Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:14](=[O:16])[NH:13][C:12](=[O:17])[N:11]([CH3:18])[C:10]=3[N:9]=[C:8]2[S:19]([NH:22][CH:23]([CH3:25])[CH3:24])(=[O:21])=[O:20])=[CH:4][CH:3]=1.Br[CH2:29][CH2:30][CH2:31][O:32][CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][O:34]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:14](=[O:16])[N:13]([CH2:29][CH2:30][CH2:31][O:32][CH:33]4[CH2:38][CH2:37][CH2:36][CH2:35][O:34]4)[C:12](=[O:17])[N:11]([CH3:18])[C:10]=3[N:9]=[C:8]2[S:19]([NH:22][CH:23]([CH3:24])[CH3:25])(=[O:21])=[O:20])=[CH:26][CH:27]=1
Reactant: BrCCCOC1CCCCO1
Reactant: CC(C)NS(=O)(=O)c1nc2c(c(=O)[nH]c(=O)n2C)n1Cc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)NS(=O)(=O)c1nc2c(c(=O)n(CCCOC3CCCCO3)c(=O)n2C)n1Cc1ccc(Cl)cc1
Temperature: 60 °C
Reaction time: 4 h
Yield: 77 %

Procedure:
To a solution of 7-(4-chlorobenzyl)-N-isopropyl-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purine-8-sulfonamide (59 mg, 0.143 mmol) in DMF (3 mL) was added 2-(3-bromopropoxy)tetrahydro-2H-pyran (32 mg, 0.143 mmol) followed by potassium carbonate (30 mg, 0.214 mmol) and the mixture was stirred at 60° C. for 4 h. The reaction was diluted with ethyl acetate and washed with brine and saturated aqueous ammonium chloride. The organic phase was dried and concentrated to give 7-(4-chlorobenzyl)-N-isopropyl-3-methyl-2,6-dioxo-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-2,3,6,7-tetrahydro-1H-purine-8-sulfonamide (61 mg, 77% yield) as yellow solid. LCMS retention time 1.805 min; LCMS MH+-THP 470.
Reaction SMILES: [CH3:1][CH2:2][C@@:3]1([OH:28])[C:8](=[O:9])[O:7][CH2:6][C:5]2[C:10]([N:12]3[C:16](=[CH:17][C:4]1=2)[C:15]1[N:18]=[C:19]2[C:24](=[CH:25][C:14]=1[CH2:13]3)[C:23]([O:26]C)=[CH:22][CH:21]=[CH:20]2)=[O:11]>Br>[CH3:1][CH2:2][C@@:3]1([OH:28])[C:8](=[O:9])[O:7][CH2:6][C:5]2[C:10]([N:12]3[C:16](=[CH:17][C:4]1=2)[C:15]1[NH:18][C:19]2[C:24](=[CH:25][C:14]=1[CH2:13]3)[C:23](=[O:26])[CH:22]=[CH:21][CH:20]=2)=[O:11]
Reactant: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2cc3c(OC)cccc3nc2-1
Agent: Br
Product: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2cc3c(=O)cccc-3[nH]c2-1
Temperature: 25 °C
Yield: 67 %

Procedure:
9-Methoxycamptothecin (9-MC; 10.0 g, 26.43 mmol) was suspended in 47% hydrobromic acid (200 ml), degassed by suction and then displaced by argon gas, and refluxed for 3.5 hr. The reaction mixture was cooled to ambient temperature and poured into water (900 ml) in portion wise under stirring. The deposit was collected on a celite pad and washed with water. The obtained material by filtration was dissolved in chloroform containing 20% methanol, added with active carbon (20 g) and anhydrous sodium sulfate, stirred for 1 hr, filtered, concentrated to dryness under reduced pressure to give a crude product. The crude product was purified through silica gel column chromatography (chloroform containing 8% methanol) to give 9-hydroxycamptothecin (9-HC) as a brown solid; mp 231-237° C. (decomposition) (6.47 g, yield 67%).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:11]2[C:6](=[CH:7][C:8]([CH2:12][CH3:13])=[CH:9][CH:10]=2)[C:5]([CH3:15])([CH3:14])[CH2:4][CH2:3]1.C(Cl)(=[O:19])C.[Cl-].[Al+3].[Cl-].[Cl-].C(C[C:29]([CH3:32])(C)C)(C)C>>[CH3:14][C:5]1([CH3:15])[C:6]2[C:11](=[CH:10][C:9]([CH2:29][CH3:32])=[C:8]([C:12](=[O:19])[CH3:13])[CH:7]=2)[C:2]([CH3:16])([CH3:1])[CH2:3][CH2:4]1.[CH3:1][C:2]1([CH3:16])[C:11]2[C:6](=[CH:7][C:8]([CH2:12][CH3:13])=[CH:9][CH:10]=2)[C:5]([CH3:15])([CH3:14])[CH2:4][CH2:3]1
Reactant: CC(=O)Cl
Reactant: CC(C)CC(C)(C)C
Agent: CCc1ccc2c(c1)C(C)(C)CCC2(C)C
Agent: [Al+3]
Agent: [Cl-]
Product: CCc1cc2c(cc1C(C)=O)C(C)(C)CCC2(C)C
Yield: 89 %

