Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][C:14]([CH3:21])([CH3:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:9][CH:8]=[CH:7][CH:6]=2.[C:22](OCC)(OCC)(OCC)[CH2:23][CH3:24].C(OC)(OC)(OC)CCC.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>>[CH2:23]([C:24]1[N:12]([CH2:13][C:14]([CH3:20])([CH3:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=1)[CH3:22]
Reactant: CCOC(CC)(OCC)OCC
Reactant: CCOC(=O)C(C)(C)CNc1c(N)cnc2ccccc12
Agent: CCCC(OC)(OC)OC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Product: CCOC(=O)C(C)(C)Cn1c(CC)nc2cnc3ccccc3c21
Temperature: 25 °C

Procedure:
Ethyl 3-[(3-aminoquinolin-4-yl)amino]-2,2-dimethylpropanoate (see Example 26 Parts A through D, 3.6 g, 12 mmol) was treated according to a modification of the method described in Part B of Example 8 using triethyl orthopropionate in lieu of trimethyl orthobutyrate. Prior to the addition of triethyl orthopropionate (4.0 mL, 20 mmol) and pyridinium p-toluenesulfonate (0.030 g), the reaction was heated at reflux for 15 minutes. After the reaction was heated at reflux for three hours, it was concentrated under reduced pressure and found to be incomplete by 1H NMR. The oil was dissolved in toluene (100 mL), and concentrated sulfuric acid (one drop) was added. The reaction was heated at reflux for two hours and allowed to cool. Triethylamine (5 mL) was added, and the reaction was heated at reflux for two hours, allowed to cool to ambient temperature, washed with saturated aqueous sodium bicarbonate (2×35 mL), dried over potassium carbonate, filtered, and concentrated to provide 3.6 g of ethyl 3-(2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)-2,2-dimethylpropanoate as an oil.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([N:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[O:11][CH2:10][CH2:9][CH2:8]1)=[O:6].[F:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([CH:32]3[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)=[CH:28][CH:27]=2)=[CH:21][CH:20]=1>>[F:18][C:19]1[CH:20]=[CH:21][C:22]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([CH:32]3[CH2:33][CH2:34][N:35]([CH2:2][CH2:3][CH2:4][C:5]([N:7]4[C:13]5[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=5[O:11][CH2:10][CH2:9][CH2:8]4)=[O:6])[CH2:36][CH2:37]3)=[CH:28][CH:27]=2)=[CH:23][CH:24]=1
Reactant: Fc1ccc(Cc2ccc(C3CCNCC3)cc2)cc1
Reactant: O=C(CCCCl)N1CCCOc2ccccc21
Product: O=C(CCCN1CCC(c2ccc(Cc3ccc(F)cc3)cc2)CC1)N1CCCOc2ccccc21

Procedure:
The compound (16) synthesized in Reference Example 16 and the compound (7) synthesized in Reference Example 7 were used to produce the above compound in the same way as Example 1.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:35][C@@H:36](O)[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42].N(C(OCC)=O)=NC(OCC)=O>ClCCl.O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][C@@H:36]([CH3:35])[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCCC[C@@H](C)O
Reactant: Oc1ccc(OCc2ccccc2)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Product: CCCCCC[C@H](C)Oc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 19 h
Yield: 70.8 %

