Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]([OH:9])=O)=[CH:3][CH:2]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.C(=O)=O.Cl.[CH3:26][NH:27][O:28][CH3:29]>C(Cl)Cl>[CH3:26][N:27]([O:28][CH3:29])[C:7](=[O:9])[C:4]1[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=1
Reactant: O=C(O)c1ccncc1
Reactant: CNOC
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Agent: O=C=O
Solvent: ClCCl
Product: CON(C)C(=O)c1ccncc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.5 %

Procedure:
4-pyridinecarboxylic acid (18) (17.0 g, 0.138 mol) is slurried in methylene chloride (200 mL) and treated with 1,1′-carbonyldiimidazole (25 g, 0.154 mol). After a 1 minute induction period, CO2 evolution begins and the solution becomes homogeneous. After stirring at ambient temperature for 2 hours, the solution is treated with N,O-dimethylhydroxylamine hydrochloride (20 g, 0.20 mol) and stirred at room temperature overnight. The reaction mixture is quenched with 1 N NaOH and the phases separated. After a normal work-up, the organic phase is concentrated to leave an oil. Kugelrohr distillation provided the title compound (19) as a clear liquid (14.34 g, 62% yield); b.p. 120-135° C./0.5 mm Hg.
Reaction SMILES: Br[C:2]1[C:3]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH:10]2[C:15]([NH:17][C@@H:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][CH2:19]2)=[O:16])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:8][C:5]1[N:6]=[CH:7][C:2]2[N:17]([CH:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH2:20][CH2:19]3)[C:15](=[O:16])[C@@H:10]3[CH2:11][O:12][CH2:13][CH2:14][N:9]3[C:3]=2[N:4]=1
Reactant: O=C(N[C@H]1CCc2ccccc21)C1COCCN1c1nc(Cl)ncc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Product: O=C1[C@@H]2COCCN2c2nc(Cl)ncc2N1C1CCc2ccccc21
Temperature: 120 °C
Yield: 26.5 %

Procedure:
To a 5 mL microwave vial were added 4-(5-bromo-2-chloropyrimidin-4-yl)-N—((S)-2,3-dihydro-1H-inden-1-yl)morpholine-3-carboxamide (PREPARATION x48, 407 mg, 0.93 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (26.9 mg, 0.047 mmol), palladium (II)acetate (6.26 mg, 0.028 mmol), and potassium phosphate, tribasic (276 mg, 1.302 mmol). The vessel was evacuated, refilled with nitrogen, and sealed. Dioxane (3.9 mL) and tert-butanol (0.78 mL) were added and the mixture was heated in a microwave to 120° C. for 90 minutes. An additional portion of catalyst was added, and the reaction mixture was heated in the microwave to 120° C. for another 6 hours. The reaction mixture was subsequently partitioned between aqueous saturated NaHCO3 and ethyl acetate. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were dried over MgSO4, filtered, and concentrated. The dark brown crude product was purified by normal phase column chromatography (SiO2, 60 g) eluting with a gradient of 50-100% EtOAc in hexanes over 20 minutes. The product-containing fractions were combined and concentrated to give the title compound as a white foam (88 mg, 26.5%). ESI-MS m/z [M+H]+ calc'd for C17H17ClN4O2, 357.10. found 357.3.
Reaction SMILES: N1C=CN=C1.[Si:6](Cl)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].[OH:14][C@@H:15]([C@H:17]1[C@@H:20]([C:21]#[C:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[NH:19][C:18]1=[O:27])[CH3:16].C(OCC)(=O)C>CN(C)C=O.O>[Si:6]([O:14][C@@H:15]([C@H:17]1[C@@H:20]([C:21]#[C:22][Si:23]([CH3:24])([CH3:26])[CH3:25])[NH:19][C:18]1=[O:27])[CH3:16])([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7]
Reactant: C[C@@H](O)[C@@H]1C(=O)N[C@@H]1C#C[Si](C)(C)C
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H]1C(=O)N[C@@H]1C#C[Si](C)(C)C
Reaction time: 1.5 h

