in dioxane (50 mL) and stirred for 30 min. The reaction mixture was decanted and the solid was taken in a biphasic mixture of dichloromethane and aqueous NaHCO3. The organic layer was separated, washed with water, dried over sodium sulfate and concentrated. Purification by column chromatography yielded 1.3 g of the title compound as pale yellow solid.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[O:26][CH3:27])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:4].[N-:28]=[N+:29]=[N-:30].[Na+].O>CN(C)C=O>[N:28]([CH2:2][C:3]([N:5]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[O:26][CH3:27])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:4])=[N+:29]=[N-:30]
Reactant: [N-]=[N+]=[N-]
Reactant: COc1ccccc1CN(C(=O)CCl)c1ccccc1Oc1ccccc1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccccc1CN(C(=O)CN=[N+]=[N-])c1ccccc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.9 %

Procedure:
A solution of 1.51 g of N-chloroacetyl-N-(2-methoxybenzyl)-2-phenoxyaniline synthesized in the same manner as in Example 1 and 770 mg of sodium azide in 10 ml of dimethylformamide was stirred at room temperature overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with 5% hydrochloric acid, a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, successively, and dried over anhydrous sodium sulfate. After removal of the drying agent by filtration, the solvent was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent; ethyl acetate−hexane=1:4) to give 1.55 g of N-azidoacetyl-N-(2-methoxybenzyl)-2-phenoxyaniline as an oil.
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Cl:11][C:12]1[C:20]2[CH:19]=[C:18]([C:21](=[O:23])[CH3:22])[S:17][C:16]=2[CH:15]=[CH:14][CH:13]=1.[Cl:24][C:25]1[CH:26]=[C:27]([C:32](=[O:37])[C:33]([F:36])([F:35])[F:34])[CH:28]=[C:29]([Cl:31])[CH:30]=1>C1COCC1>[Cl:11][C:12]1[C:20]2[CH:19]=[C:18]([C:21](=[O:23])[CH2:22][C:32]([C:27]3[CH:28]=[C:29]([Cl:31])[CH:30]=[C:25]([Cl:24])[CH:26]=3)([OH:37])[C:33]([F:36])([F:35])[F:34])[S:17][C:16]=2[CH:15]=[CH:14][CH:13]=1
Reactant: CC(=O)c1cc2c(Cl)cccc2s1
Reactant: O=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(CC(O)(c1cc(Cl)cc(Cl)c1)C(F)(F)F)c1cc2c(Cl)cccc2s1
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 84.5 %

Procedure:
Add a solution of LiHMDS (1 M in THF, 4.3 ml, 4.31 mmol) to a mixture of 1-(4-chlorobenzo[b]thiophen-2-yl)ethanone (0.6 g, 2.87 mmol) in dry THF (10 mL) at −78° C. under N2. After stirring 1.5 hour at −78° C., add 1-(3,5-dichlorophenyl)-2,2,2-trifluoroethanone (836 mg, 3.44 mmol) to the reaction mixture and stir the resultant mixture for additional 2 hours. Quench the reaction with saturated NH4Cl solution and extract the aqueous mixture with EtOAc (10 mL×3). The combined organic layers are washed with brine, dried over anhydrous Na2SO4 and concentrated under vacuum afford crude 1-(4-chlorobenzo[b]thiophen-2-yl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutan-1-one as brown solid (1.1 g, 84.6%). 1H NMR (400 MHz, CDCl3) δ 8.10-8.07 (s, 1H), 7.75 (d, J=5.2, 1H), 7.47-7.36 (m, 2H), 2.72-2.68 (s, 3H).
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][CH:11]([CH3:13])[CH3:12])[N:3]=1.[B:14]1([OH:24])[C:18]2[CH:19]=[CH:20][C:21]([OH:23])=[CH:22][C:17]=2[CH2:16][O:15]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[OH:24][B:14]1[C:18]2[CH:19]=[CH:20][C:21]([O:23][C:2]3[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][CH:11]([CH3:13])[CH3:12])[N:3]=3)=[CH:22][C:17]=2[CH2:16][O:15]1
Reactant: CC(C)Oc1nc(Cl)ccc1C#N
Reactant: OB1OCc2cc(O)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)Oc1nc(Oc2ccc3c(c2)COB3O)ccc1C#N
Temperature: 80 °C
Yield: 25.5 %