Procedure:
To an argon-flushed flask containing a solution of 3.01 g (15 mmol) of p-benzyloxy-phenol and 1.25 eq of triphenylphosphine in 220 ml in dry dichloromethane, was added a solution of 4.91 g (15.14 mmol) of (R)-2-octanol in 30 ml of dry dichloromethane via syringe. Then 1.20 eq of diethyl azodicarboxylate dissolved in 60 ml of dry dichloromethane was added dropwise for 30 min. The reaction mixture was stirred at room temperature for 19 h, Then 5 drops of water were added and the mixture was stirred for 1 h. The solvent was then evaporated and the residual crude product was triturated in a mixture of hexanes/ethyl acetate [70/30] for 1 h and filtered through a short silica gel pad. The filtrate was evaporated and the product was purified by flash chromatography on silica gel using dichloromethane/hexanes [10/90] as eluent, affording 3.32 g (71%) of (S)-p-Benzyloxy-(1-methylheptyloxy)benzene (Compound 18, Scheme III, R2 =(S)-OCH(CH3)C6H13) as a colorless liquid: Rf [dichloromethane/hexanes 10/90]: 0.13; 1H NMR (300 MHz, CDCl3): δ 0.87(t, 3H, J=6.6 Hz), 1.20-1.60(m, 12H), 1.70(m, 1H), 4.21(m, 1H), 5.00(s, 2H), Distorted AA'BB' System [6.82(d, 2H) 6.88(d, 2H)], 7.30-7.46(m, 5H); 13C NMR (300 MHz, CDCl3): δ 14.02, 19.77, 22.55, 25.52, 29.26, 31.77, 36.51, 70.63, 74.95, 115.77, 117.35, 127.49, 127.87, 128.55, 137.39, 152.53, 153.01; IR (CHCl3): 3010, 2940, 2850, 1600, 1500, 1475, 1450, 1375, 1230, 1200, 1125, 1025, 925, 825 cm-1 ; Mass spectrum, m/z (rel.Intensity): 312(M+ 7), 212(15), 91(100), 71(5), 57(8), 43(10).
Reaction SMILES: CC(S([NH:7][C:8]1([CH:12]([C:15]2[NH:16][CH:17]=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:22][CH:21]=3)[N:19]=2)[CH2:13][CH3:14])[CH2:11][O:10][CH2:9]1)=O)(C)C.Cl.C(=O)([O-])O.[Na+]>CO.O1CCOCC1>[F:30][C:27]([F:28])([F:29])[O:26][C:23]1[CH:24]=[CH:25][C:20]([C:18]2[N:19]=[C:15]([CH:12]([C:8]3([NH2:7])[CH2:9][O:10][CH2:11]3)[CH2:13][CH3:14])[NH:16][CH:17]=2)=[CH:21][CH:22]=1
Reactant: CCC(c1nc(-c2ccc(OC(F)(F)F)cc2)c[nH]1)C1(NS(=O)C(C)(C)C)COC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: C1COCCO1
Product: CCC(c1nc(-c2ccc(OC(F)(F)F)cc2)c[nH]1)C1(N)COC1
Reaction time: 4 h
Yield: 44.7 %

Procedure:
To a solution of 2-methyl-N-[3-(1-{4-[4-(trifluoromethoxy)phenyl]-1H-imidazol-2-yl}-propyl)oxetan-3-yl]propane-2-sulfinamide (Preparation 10, 0.450 g, 1.01 mmol) in methanol (5 mL) at 0° C. was added 4M hydrogen chloride in 1,4-dioxane (1 mL) and the reaction left to stir for 4 hours. Solid sodium hydrogen carbonate was added to the reaction, followed by a saturated aqueous solution of sodium hydrogen carbonate. The mixture was extracted with dichloromethane. The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography to afford the title compound (0.154 g, 45% yield).
Reaction SMILES: [H-].[Na+].[CH:3]1([SH:6])[CH2:5][CH2:4]1.[Br:7][C:8]1[CH:9]=[CH:10][C:11](F)=[N:12][CH:13]=1>C1COCC1>[Br:7][C:8]1[CH:9]=[CH:10][C:11]([S:6][CH:3]2[CH2:5][CH2:4]2)=[N:12][CH:13]=1
Reactant: SC1CC1
Reactant: Fc1ccc(Br)cn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Brc1ccc(SC2CC2)nc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of NaH (60% in mineral oil, 2.40 g) in THF (100 mL) was added dropwise cyclopropanethiol (0.25 M in Et2O, 160 mL) at 0° C. After stirring for 30 min, 5-bromo-2-fluoropyridine (3.52 g) was added in portions at 0° C. and then warmed to r.t. slowly. The reaction mixture was stirred at r.t. overnight. The reaction mixture was quenched with water (30 mL) and extracted with ethyl acetate (50 mL×3). The combined organic layers were washed with brine (50 mL) and dried over Na2SO4. After filtration and evaporation of the solvent, the crude product was obtained and used in next step without further purification.
Reaction SMILES: [C:1]([C:3]1[C:12]2[C:7](=[C:8]([NH2:13])[CH:9]=[CH:10][CH:11]=2)[CH:6]=[N:5][CH:4]=1)#[CH:2].I[C:15]1[CH:16]=[C:17]([NH:22][C:23](=[O:42])[C:24]2[CH:29]=[CH:28][C:27]([CH2:30][N:31]3[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]3)=[C:26]([C:38]([F:41])([F:40])[F:39])[CH:25]=2)[CH:18]=[CH:19][C:20]=1[CH3:21]>>[NH2:13][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:7]=1[CH:6]=[N:5][CH:4]=[C:3]2[C:1]#[C:2][C:15]1[CH:16]=[C:17]([NH:22][C:23](=[O:42])[C:24]2[CH:29]=[CH:28][C:27]([CH2:30][N:31]3[CH2:32][CH2:33][N:34]([CH3:37])[CH2:35][CH2:36]3)=[C:26]([C:38]([F:39])([F:40])[F:41])[CH:25]=2)[CH:18]=[CH:19][C:20]=1[CH3:21]
Reactant: C#Cc1cncc2c(N)cccc12
Reactant: Cc1ccc(NC(=O)c2ccc(CN3CCN(C)CC3)c(C(F)(F)F)c2)cc1I
Product: Cc1ccc(NC(=O)c2ccc(CN3CCN(C)CC3)c(C(F)(F)F)c2)cc1C#Cc1cncc2c(N)cccc12