Procedure:
Imidazole (0.2 g) and tert-butyldimethylsilyl chloride (0.3 g) are added to a solution of cis-3-[(R)-1-hydroxyethyl]-4-trimethylsilylethynyl-2-azetidinone (0.2 g) in N,N-dimethylformamide (7 ml), and the mixture is stirred at 60° C.-65° C. for 1.5 hours and then poured into a mixture of ethyl acetate (50 ml) and water (50 ml). The organic layer is separated, washed with aqueous sodium chloride, dried over magnesium sulfate and concentrated under reduced pressure, and the residue is subjected to silica gel column chromatography to give cis i.e. (3R,4S)-3-[(R)-1-(tert-butyldimethylsilyloxy)ethyl]-4-trimethylsilylethynyl-2-azetidinone as crystals. (0.24 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1.[Cl:13][S:14](O)(=[O:16])=[O:15].P(Cl)(Cl)(Cl)(Cl)Cl>ClCCl>[CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([S:14]([Cl:13])(=[O:16])=[O:15])=[CH:5][CH:4]=1
Reactant: COc1cccc2ccccc12
Reactant: O=S(=O)(O)Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)Cl)c2ccccc12
Temperature: 0 °C
Yield: 93 %

Procedure:
To a cooled (0° C.) solution of 1-methoxy naphthalene (5 cm3, 34.5 mmol) in dichloromethane (20 cm3) was added, over a 10 minute period, chlorosulfonic acid (4.6 cm3, 69.0 mmol). Following this addition, phosphorus pentachloride (7.2 g, 34.5 mmol) was added and the reaction was maintained at 0° C. for a further 45 min. The reaction was then quenched by pouring onto ice/water (50 cm3), and allowed to warm to room temperature. Further dichloromethane (40 cm3) was added and the solution was transferred to a separating funnel, where the organic layer was collected and washed with saturated aqueous sodium chloride solution (70 cm3) and dried over sodium sulfate. The solvent was then evaporated under reduced pressure to afford title compound (8.23 g, 32.1 mmol; 93%).
Reaction SMILES: O[CH2:2][C:3]1[N:4]=[C:5]([C:8]2[CH:13]=[C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:11]([OH:18])=[C:10]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:9]=2)[O:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:43]>C(#N)C>[Br:43][CH2:2][C:3]1[N:4]=[C:5]([C:8]2[CH:13]=[C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:11]([OH:18])=[C:10]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:9]=2)[O:6][CH:7]=1
Reactant: BrC(Br)(Br)Br
Reactant: CC(C)(C)c1cc(-c2nc(CO)co2)cc(C(C)(C)C)c1O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: CC(C)(C)c1cc(-c2nc(CBr)co2)cc(C(C)(C)C)c1O
Temperature: 22 °C
Reaction time: 3 h
Yield: 59.9 %

Procedure:
A suspension of 4-(hydroxymethyl)-2-(3,5-di-tert-butyl-4-hydroxyphenyl) oxazole (44.2 mmole, 13.41 g) in acetonitrile (230 ml) was treated with triphenylphosphine (53.0 mmole, 13.91 g) followed by carbon tetrabromide (53.0 mmole, 17.59 g). The resulting solution was stirred at approximately 22° C. for 3 hours. Next, additional carbon tetrabromide (22.0 mmole, 13.13 g) and triphenylphosphine 22.0 mmole, 5.79 g) was added to the reaction. After stirring for an additional 40 minutes, the reaction was quenched with water (5 mL), stirred 10 minutes and concentrated in vacuo and stored at 5° C. for approximately 16 hours. The material was then taken up into chloroform and subjected to prepatory chromatography eluting with 35 to 50% chloroform:hexane over a thirty-minute period. Fractions containing title compound were combined, dried over sodium sulfate, filtered, concentrated in vacuo to afford 9.7 g of the title compound that crystallized out upon standing at 22° C.
Reaction SMILES: BrC1C2C(=CC(F)=CC=2)C(=O)NC=1.CC1(C)C(C)(C)OB(B2OC(C)(C)C(C)(C)O2)O1.FC1C=C2C(C(B3OC(C)(C)C(C)(C)O3)=CN(C)C2=O)=CC=1.ClC1C(OCC2CC2)=CN=C(S(C)(=O)=O)N=1.[CH:70]1([CH2:73][O:74][C:75]2[C:76]([C:85]3[C:94]4[C:89](=[CH:90][C:91]([F:95])=[CH:92][CH:93]=4)[C:88](=[O:96])[N:87]([CH3:97])[CH:86]=3)=[N:77][C:78](S(C)(=O)=O)=[N:79][CH:80]=2)[CH2:72][CH2:71]1.[CH3:98][S:99]([NH2:102])(=[O:101])=[O:100]>>[CH:70]1([CH2:73][O:74][C:75]2[C:76]([C:85]3[C:94]4[C:89](=[CH:90][C:91]([F:95])=[CH:92][CH:93]=4)[C:88](=[O:96])[N:87]([CH3:97])[CH:86]=3)=[N:77][C:78]([NH:102][S:99]([CH3:98])(=[O:101])=[O:100])=[N:79][CH:80]=2)[CH2:71][CH2:72]1
Reactant: Cn1cc(-c2nc(S(C)(=O)=O)ncc2OCC2CC2)c2ccc(F)cc2c1=O
Reactant: CS(N)(=O)=O
Agent: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Agent: CS(=O)(=O)c1ncc(OCC2CC2)c(Cl)n1
Agent: Cn1cc(B2OC(C)(C)C(C)(C)O2)c2ccc(F)cc2c1=O
Product: Cn1cc(-c2nc(NS(C)(=O)=O)ncc2OCC2CC2)c2ccc(F)cc2c1=O