Procedure:
To a mixture of 6-chloro-2-isopropoxy-nicotinonitrile (0.73 g, 4.0 mmol) and 3H-Benzo[c][1,2]oxaborole-1,5-diol (0.40 g, 2.66 mmol) in DMF (10 mL) was added potassium carbonate (1.10 g, 7.98 mmol). The resulting suspension was heated at 80° C. overnight. DMF was removed under reduced pressure, the residue was diluted with EtOAc (50 mL), washed with water (10 mL) and brine (2×10 mL), dried over Na2SO4, filtered, and concentrated to give brown oil. Purification was accomplished by reverse phase preparative HPLC using MeOH/H2O (0.1% AcOH) as the eluent to yield the title compound (0.21 g, 21%) as white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.27 (s, 1 H), 8.23 (d, J=8.6 Hz, 1 H), 7.79 (d, J=7.8 Hz, 1H), 7.29 (s, 1 H), 7.22-7.14 (m, 1 H), 6.70 (d, J=8.2 Hz, 1 H), 4.99 (s, 2 H), 4.85 (sept., J=6.3 Hz, 1 H), 1.19 (d, J=6.3 Hz, 6 H); MS (ES) m/z: 311 (M+1)+; HPLC purity 98.44% (Maxplot), 97.99% (220 nm).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][S:18]([CH3:21])(=[O:20])=[O:19])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[OH:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27]([C:32]([F:35])([F:34])[F:33])=[CH:26]2.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH2:15][CH2:16][CH2:17][S:18]([CH3:21])(=[O:20])=[O:19])[N:5]=[CH:4][N:3]=[C:2]2[O:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27]([C:32]([F:35])([F:33])[F:34])=[CH:26]2
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCS(C)(=O)=O
Reactant: Oc1ccc2[nH]c(C(F)(F)F)cc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4[nH]c(C(F)(F)F)cc4c3)ncnc2cc1OCCCS(C)(=O)=O
Temperature: 100 °C
Yield: 87.5 %

Procedure:
A suspension of 4-chloro-6-methoxy-7-(3-methylsulphonylpropoxy)quinazoline (150 mg, 0.45 mmol) and 5-hydroxy-2-trifluoromethylindole (109 mg, 0.54 mmol), (prepared as described for the starting material in Example 44), in DMF (1.5 ml) containing potassium carbonate (94 mg, 0.67 mmol) was heated at 100° C. for 1 hour. After cooling, the precipitate was collected by filtration, washed with ether, and dried under vacuum to give 6-methoxy-7-(3-methylsulphonylpropoxy)4-(2-trifluoromethylindol-5-yloxy)quinazoline (195 mg, 87%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:18]([C:19]3[CH:24]=[CH:23][N:22]=[C:21](F)[CH:20]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[C:15]([O:16][CH3:17])[N:10]3[N:9]=2)=[CH:4][CH:3]=1.[CH2:26]([NH2:30])[CH2:27][CH2:28][CH3:29]>C(OCC)(=O)C>[CH2:26]([NH:30][C:21]1[CH:20]=[C:19]([C:18]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[N:9][N:10]3[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=23)[CH:24]=[CH:23][N:22]=1)[CH2:27][CH2:28][CH3:29]
Reactant: CCCCN
Reactant: COc1cccc2c(-c3ccnc(F)c3)c(-c3ccc(F)cc3)nn12
Solvent: CCOC(C)=O
Product: CCCCNc1cc(-c2c(-c3ccc(F)cc3)nn3c(OC)cccc23)ccn1
Temperature: 130 °C

Procedure:
In a sealed-tube was combined 2-(4-Fluorophenyl)-3-(2-fluoro-4-pyridinyl)-7-methoxypyrazolo[1,5-α]pyridine (from Example 30, 20 mg, 0.06 mmol) and n-butylamine (2.0 mL, 1.5 g, 20 mmol), and the reaction was placed in a pre-heated oil bath at 130° C. The reaction was stirred at 130° C. until consumption of starting material was indicated by TLC analysis (50% ethyl acetate in hexanes). The contents of the sealed-tube was transferred to a flask and concentrated to dryness at 50° C. under high vacuum. The residue was purified by silica gel chromatography to yield the title compound, 2.0 mg (0.005 mmol, 8%). 1H NMR (d6-acetone): δ 8.04(d, 1H, J=5.1 Hz), 7.74(dd, 2H, J=5.7, 9.0 Hz), 7.33–7.38(m, 2H), 7.22(t, 2H, J=9.0 Hz), 6.45–6.54(m, 3H), 4.25(s, 3H), 3.30–3.40(m, 2H), 1.60(quint, 2H, J=7.2 Hz), 1.45(sext, 2H, J=7.2 Hz), 0.9(t, 3H, J=7.2 Hz). MS (ES+ve): 391.1 (100, M+), 376.3 (100).
Reaction SMILES: C([N:4]1[C:13]([C:14]#[N:15])=[C:12](C2C=CC=C(F)C=2)[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:23]C)[CH:10]=2)[C:5]1=[O:25])C=C.[C-]#N.[Na+]>CS(C)=O.[OH-].[Na+].C(Cl)Cl>[OH:23][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[C:5](=[O:25])[NH:4][C:13]([C:14]#[N:15])=[CH:12]2
Reactant: C=CCn1c(C#N)c(-c2cccc(F)c2)c2cc(OC)ccc2c1=O
Agent: [C-]#N
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: ClCCl
Product: N#Cc1cc2cc(O)ccc2c(=O)[nH]1