Procedure:
The title compound can be synthesized from 4-ethynylisoquinolin-8-amine and N-(3-iodo-4-methylphenyl)-4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)benzamide in a manner similar to that described for Example 1. 4-ethynylisoquinolin-8-amine is prepared from 4-bromoisoquinolin-8-amine and ethynyitrimethylsilane according to the 2 steps procedure described in example 1.
Reaction SMILES: CCOP(OCC)([CH:6]1[NH:12][C:10](=[O:11])[NH:9][C:7]1=[O:8])=O.C(N(CC)CC)C.[CH:23]1([O:28][C:29]2[CH:30]=[C:31]([CH:34]=[CH:35][C:36]=2[O:37][CH3:38])[CH:32]=O)[CH2:27][CH2:26][CH2:25][CH2:24]1>C(#N)C>[CH:23]1([O:28][C:29]2[CH:30]=[C:31]([CH:34]=[CH:35][C:36]=2[O:37][CH3:38])[CH2:32][CH:6]2[NH:12][C:10](=[O:11])[NH:9][C:7]2=[O:8])[CH2:24][CH2:25][CH2:26][CH2:27]1
Reactant: COc1ccc(C=O)cc1OC1CCCC1
Reactant: CCOP(=O)(OCC)C1NC(=O)NC1=O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1ccc(CC2NC(=O)NC2=O)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.3 %

Procedure:
To a stirred solution of diethyl 5-hydantoylphosphonate (10 g, 42.3 mmol) and triethylamine (5.70 g, 56 mmol), in dry acetonitrile (100 ml), at room temperature was added a solution of 3-cyclopentyloxy-4-methoxybenzaldehyde (8 g, 36.3 mmol) in dry acetonitrile (75 ml), dropwise over 30 minutes. The resulting mixture was stirred at room temperature overnight, after which volatiles were removed in vacuo. The residue was diluted with 0.05N HCl (120 ml) and the precipitate collected by filtration. Recrystallization of this material with methylene chloride/methanol/diethyl ether afforded the title compound as a pale yellow solid (8.54 g). m.p. 220-222° C.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][NH2:7].C(N(CC)CC)C.Cl[C:19]([O:21][CH:22]([CH3:24])[CH3:23])=[O:20].[Cl-].[Na+]>C(Cl)(Cl)Cl>[Br:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][NH:7][C:19](=[O:20])[O:21][CH:22]([CH3:24])[CH3:23]
Reactant: CC(C)OC(=O)Cl
Reactant: NCc1cccc(Br)c1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C)OC(=O)NCc1cccc(Br)c1
Yield: 90.8 %