Procedure:
The title compound of Example 58, step 2 was treated with 4,4,5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane in a manner similar to Example 89, step 1 and the resulting 7-fluoro-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin-1-one was coupled to the title compound of Example 152, step 4 in a manner similar to Example 152, step 5 and the resulting 4-[5-(cyclopropylmethoxy)-2-methylsulfonylpyrimidin-4-yl]-7-fluoro-2-methylisoquinolin-1-one was treated with MeSO2NH2 in a manner similar to Example 152, step 6 to give the title compound. 1H NMR (DMSO-d6, 400 MHz) δ 11.15 (s, 1H), 8.55 (s, 1H), 8.36 (dd, J1=9.2 Hz, J2=6.0 Hz, 1H), 8.00 (s, 1H), 7.60 (dd, J1=11.2 Hz, J2=2.4 Hz, 1H), 7.44-7.37 (m, 1H), 3.95 (d, J=7.2 Hz, 2H), 3.58 (s, 3H), 3.32 (s, 3H), 1.15-1.03 (m, 1H), 0.49-0.42 (m, 2H), 0.26-0.20 (m, 2H). LCMS: 419.0 (M+1)+
Reaction SMILES: [OH-].[K+].CS(C)=O.[CH3:7][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]([NH2:17])[C:13]=1[C:14]([OH:16])=[O:15].I[CH3:19]>CCOCC>[CH3:7][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]([NH2:17])[C:13]=1[C:14]([O:16][CH3:19])=[O:15]
Reactant: Cc1cccc(N)c1C(=O)O
Reactant: CI
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CS(C)=O
Product: COC(=O)c1c(C)cccc1N
Reaction time: 0.08 h
Yield: 38.8 %

Procedure:
Powdered potassium hydroxide (7.4 g, 0.132 mol) was admixed with dimethyl sulfoxide (DMSO) (100 ml), and the mixture was stirred for 5 minutes. 6-Methylanthranilic acid (10.0 g, 0.066 mol) was then added to the mixture and iodomethane (4.52 ml, 0.073 mol) added dropwise. The reaction mixture was stirred for 30 minutes at room temperature, then diluted with 250 ml of ether, washed with water (3×100 ml), dried over magnesium sulfate and concentrated. The crude product was filtered through a pad of flash grade (32-63) silica gel and eluted with 1:9 ether:hexane to afford 4.23 g (39%) of methyl 6-methylanthranilate as an oil.
Reaction SMILES: [Cl:1][C:2]1[C:12]2[C:13]3[C:5]([CH2:6][CH2:7][C:8]=3[CH:9]=[CH:10][C:11]=2[Cl:14])=[C:4]([N+:15]([O-])=O)[CH:3]=1.[H][H]>O1CCCC1.[Ni]>[NH2:15][C:4]1[CH:3]=[C:2]([Cl:1])[C:12]2[C:13]3[C:5]=1[CH2:6][CH2:7][C:8]=3[CH:9]=[CH:10][C:11]=2[Cl:14]
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cc(Cl)c2c(Cl)ccc3c2c1CC3
Agent: [Ni]
Solvent: C1CCOC1
Product: Nc1cc(Cl)c2c(Cl)ccc3c2c1CC3
Reaction time: 14 h
Yield: 100.4 %