Procedure:
A solution of 1,1,4,4-tetramethyl-6-ethyl-1,2,3,4-tetrahydronaphthalene (528 grams) and acetyl chloride (234 grams) is added over a 31/2 hour period at 70° C. to a well-stirred slurry of aluminum chloride (534 grams), 1,1,4,4-tetramethyl-6-ethyl-1,2,3,4-tetrahydronaphthalene (1200 grams) and isooctane (432 grams). The reaction is worked up as in Example I to afford 689 grams of 1,1,4,4-tetramethyl-6-ethyl-7-acetyl-1,2,3,4-tetrahydronaphthalene (89% based on consumed 1,1,4,4-tetramethyl-6-ethyl-1,2,3,4-tetrahydronaphthalene) and 1106 grams of recovered 1,1,4,4-tetramethyl-6-ethyl-1,2,3,4-tetrahydronaphthalene.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[C:9]2[C:14](=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=3)[N:16]=1)[N:13]=[CH:12][CH:11]=[CH:10]2)(=O)=O.[CH:28]([Sn](CCCC)(CCCC)CCCC)=[CH2:29].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl-].[Li+]>O1CCCC1.C(OCC)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[CH:28]([C:7]1[CH:8]=[C:9]2[C:14](=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=3)[N:16]=1)[N:13]=[CH:12][CH:11]=[CH:10]2)=[CH2:29]
Reactant: O=[N+]([O-])c1cccc(-c2nc(OS(=O)(=O)C(F)(F)F)cc3cccnc23)c1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=Cc1cc2cccnc2c(-c2cccc([N+](=O)[O-])c2)n1
Reaction time: 8 h

Procedure:
To a solution of 6-trifluoromethylsulfonyloxy-8-(3-nitrophenyl)-1,7-naphthyridine (250 mg, 0.62 mmol prepared according to example 13) in tetrahydrofuran (3 ml) is added vinyltributylstannane (218 mg, 0.68 mmol), bis(dibenzylideneacetone)palladium (14 mg, 0.025 mmol), triphenylphosphine (13 mg, 0.049 mmol) and lithium chloride (78 mg, 1.86 mmol). The mixture is kept at 70° C. overnight. The solution is diluted with ethyl acetate, filtered and washed with water. Preparative thin layer chromatography (8:2 dichloromethane/n-hexane) affords the title compound. Mass M+H 278; mp 145-151° C.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][O:9][C:10]1[C:11]([O:27][CH3:28])=[CH:12][C:13]2[O:18][C:17](=[O:19])[CH:16]=[C:15]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:14]=2[CH:26]=1)(=O)=O.[C:29]1([N:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.CC(OC)(C)C.C([O-])(=O)/C=C/C([O-])=O>C(OCC)C.CC(C)=O.C(O)(C)C>[CH3:28][O:27][C:11]1[C:10]([O:9][CH2:8][CH2:7][CH2:6][N:38]2[CH2:39][CH2:40][N:35]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:36][CH2:37]2)=[CH:26][C:14]2[C:15]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:16][C:17](=[O:19])[O:18][C:13]=2[CH:12]=1
Reactant: COc1cc2oc(=O)cc(-c3ccccc3)c2cc1OCCCOS(C)(=O)=O
Reactant: c1ccc(N2CCNCC2)cc1
Agent: O=C([O-])/C=C/C(=O)[O-]
Solvent: CC(C)=O
Solvent: COC(C)(C)C
Solvent: CCOCC
Product: COc1cc2oc(=O)cc(-c3ccccc3)c2cc1OCCCN1CCN(c2ccccc2)CC1
Yield: 86 %

Procedure:
Method B (60 h at 60° C.); starting materials: 6-[3-(methanesulfonyloxy)propoxy]-7-methoxy-4-phenyl-2H-1-benzopyran-2-one (example 78) and 1-phenylpiperazine; yield 86%; fusion point 139°-141° C. (from TBME and isopropanol). Fumarate: method E; yield 93%; fusion point 145°-147° C. (from acetone and diethylether).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[C:17]([F:25])[C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:14]([O-:16])=[O:15])=[C:9]([CH:13]=1)[C:10](O)=[O:11].S(Cl)([Cl:28])=O>>[Cl:1][C:2]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[C:17]([F:25])[C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:14]([O-:16])=[O:15])=[C:9]([CH:13]=1)[C:10]([Cl:28])=[O:11]
Reactant: O=C(O)c1cc(Oc2c(F)cc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1cc(Oc2c(F)cc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]