Procedure:
3.00 g of 3-bromobenzylamine hydrochloride suspended in chloroform (20 ml) was mixed with 2.86 g of triethylamine at room temperature. The resulting solution was stirred under cooling with ice while 1.82 g of isopropyl chloroformate was added dropwise and then stirred at room temperature for 2 hours. After the reaction, the reaction solution was poured into saturated aqueous sodium chloride, and the organic layer was separated, dried over anhydrous magnesium sulfate and evaporated at ordinary pressure for removal of the solvent. The residue was purified by silica gel column chromatography to give 3.33 g of isopropyl N-(3-bromobenzyl)carbamate as a colorless transparent viscous liquid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]([OH:17])([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:6][CH:7]=1.[C:18]([O:22][C:23]([N:25]1[CH2:29][CH2:28][CH2:27][CH:26]1[CH2:30]O)=[O:24])([CH3:21])([CH3:20])[CH3:19].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1>[C:18]([O:22][C:23]([N:25]1[CH2:29][CH2:28][CH2:27][CH:26]1[CH2:30][O:17][C:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([NH2:1])[CH:3]=1)([C:9]([F:10])([F:11])[F:12])[C:13]([F:14])([F:15])[F:16])=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)OC(=O)N1CCCC1CO
Reactant: Nc1cccc(C(O)(C(F)(F)F)C(F)(F)F)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCC1COC(c1cccc(N)c1)(C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a mixture of 2-(3-amino-phenyl)-1,1,1,3,3,3-hexafluoro-propan-2-ol (1.30 g), 2-hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (1.04 g), PPh3 (2.64 g) and molecular sieves 4 Å in THF (100 mL) was added diethyl diazocarboxylate (1.55 mL) slowly. The reaction was stirred at RT for 4 h and at reflux for overnight. After filtration to remove solids, the filtrate was concentrated and the residue was taken into Et2O. The organic phase was washed with saturated NaHCO3 and brine. The organic layer was dried over MgSO4 and evaporated to give a crude compound as very viscous brown oil, which was purified by chromatography through silica gel (500 g, 30% to 50% EtOAc in hexanes) to afford 2-[1-(3-amino-phenyl)-2,2,2-trifluoro-1-trifluoromethyl-ethoxymethyl]-pyrrolidine-1-carboxylic acid tert-butyl ester as a light brown oil.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.F[C:11]1([CH:19]=[CH:18][N:17]=[CH:16][CH2:15]1)[C:12]([OH:14])=[O:13]>>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:7][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][C:11]=2[C:12]([OH:14])=[O:13])=[CH:4][CH:3]=1
Reactant: O=C(O)C1(F)C=CN=CC1
Reactant: NCc1ccc(F)cc1
Product: O=C(O)c1ccncc1NCc1ccc(F)cc1
Yield: 55 %

Procedure:
The title compound was prepared in 55% yield from 4-fluorobenzylamine and 4-fluoroisonicotinic acid according to the procedure for the preparation of Example 3. NMR (500 MHz, DMSO-d6): δ 13.45 (br s, 1H), 8.11 (s, 1H), 8.03 (br s, 1H), 7.83 (d, 1H, J=5.0 Hz), 7.58 (d, 1H, J=5.0 Hz), 7.36-7.42 (m, 1H), 7.16-7.23 (m, 2H), 7.05-7.11 (m, 1H), 4.60 (s, 2H). [M+H] calc'd for C13H11FN2O2, 247; found 247.
Reaction SMILES: [H-].[Na+].[CH:3]([C:6]1([OH:10])[CH2:9][O:8][CH2:7]1)([CH3:5])[CH3:4].[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17][C:18](=O)[O:19]C1C=CC=CN=1>C1COCC1.CCOC(C)=O>[C:18](=[O:19])([O:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][N:11]=1)[O:10][C:6]1([CH:3]([CH3:5])[CH3:4])[CH2:9][O:8][CH2:7]1
Reactant: O=C(Oc1ccccn1)Oc1ccccn1
Reactant: CC(C)C1(O)COC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)C1(OC(=O)Oc2ccccn2)COC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 19.6 %