Procedure:
A solution of 5,6-dichloro-3-nitroacenaphthene (3.7 g, 13.8 mmol, from Example C4) in 250 mL of tetrahydrofuran was treated with 1.0 g of Raney-nickel and shaken in a hydrogen atmosphere at 21° C. and a pressure of 52.8 psi for 14 hours. The catalyst was removed by filtration, and the solvent was removed in vacuo to give 3.3 g of the title compound.
Reaction SMILES: [CH2:1]([Li])CCC.[CH3:6][O:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=1>CCOCC.[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:6][O:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=[CH2:1])=[CH:10][CH:9]=1
Reactant: COc1ccc(C=O)cc1
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: CCOCC
Product: C=Cc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of n-butyllithium (4 mL, 2,5 M solution in Hexane, 10 mmol) (Aldrich) in ether (30 mL) was added methyltriphenylphosphonium bromide (3.57 g, 10 mmol) (Aldrich) over a period of 5 min. The reaction mixture was stirred for 4 h at room temperature. To the resulting orange solution was added 4-methoxybenzaldehyde (1.34 mL, 10 mmol) (Aldrich) dropwise. The solution became colorless, and a white precipitate separated. The mixture was then heated to reflux and immediately allowed to cool to room temperature. The precipitate was removed by filtration. The precipitate was washed with ether and the combined ethereal filtrates were washed with water until neutral and then dried over anhydrous MgSO4. The solvent was removed, and the residue was used in the next reaction without further purification.
Reaction SMILES: [N:1]1[N:12]2[C:4]([N:5]=[C:6]3[C:10](=[C:11]2[C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)[CH2:9][CH2:8][CH2:7]3)=[CH:3][CH:2]=1.[Na+].[I-:21].[OH-].[Na+].[O-]Cl.[Na+]>CO>[N:1]1[N:12]2[C:4]([N:5]=[C:6]3[C:10](=[C:11]2[C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([I:21])[CH:14]=2)[CH2:9][CH2:8][CH2:7]3)=[CH:3][CH:2]=1
Reactant: Oc1ccc(-c2c3c(nc4ccnn24)CCC3)cc1
Reactant: [I-]
Agent: [Na+]
Agent: [O-]Cl
Agent: [OH-]
Solvent: CO
Product: Oc1ccc(-c2c3c(nc4ccnn24)CCC3)cc1I
Temperature: 0 °C
Reaction time: 1 h

Procedure:
4-(6,7-Dihydro-5H-1,4,8a-triaza-s-indacen-8-yl)-phenol (500 mg, 0.002 mmol) was dissolved in methanol (10 mL) followed by addition of NaI (368 mg, 2.45 mmol) and NaOH (98 mg, 2.45 mmol). The solution was cooled to 0° C. followed by dropwise addition of NaOCl (5.25% aq, 3.8 ml) over 3 minutes. The reaction mixture was stirred at 0° C. for 1 hour followed by warming to room temperature and quenching with sodium thiosulphate (saturated. aq., 6 ml). The pH of the reaction was adjusted to ˜7 by addition of sodium dihydrogen phosphate. The solution was extracted with CH2Cl2. The organic layer was dried and concentrated. The residue was purified on silica gel (10%→60% EtOAc in hexane) to give 4-(6,7-dihydro-5H-1,4,8a-triaza-s-indacen-8-yl)-2-iodo-phenol.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](=[O:22])[NH:19][C:18]4=[O:23])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:29])([F:28])[F:27])[CH:3]=1.[C:30]([O:34][C:35]([N:37]1[CH2:42][CH:41]2[CH:39]([O:40]2)[CH2:38]1)=[O:36])([CH3:33])([CH3:32])[CH3:31]>>[C:30]([O:34][C:35]([N:37]1[CH2:38][C@@H:39]([OH:40])[C@H:41]([N:19]2[C:18](=[O:23])[C:17](=[CH:16][C:12]3[CH:11]=[C:10]4[C:15](=[CH:14][CH:13]=3)[N:7]([CH2:6][C:5]3[CH:24]=[CH:25][C:2]([Cl:1])=[CH:3][C:4]=3[C:26]([F:27])([F:29])[F:28])[N:8]=[CH:9]4)[S:21][C:20]2=[O:22])[CH2:42]1)=[O:36])([CH3:33])([CH3:31])[CH3:32]
Reactant: CC(C)(C)OC(=O)N1CC2OC2C1
Reactant: O=C1NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Product: CC(C)(C)OC(=O)N1C[C@@H](O)[C@H](N2C(=O)SC(=Cc3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)C2=O)C1