Procedure:
To a solution of 2-allyl-4-(3-fluorophenyl)-6-methoxy-1-oxo-1,2-dihydroisoquinoline-3-carbonitrile (2.0 g) in 24 mL DMSO was added NaCN (1.47 g). The reaction was heated to 150 C for 6.5 h, then diluted with 1N NaOH and extracted with EtOAc (2×). The organic solutions were extracted once with 1N NaOH. The combine aqueous solutions were acidified with conc. HCl and extracted with EtOAc (3×). All organic solutions were combined and dried (MgSO4), then concentrated to give a dark solid. The solid was suspended in CH2Cl2 and filtered to give 1.04 g of 2-allyl-4-3-fluorophenyl)-6-hydroxy-1-oxo-1,2-dihydroisoquinoline-3-carbonitrile, which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:17]([Cl:18])=[CH:16][C:5]2[NH:6][C:7](=S)[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[NH:10][C:4]=2[CH:3]=1.[NH2:19][CH2:20][C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1>C(OCCO)C>[Cl:1][C:2]1[C:17]([Cl:18])=[CH:16][C:5]2[N:6]=[C:7]([NH:19][CH2:20][C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[NH:10][C:4]=2[CH:3]=1
Reactant: NCc1cccnc1
Reactant: S=C1Nc2cc(Cl)c(Cl)cc2Nc2ccccc21
Solvent: CCOCCO
Product: Clc1cc2c(cc1Cl)Nc1ccccc1C(NCc1cccnc1)=N2
Yield: 53.4 %

Procedure:
A solution of 329 mg (1.1 mmol) of 7,8-dichloro-5,10-dihydro-dibenzo[b,e][1,4]diazepin-11-thione in 10 mL of 2-ethoxyethanol was treated with 0.3 mL (2.2 mmol) of 3-(aminomethyl)pyridine and heated at reflux overnight. The solvent was removed under reduced pressure and the residue taken up in EtOAc and washed three times with H2O, then saturated NaHCO3 solution and saturated NaCl solution. Drying over MgSO4 and removal of the solvent under reduced pressure left the crude product. Chromatography on silica gel, eluting with CHCl3 /MeOH (97/3) followed by recrystallization from acetone/H2O gave 217 mg (52.8% yield) of the product as a yellow solid, mp 209-210° C. The structure was confirmed by NMR and mass spectroscopy. (m+H)+ =370.
Reaction SMILES: [CH2:1]([C:5]1([CH3:29])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([OH:15])=[C:7]([C:16]2[NH:21][C:20]3[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=3[S:18](=[O:27])(=[O:26])[N:17]=2)[C:6]1=[O:28])[CH2:2][CH2:3][CH3:4].[OH-].[Na+:31]>O>[CH2:1]([C:5]1([CH3:29])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([O-:15])=[C:7]([C:16]2[NH:21][C:20]3[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=3[S:18](=[O:26])(=[O:27])[N:17]=2)[C:6]1=[O:28])[CH2:2][CH2:3][CH3:4].[Na+:31]
Reactant: CCCCC1(C)C(=O)C(C2=NS(=O)(=O)c3ccccc3N2)=C(O)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCC1(C)C(=O)C(C2=NS(=O)(=O)c3ccccc3N2)=C([O-])c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.3 %