Procedure:
To a suspension of sodium hydride, 60% in mineral oil (331 mg, 8.26 mmol) in THF (25 mL) was added 3-isopropyloxetan-3-ol (800 mg, 6.89 mmol) at 0° C. After stirring 30 min, the solution was transferred to a solution of di(pyridin-2-yl)carbonate (1489 mg, 6.89 mmol) in THF (25 mL) through a cannula. The formed slurry was stirred at 0° C. for 30 min. The slurry was warmed to rt and stirred for 2 h. The reaction was diluted with EtOAc, washed with brine, dried over MgSO4, filtered, concentrated to give a residue that was purified by Biotage eluting with 20% EtOAc in hexanes to afford the desired product 3-isopropyloxetan-3-yl pyridin-2-yl carbonate (320 mg, 20.2% yield) as an oil. 1H NMR (400 MHz, CHLOROFORM-d) d 8.47-8.39 (m, 1H), 7.86-7.78 (m, 1H), 7.31-7.24 (m, 1H), 7.15 (d, J=8.0 Hz, 1H), 4.89 (d, J=8.5 Hz, 2H), 4.67 (d, J=8.5 Hz, 2H), 2.53 (dt, J=13.7, 7.0 Hz, 1H), 1.13 (s, 3H), 1.12 (s, 3H).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:16]=[CH:15][C:8]([O:9][C:10]2[S:11][CH:12]=[CH:13][N:14]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2].C([Li])CCC.[CH2:22]([Sn:26](Cl)([CH2:31][CH2:32][CH2:33][CH3:34])[CH2:27][CH2:28][CH2:29][CH3:30])[CH2:23][CH2:24][CH3:25].O>O1CCCC1>[CH:1]([O:4][C:5]1[CH:16]=[CH:15][C:8]([O:9][C:10]2[S:11][C:12]([Sn:26]([CH2:27][CH2:28][CH2:29][CH3:30])([CH2:31][CH2:32][CH2:33][CH3:34])[CH2:22][CH2:23][CH2:24][CH3:25])=[CH:13][N:14]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: CC(C)Oc1ccc(Oc2nccs2)cc1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cnc(Oc2ccc(OC(C)C)cc2)s1
Reaction time: 1 h
Yield: 92.5 %

Procedure:
To a solution of Example 1B (2.4 g, 0.01 mol) in dry tetrahydrofuran was added n-butyl lithium (4.4 mL, 2.5 M in hexane) at −78° C. drop wise. After stirring at this temperature for 1 h, tributyltin chloride (3.0 mL, 0.011 mol) was added slowly to the mixture. The brown solution was then stirred for 3 hours while warning up to room temperature. Water was added and the solution was extracted with ethyl acetate. The organic layer washed with saturated NH4Cl, brine, and then dried over magnesium sulfate. The solution was concentrated and the crude was purified on a silica gel flash column, eluting with 5-30% EtOAc in hexane, to give 4.85 g of the title compound (93% yield), 1H NMR (300 MHz, CDCl3) δ ppm 0.77-1.74 (m, 33 H) 4.40-4.63 (m, 1 H) 6.84-6.95 (m, 2 H) 7.12 (s, 1 H) 7.14-7.23 (m, 2 H). MS (ESI), m/z 526.2 (M+H)+.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH2:9][CH2:8][NH:7][CH2:6][C:5]=12.[F:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[N:17]1[N:21]=[N:22][C:23]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[F:30])=[C:16]1[N:15]=[C:14]2OS(C1C=CC(C)=CC=1)(=O)=O>>[N:1]1[CH:2]=[CH:3][N:4]2[CH2:9][CH2:8][N:7]([C:14]3[C:13]4[C:18](=[CH:19][CH:20]=[C:11]([F:10])[CH:12]=4)[N:17]4[N:21]=[N:22][C:23]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=5[F:30])=[C:16]4[N:15]=3)[CH2:6][C:5]=12
Reactant: Cc1ccc(S(=O)(=O)Oc2nc3c(-c4ccccc4F)nnn3c3ccc(F)cc23)cc1
Reactant: c1cn2c(n1)CNCC2
Product: Fc1ccc2c(c1)c(N1CCn3ccnc3C1)nc1c(-c3ccccc3F)nnn12