Procedure:
3-{5-[1-(4-Chloro-2-trifluoromethylbenzyl)-1H-indazol-5-ylmethylene]-2,4-dioxothiazolidin-3-yl}-(trans)-4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester was prepared from 5-[1-(4-chloro-2-trifluoromethylbenzyl)-1H-indazol-5-ylmethylene]thiazolidine-2,4-dione (from Example 1) and 6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester following a similar procedure as described for Example 270.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)=[CH:12][CH:11]=[C:10]([CH3:22])[N:9]=2)=[CH:4][CH:3]=1.Cl.Cl[CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1.C([O-])([O-])=O.[K+].[K+]>C(C(C)=O)C>[N:27]1([CH2:26][CH2:25][O:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[C:13]([C:14]4[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=4)=[CH:12][CH:11]=[C:10]([CH3:22])[N:9]=3)=[CH:6][CH:7]=2)[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1
Reactant: ClCCN1CCOCC1
Reactant: COc1ccc(-c2ccc(C)nc2-c2ccc(O)cc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COc1ccc(-c2ccc(C)nc2-c2ccc(OCCN3CCOCC3)cc2)cc1
Yield: 84.1 %

Procedure:
The 2-(4-hydroxyphenyl)-3-(4-methoxyphenyl)-6-methylpyridine (3.0 g, 10 mmol), N-(2-chloroethyl)morpholine hydrochloride (1.9 g, 10 mmol), and powdered K2CO3 (7.1 g, 51 mmol) were stirred in 200 mL methyl ethyl ketone and refluxed 20 h. The reaction mixture was worked up and purified by prep. chromatography (EtOH/ CH2Cl2 gradient), triturated with Et2O/ pet. ether, filtered, and dried in vacuo to give 3.4 g (82% yield) of white solid: mp 66°-67° C.; 1H NMR (CDCl3) d 2.55-2.58 (m 4H, morpholine), 2.62 (s, 3H, pyr-CH3), 2.76-2.80 (t, 2H, J=6 Hz, NCH2), 3.72-3.75 (m, 4H, morpholine), 3.80 (s, 3H, ArOCH3), 4.06-4.10 (t, 2H, J=6 Hz, OCH2), 6.75-6.81 (m, 4H, ArH), 7.05-7.14 (m, 4H, ArH), 7.26-7.29 (m, 1H, ArH) 7.54-7.56 (d, 1H, J=8 Hz, ArH); MS(FD) 404(M+). Anal. Calcd for C25H28N2O3 : C, 74.23; H, 6.98; N, 6.93. Found: C, 74.50; H, 6.91; N, 7.05.
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][C:7]2[NH:15][C:14]3[C:13](=[O:16])[N:12]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[F:24])[C:11](=[O:25])[N:10]([CH2:26][CH2:27][CH2:28][CH3:29])[C:9]=3[N:8]=2)=[CH:4][CH:3]=1.[C:32]1([CH:38]=[CH:39][S:40](Cl)(=[O:42])=[O:41])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[CH2:26]([N:10]1[C:9]2[N:8]=[C:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:40]([CH:39]=[CH:38][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)(=[O:42])=[O:41])=[CH:31][CH:30]=3)[NH:15][C:14]=2[C:13](=[O:16])[N:12]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])[C:11]1=[O:25])[CH2:27][CH2:28][CH3:29]
Reactant: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(N)cc3)nc21
Reactant: O=S(=O)(Cl)C=Cc1ccccc1
Product: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(NS(=O)(=O)C=Cc4ccccc4)cc3)nc21