Procedure:
5-(2-Chloro-6-fluoro-4-trifluoromethylphenoxy)-2-nitrobenzoic acid (2.5 g) was heated under reflux for 5 hours with thionyl chloride (40 ml). The solution was evaporated under reduced pressure and the yellow oil remaining was taken up in toluene (100 ml). The solution was divided into four portions. Each portion was separately evaporated to give 5-(2-chloro-6-fluoro-4-trifluoromethylphenoxy)-2-nitrobenzoyl chloride as an oil. Three portions were used to prepare esters as follows:
Reaction SMILES: [ClH:1].Cl.Cl.[CH3:4][N:5]1[CH2:10][CH2:9][CH:8]([N:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([NH2:19])[CH:14]=2)[CH3:12])[CH2:7][CH2:6]1.[F:20][C:21]1[CH:29]=[C:28]([F:30])[CH:27]=[C:26]([F:31])[C:22]=1[C:23]([Cl:25])=[O:24]>CO>[ClH:25].[ClH:1].[F:20][C:21]1[CH:29]=[C:28]([F:30])[CH:27]=[C:26]([F:31])[C:22]=1[C:23]([NH:19][C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([N:11]([CH3:12])[CH:8]2[CH2:7][CH2:6][N:5]([CH3:4])[CH2:10][CH2:9]2)[CH:14]=1)=[O:24]
Reactant: O=C(Cl)c1c(F)cc(F)cc1F
Reactant: CN1CCC(N(C)c2cccc(N)c2)CC1
Agent: Cl
Solvent: CO
Product: CN1CCC(N(C)c2cccc(NC(=O)c3c(F)cc(F)cc3F)c2)CC1
Temperature: 106.5 °C
Yield: 47.6 %

Procedure:
Load 1-methyl-4-(N-(3-aminophenyl)-N-methylamino)piperidine trihydrochloride (Preparation 11, 240 mg, 1.094 mmol) in methanol (2 ml) onto a SCX column (2 g cartridge, Varian). Elute with ammonia (2.0 M in methanol) to obtain the corresponding free base. Concentrate to dryness. Dissolve the resulting brown oil in dioxane (2 mL) and divide the solution into two aliquots (2×1 mL). Take one of the aliquots and add dioxane (1 mL). Add 2,4,6-trifluoro-benzoyl chloride (0.052 mL, 0.401 mmol) neat. Shake and heat at 106.5° C. for 2 hr. Cool to ambient temperature and load onto a SCX column (1 g cartridge, Varian). Elute with ammonia (2.0 M in methanol). Purify further by flash chromatography using 20/1 mixture of dichloromethane and 2.0 M ammonia in methanolto provide the free base of the title compound (86 mg, 62%). Following a salt formation method similar to Example 1 gives the title compound as a white solid (99 mg): mp 199–200° C.; mass spectrum (free base, ion spray): m/z=378.2 (M+1), 1H NMR (free base, CDCl3): 7.44 (bs, N—H), 7.31 (bs, 1H), 7.19 (t, J=8.3 Hz, 1H), 6.80–6.73 (m, 3H), 6.60 (dd, J=2.2 Hz, 8.3 Hz, 1H), 3.64 (tt, J=4.0 Hz, 11.9 Hz, 1H), 3.05 (bd, J=10.8 Hz, 2H), 2.81 (s, 3H), 2.38 (s, 3H), 2.28–2.17 (bm, 2H), 2.06–1.92 (bm, 2H), 1.76 (bd, J=12.2 Hz, 2H).
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[C:6](/[CH:9]=[CH:10]/[C:11]3[CH:12]=[C:13]([NH2:17])[CH:14]=[CH:15][CH:16]=3)[S:7][CH:8]=2)[CH2:3][CH2:2]1.[C:18]1(=[O:29])[O:24][C:22](=[O:23])[C:21]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:20]2[CH2:19]1>C1(C)C=CC=CC=1>[CH:1]1([C:4]2[N:5]=[C:6](/[CH:9]=[CH:10]/[C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:29])[CH2:19][C:20]4[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=4[C:22]([OH:24])=[O:23])[CH:14]=[CH:15][CH:16]=3)[S:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: Nc1cccc(/C=C/c2nc(C3CC3)cs2)c1
Reactant: O=C1Cc2ccccc2C(=O)O1
Solvent: Cc1ccccc1
Product: O=C(Cc1ccccc1C(=O)O)Nc1cccc(/C=C/c2nc(C3CC3)cs2)c1
Yield: 88.7 %