Procedure:
Prepared from 5,6,7,8-tetrahydroimidazo[1,2-α]pyrazine and 7-fluoro-3-(2-fluorophenyl)-5-(4-methylbenzenesulfonyloxy)-[1,2,3]triazolo[1,5-α]quinazoline as described for Example 1, step c (0.031 g, 26%). Found: C, 61.72; H, 3.79; N, 23.14. C21H15F2N7.0.33(H2O) requires C, 61.65; H, 3.86; N, 23.96%. δH (360 MHz; CDCl3) 4.09 (2H, dd, J=5 and 5), 4.05 (2H, dd, J=5 and 5), 4.97 (2H, s), 6.93 (1H, d, J=1), 7.07 (1H, d, J=1), 7.21-7.32 (2H, m), 7.37-7.40 (1H, m), 7.67-7.74 (2H, m), 8.06 (1H, ddd, J=7, 7 and 2), 8.75 (1H, dd, J=8 and 5); m/z (ES+) 404 (M+H+).
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=[O:4].C(N(CC)CC)C.O=[S:22]1[CH2:27][CH2:26][CH2:25][N:24]2[C:28](=[O:42])[N:29]([CH2:39][CH2:40][CH3:41])[C:30](=[O:38])[C:31]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[C:23]12>C(Cl)Cl>[OH:4][CH:27]1[S:22][C:23]2=[C:31]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:30](=[O:38])[N:29]([CH2:39][CH2:40][CH3:41])[C:28](=[O:42])[N:24]2[CH2:25][CH2:26]1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: CCCn1c(=O)c(-c2ccccc2)c2n(c1=O)CCCS2=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCn1c(=O)c(-c2ccccc2)c2n(c1=O)CCC(O)S2
Temperature: 40 °C
Reaction time: 60 h
Yield: 77.5 %

Procedure:
Trifluoroacetic anhydride (3.78 g) and triethylamine (1.82 g) were added to a solution of 1-oxo-9-phenyl-7-propyl-3,4-dihydro-2H,6H-pyrimido[6,1-b][1,3]thiazine-6,8(7H)-dione (4 g) in methylene chloride (60 ml) and the mixture was stirred at 40° C. for 60 hours. The reaction solution was evaporated to dryness, and the residue was dissolved in methylene chloride-H2O. Then, the organic layer was washed with a saturated aqueous sodium bicarbonate. After drying, the organic solution was concentrated, and the resulting residue was purified by column chromatography on silica gel. The resulting crude crystals were recrystalized from methylene chloride-isopropyl ether to give colorless needles (3.1 g, 78%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:22]2[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][C:9]1[C:10](=[O:21])[NH:11][C:12]2[N:13]([N:18]=[CH:19][N:20]=2)[C:14]=1[CH2:15][CH2:16][CH3:17].N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC.[CH3:61][O:62][C:63]1[CH:68]=[C:67]([O:69][CH3:70])[CH:66]=[CH:65][C:64]=1[CH2:71]O>C(OCC)(=O)C.O1CCCC1>[CH3:61][O:62][C:63]1[CH:68]=[C:67]([O:69][CH3:70])[CH:66]=[CH:65][C:64]=1[CH2:71][N:11]1[C:10](=[O:21])[C:9]([CH2:8][C:7]2[CH:6]=[CH:5][C:4]([C:22]3[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=3)=[CH:3][C:2]=2[F:1])=[C:14]([CH2:15][CH2:16][CH3:17])[N:13]2[N:18]=[CH:19][N:20]=[C:12]12
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)[nH]c2ncnn12
Reactant: COc1ccc(CO)c(OC)c1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n(Cc2ccc(OC)cc2OC)c2ncnn12
Temperature: 25 °C
Reaction time: 4 h
Yield: 25.9 %