Procedure:
Prepared from 8-(4-amino-benzyl)-3-butyl-1-(2-fluoro-benzyl)-3,7-dihydro-purine-2,6-dione and 2-phenyl-ethenesulfonyl chloride. Purity (ELSD, based on MW=587.7)=97%.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=O.[O:14]1[C:18]2[CH:19]=[CH:20][C:21]([CH2:23][NH2:24])=[CH:22][C:17]=2[O:16][CH2:15]1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[F:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([NH:24][CH2:23][C:21]1[CH:20]=[CH:19][C:18]2[O:14][CH2:15][O:16][C:17]=2[CH:22]=1)=[O:6]
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1F
Reactant: NCc1ccc2c(c1)OCO2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(NCc1ccc2c(c1)OCO2)c1cc([N+](=O)[O-])ccc1F
Temperature: 25 °C
Reaction time: 40 h
Yield: 86.1 %

Procedure:
A mixture of 2-fluoro-5-nitrobenzoic acid (1.00 g), (1,3-benzodioxol-5-ylmethyl)amine (980 mg), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (1.55 g) and 1-hydroxybenzotriazole (1.09 g) in anhydrous dimethylformamide (10 mL) was stirred for 40 hours at ambient temperature. The mixture was partitioned between water and ethyl acetate. The separated organic layer was washed with an aqueous saturated sodium bicarbonate solution, 1N-hydrochloric acid, water and brine. Then, the resultant was dried over magnesium sulfate and evaporated in vacuo. The residue was triturated with diisopropyl ether to give 2-fluoro-5-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamide as yellow powders (1.48 g).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[C:16]3[N:17]([C:21]([C:24]4[CH:29]=[CH:28][N:27]=[C:26]([NH:30][CH2:31][C:32]5[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[CH:33]=5)[N:25]=4)=[CH:22][N:23]=3)[CH:18]=[CH:19][N:20]=2)[CH2:10][CH2:9]1)(C)(C)C.Cl>C(O)C>[Cl:38][C:34]1[CH:33]=[C:32]([CH:37]=[CH:36][CH:35]=1)[CH2:31][NH:30][C:26]1[N:25]=[C:24]([C:21]2[N:17]3[CH:18]=[CH:19][N:20]=[C:15]([NH:14][CH:11]4[CH2:10][CH2:9][CH:8]([NH2:7])[CH2:13][CH2:12]4)[C:16]3=[N:23][CH:22]=2)[CH:29]=[CH:28][N:27]=1
Reactant: CC(C)(C)OC(=O)NC1CCC(Nc2nccn3c(-c4ccnc(NCc5cccc(Cl)c5)n4)cnc23)CC1
Agent: Cl
Solvent: CCO
Product: NC1CCC(Nc2nccn3c(-c4ccnc(NCc5cccc(Cl)c5)n4)cnc23)CC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of crude (4-{3-[2-(3-chloro-benzylamino)-pyrimidin-4-yl]-imidazo[1,2-a]pyrazin-8-ylamino}-cyclohexyl)-carbamic acid tert-butyl ester (110 mg, 0.205 mmol) in ethanol (5 mL) was added concentrated hydrochloric acid (5 mL) slowly. The reaction mixture was stirred at room temperature for 15 hours. The solvent was removed under reduced pressure and then the solid was purified by prep-HPLC. Several drops of concentrated HCl were added to the fractions with product. After sonicating for several minutes, solution was concentrated under reduced pressure to afford N-{3-[2-(3-chloro-benzylamino)-pyrimidin-4-yl]-imidazo[1,2-a]pyrazin-8-yl}-cyclohexane-1,4-diamine; hydrochloride. (Yield 58 mg, 60.9%).
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([NH2:11])[C:8]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[C:7]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=2[Cl:26])[N:6]=1)(=O)=O.[F:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][C:35]=1[F:36])[CH2:31][OH:32]>>[F:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][C:35]=1[F:36])[CH2:31][O:32][C:5]1[N:10]=[C:9]([NH2:11])[C:8]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[C:7]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=2[Cl:26])[N:6]=1
Reactant: CS(=O)(=O)c1nc(N)c(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1
Reactant: OCc1ccc(F)c(F)c1
Product: Nc1nc(OCc2ccc(F)c(F)c2)nc(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1