Procedure:
A suspension of the product of Example 30A (0.067 g) in water (2 mL) was treated with 0.997N sodium hydroxide solution (0.163 mL, 0.163 mmol) and stirred at 25° C. for 1 hour. The solution was lyophilized to give the title compound (0.070 g, 99%). 1H NMR (300 MHz, DMSO-d6): δ ppm 0.55 (m, 1 H) 0.68 (m, 3 H) 0.87 (m, 1 H) 1.06 (m, 2 H) 1.38 (m, 3H) 1.72 (m, 1 H) 2.13 (m, 1 H) 7.29 (m, 3 H) 7.49 (m, 3 H) 7.64 (m, 1 H) 8.05 (m, 1 H) 15.46 (m, 1 H). MS (ESI−) m/z 409 (M−H)−.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([CH2:9]P(=O)(OCC)OCC)#[N:8].[Si:18]([O:25][CH:26]1[CH2:31][CH2:30][C:29](=O)[CH2:28][CH2:27]1)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]>O1CCCC1>[Si:18]([O:25][CH:26]1[CH2:31][CH2:30][C:29](=[CH:9][C:7]#[N:8])[CH2:28][CH2:27]1)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]
Reactant: CCOP(=O)(CC#N)OCC
Reactant: CC(C)(C)[Si](C)(C)OC1CCC(=O)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OC1CCC(=CC#N)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.6 %

Procedure:
To a solution of 1.0 M of potassium tert-butoxide in tetrahydrofuran (46.0 mL) at 0° C. was added drop wise a solution of diethyl cyanomethylphosphonate (7.80 mL, 0.0482 mol) in tetrahydrofuran (80 mL). The reaction was warmed to room temperature and then cooled at 0° C. again. To the reaction mixture was a solution of 4-(tert-butyl(dimethyl)silyl)oxycyclohexanone (10.0 g, 0.04378 mol) in tetrahydrofuran (40 mL). The reaction was allowed to warm up to room temperature and stirred overnight. After being quenched with water, the mixture was extracted with ether. The combined organic layers were washed with water, brine, dried over MgSO4 and evaporated to dryness. The crude mixture was purified on silica gel, eluting with 0 to 20% EtOAc in hexanes, to give the desired product (8.54 g, 77.58%). LCMS (M+H) 252.4.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([S:14][CH3:15])[N:11]3[C:16](=[O:19])[NH:17][N:18]=[C:10]3[C:9]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:4][CH:3]=1.[F:26][C:27]([F:37])([F:36])[C:28]1[CH:35]=[CH:34][C:31]([CH2:32]Br)=[CH:30][CH:29]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:13]=[C:12]([S:14][CH3:15])[N:11]3[C:16](=[O:19])[N:17]([CH2:32][C:31]4[CH:30]=[CH:29][C:28]([C:27]([F:26])([F:36])[F:37])=[CH:35][CH:34]=4)[N:18]=[C:10]3[C:9]=2[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[CH:6][CH:7]=1
Reactant: CSc1nc(-c2ccc(Cl)cc2)c(-c2ccccc2)c2n[nH]c(=O)n12
Reactant: FC(F)(F)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CSc1nc(-c2ccc(Cl)cc2)c(-c2ccccc2)c2nn(Cc3ccc(C(F)(F)F)cc3)c(=O)n12
Temperature: 25 °C
Reaction time: 5 h
Yield: 78.7 %

Procedure:
To a stirred solution of 7-(4-chlorophenyl)-5-(methylthio)-8-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (100 mg, 0.27 mmol) in DMF (2 mL) at room temperature under argon was added 4-trifluoromethylbenzyl bromide (77.7 mg, 0.33 mmol), followed by K2CO3 (74.5 mg, 0.54 mmol). The resulting mixture was stirred at room temperature for 5 h. Insoluble material was filtered off and the filtrate was purified by silica gel column chromatography eluted with ethyl acetate-hexanes, then lyophilized from 1,4-dioxane, to obtain the title compound (112 mg) as an off-white lyophilate. HPLC/MS: retention time=4.50 min, [M+H]30 =527.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH2:7][CH2:6][CH:5]2O.O>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH2:7][CH:6]=[CH:5]2
Reactant: OC1CCOc2ccc(F)cc21
Solvent: O
Solvent: Cc1ccccc1
Product: Fc1ccc2c(c1)C=CCO2
Yield: 58.3 %

Procedure:
6-Fluorochroman-4-ol (8 g, 48 mmol) and toluene-4-sulphonic acidn (1 g) were dissolved in toluene and refluxed over-night with subsequent water removal. The mixture was then cooled and washed with NaHCO3 (aq) and purified by chromatography (silica gel, n-hexane) to give 4.2 g (52%) of pure 6-fluoro-2H-chromene.