Procedure:
A mixture of 3′-fluoro-4′-[(5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile (1 g), 1,1′-(azodicarbonyl)dipiperidine (1.3 g), tributylphosphine (1.6 mL), (2,4-dimethoxyphenyl)methanol (0.58 g) and tetrahydrofuran (50 mL) was stirred at room temperature for 4 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 N hydrochloric acid and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.36 g, 26%).
Reaction SMILES: Br[C:2]1[C:3]2[CH:15]=[CH:14][CH:13]=[CH:12][C:4]=2[S:5][C:6]=1[CH2:7][CH2:8][N:9]([CH3:11])[CH3:10].CN(C)CCN(C)C.[Li]CCCC.[CH3:29][C:30](OC(C)=O)=[O:31]>C1(C)C=CC=CC=1>[CH3:10][N:9]([CH3:11])[CH2:8][CH2:7][C:6]1[S:5][C:4]2[CH:12]=[CH:13][CH:14]=[CH:15][C:3]=2[C:2]=1[C:30](=[O:31])[CH3:29]
Reactant: CN(C)CCc1sc2ccccc2c1Br
Reactant: CC(=O)OC(C)=O
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Product: CC(=O)c1c(CCN(C)C)sc2ccccc12
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 50.4 %

Procedure:
Compound 2a, [2-(3-bromo-benzo[b]thiophen-2-yl)-ethyl]-dimethyl-amine (17.5 mmol), was dissolved in anhydrous toluene (180 mL) and cooled to −78° C. Tetramethylethylenediamine (17.5 mmol) was added followed by n-BuLi (21.0 mmol, 1.6 M in hexanes). The mixture was stirred for 45 min at −78° C. Ac2O (70 mmol) was added and the mixture was allowed to slowly reach RT and was stirred overnight. The mixture was quenched with sat. NH4Cl, the pH of the aqueous layer was adjusted to 7-8 with sat. NaHCO3, and the reaction mixture was extracted with EtOAc (4×). The combined organic layer was washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The crude material was purified by silica gel column chromatography in CH2Cl2 with a gradient up to CH2Cl2/MeOH=94/6 to afford Compound 6a, 1-[2-(2-dimethylamino-ethyl)-benzo[b]thiophen-3-yl]-ethanone (2.18 g, 50%); MS (MH+)=248.1.
Reaction SMILES: [CH3:1][Si:2]([CH3:9])([CH3:8])[NH:3][Si](C)(C)C.[C:10]1(=[O:16])N[C:13](=[O:15])[CH2:12][CH2:11]1.N.O>ClCCl>[CH3:1][Si:2]([CH3:9])([CH3:8])[N:3]1[C:13](=[O:15])[CH2:12][CH2:11][C:10]1=[O:16]
Reactant: O=C1CCC(=O)N1
Reactant: C[Si](C)(C)N[Si](C)(C)C
Agent: N
Solvent: ClCCl
Solvent: O
Product: C[Si](C)(C)N1C(=O)CCC1=O
Reaction time: 2 h
Yield: 119.6 %

Procedure:
15.6 ml (0.075 mole) of hexamethyldisilazane were added dropwise over a few minutes to a refluxing suspension of 9.90 g (0.1 mole) of succinimide and 0.24 g (0.5 mmole) of di-4-nitrophenyl N-4-toluenesulfonyl-phosphoramidate in 50 ml of dichloromethane and a stream of nitrogen was led over the reaction mixture to pass the ammonia evolved into water. The progress of the reaction was established by titration of the ammonia evolved and it was found that after refluxing for 1.5 hours, the production of ammonia was completed. 90% of the theoretical amount of ammonia had been evolved and refluxing was continued for another 2 hours. Then the solvent was removed by distillation at normal pressure and fractionation under reduced pressure yielded 15.36 g (89.8%) of N-trimethylsilylsuccinimide boiling at 118°-119° C. at 18 mm Hg and nD 25=1.4745.