Procedure:
The title compound obtained by treating 2-(methylsulfonyl)-4-(amino)-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)pyrimidine (Example 32, Step A,) with 3,4-difluorobenzyl alcohol by the same general procedure described in Reference Examples 6 and 7. Workup and flash column chromatography on silica gel (eluted with 80/20 hexanes/ethyl acetate) afforded 2-(3,4-difluorobenzyloxy)-4-(amino)-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)pyrimidine. HPLC/MS: m/e=494 (M++1); Rt=3.91 min. 1H-NMR 500 MHz (CDCl3): δ 5.10 (bs, 2H), 5.38 (s, 2H), 7.0-7.10 (m, 2H), 7.11-7.23 (m, 6H), 7.15-7.19 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][S:4][C:3]=1[S:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1.C([Li])CCC.CCCCCC.CN(C)[CH:29]=[O:30]>CCOCC>[CH3:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([S:7][C:3]2[S:4][CH:5]=[CH:6][C:2]=2[CH:29]=[O:30])=[CH:9][CH:10]=1
Reactant: COc1ccc(Sc2sccc2Br)cc1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: COc1ccc(Sc2sccc2C=O)cc1
Temperature: -78 °C

Procedure:
To a stirred solution of 3-bromo-2-(4-methoxyphenylthio)thiophene (12.77 g, 0.042 mol) in anhydrous ether (100 ml) cooled to -78° C. was added dropwise over 1 hour. 1.55M n-butyl lithium in hexane (28.7 ml, 0.045 mol) under nitrogen atmosphere. The solution was stirred at -78° C. for another hour and then the temperature was allowed to rise to -30° C. over 1/4 hour. The temperature was lowered to -60° C. and dry dimethylformamide (6.2 g, 0.085 mol) was added over 5 minutes. The cooling bath was removed and the temperature was allowed to rise to 15° C. over 3/4 hour. The mixture was cooled to -20° C. and acidified by slowly adding 3NHCl (40 ml). The ether layer was separated and washed with saturated NaCl, saturated NaHCO3 and again with saturated NaCl. The solution was dried, filtered and concentrated in vacuo. A quantitative recovery of an amber oil which solidified to a waxy yellow solid was obtained. The product recrystallized from n-butyl chloride-hexane, mp 58°-60° C. The structure and purity were confirmed by NMR, mass spectral analysis and elemental analyses.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:20]([O:22][C:23](=[O:28])[CH2:24][CH2:25][CH2:26]Br)[CH3:21].CN1CCOCC1>CN(C=O)C>[CH2:20]([O:22][C:23](=[O:28])[CH2:24][CH2:25][CH2:26][NH:18][C:15]1[CH:14]=[CH:13][C:12]([CH2:11][CH2:10][CH2:9][CH2:8][NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:19])=[CH:17][CH:16]=1)[CH3:21]
Reactant: CC(C)(C)OC(=O)NCCCCc1ccc(N)cc1
Reactant: CCOC(=O)CCCBr
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CCOC(=O)CCCNc1ccc(CCCCNC(=O)OC(C)(C)C)cc1
Yield: 18.1 %

Procedure:
A solution of [4-(4-aminophenyl)butyl]carbamic acid tert-butyl ester (1.7 g, 6.43 mmol), 4-bromo-n-butyric acid ethyl ester (1.88 g, 9.64 mmol), 4-methylmorpholine (1.0 mL, 9.64 mmol), and DMF (10 mL) was stirred at 85° C. for 3 hours under a nitrogen atmosphere. The solvent was evaporated in vacuo. The residue was purified by flash chromatography (silica gel, 4:1, hexanes/ethyl acetate, v/v) to provide 420 (0.44 g, 18%) as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 1.23 (t, 3H), 1.47 (s, 9H), 1.55 (m, 4H), 1.96 (m, 2H), 2.43 (t, 2H), 2.51 (t, 2H), 3.19 (m, 4H), 4.14 (q, 2H), 6.54 (d, 2H), 7.00 (d, 2H). m/z (ESI) 379.