Procedure:
A solution of 5.0 g of (E)-3-[2-[4-(cyclopropyl)-2-thiazolyl]ethenyl]benzeneamine, 3.35 g of homophthalic anhydride, and 100 ml of toluene was heated to reflux for 0.5 hr. After cooling, the solids that formed were collected by filtration and this material was triturated with ethyl ether to yield 7.4 g of (E)-2-[2-[3-[2-[4-(cyclopropyl)-2-thiazolyl]ethenyl]phenylamino]-2-oxoethyl]benzoic acid. Recrystallization from acetonitrile yielded 5.1 g of material; m.p. 200°-201° C.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[N:9]1([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:14][CH2:13][CH:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][CH2:10]1.[CH2:27](Cl)[O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C1COCC1>[CH2:29]([O:28][CH2:27][C:12]1([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][CH2:10][N:9]([C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])[CH2:14][CH2:13]1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: ClCOCc1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C1(COCc2ccccc2)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 34.1 %

Procedure:
LDA (2.64 mL, 5.82 mmol) was added to a solution of 1-tert-butyl 4-ethyl piperidine-1,4-dicarboxylate (1 g, 3.88 mmol) in THF (35 ML) at −78° C. The reaction was stirred for 30 min, and then BOMCl (0.6 g, 3.88 mmol) was added. The reaction was allowed to warm to room temperature, and then quenched with aq. NH4Cl. The aqueous layer was extracted with EtOAc, and the organic extract was washed with brine, dried over MgSO4, and concentrated under vacuum. The residue was purified by flash chromatography (80 g SiO2, 0-10% ethylacetate:hexanes) to afford the title compound (0.5 g, 34%). MS (ES+) [M+H]+=378.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.[F:7][C:8]([F:37])([C:12]([F:36])([F:35])[C:13]([F:34])([F:33])[C:14]([F:32])([F:31])[C:15]([F:30])([F:29])[C:16]([F:28])([F:27])[C:17]([F:26])([F:25])[C:18]([F:24])([F:23])[C:19]([F:22])([F:21])[F:20])[C:9](O)=[O:10].[ClH:38]>>[F:7][C:8]([F:37])([C:12]([F:36])([F:35])[C:13]([F:34])([F:33])[C:14]([F:32])([F:31])[C:15]([F:30])([F:29])[C:16]([F:28])([F:27])[C:17]([F:26])([F:25])[C:18]([F:24])([F:23])[C:19]([F:22])([F:21])[F:20])[C:9]([Cl:38])=[O:10]
Reactant: O=C(O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Product: O=C(Cl)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Yield: 70 %

Procedure:
Phosphorus pentachloride (PCl5), (10.53 g, 50 mmol) was added in small portions to perfluorodecanoic acid (25 g, 49 mmol). Although the ensuing reaction was not too exothermic, HCl gas evolution was vigorous. The resulting solution was refluxed for three hours then a second portion of PCl5 (10.53 g, 50 mmol) was added and the mixture refluxed an additional two hours. Distillation afforded 18.25 g (70%) of perfluorodecanoyl chloride as a colorless liquid.
Reaction SMILES: [CH2:1]([C:3]([CH2:8][OH:9])([CH2:6][OH:7])[CH2:4][OH:5])[CH3:2].[CH3:10][C:11]([CH3:13])=O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH3:10][C:11]1([CH3:13])[O:7][CH2:6][C:3]([CH2:1][CH3:2])([CH2:8][OH:9])[CH2:4][O:5]1
Reactant: CC(C)=O
Reactant: CCC(CO)(CO)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CCC1(CO)COC(C)(C)OC1

Procedure:
2-Ethyl-2-hydroxymethyl-propan-1,3-diol (34 g.), acetone (37 ml.) and p-toluenesulphonic acid (0.5 g.) were refluxed in benzene (140 ml.) and water was removed using Dean and Stark apparatus. After ten hours refluxing the mixture was cooled and washed with saturated aqueous sodium hydrogen carbonate solution. The benzene solution was dried over anhydrous magnesium sulphate. The solvent was removed in vacuo. Distillation gave 2,2-dimethyl-5-ethyl-5-hydroxymethyl-1,3-dioxane (35 g.), a colourless oil (bpt) 80°-2° 0.9 mm)2.
Reaction SMILES: [C:1](=[O:27])([O:25][CH3:26])[O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-])=O)[C:6]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH3:19])[CH2:14][CH2:13]2)=[CH:5][C:4]=1[CH:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1>C(O)C.[Pd]>[C:1](=[O:27])([O:25][CH3:26])[O:2][C:3]1[CH:8]=[C:7]([NH2:9])[C:6]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH3:19])[CH2:14][CH2:13]2)=[CH:5][C:4]=1[CH:20]1[CH2:21][CH2:22][CH2:23][CH2:24]1
Reactant: CCN1CCN(c2cc(C3CCCC3)c(OC(=O)OC)cc2[N+](=O)[O-])CC1
Agent: [Pd]
Solvent: CCO
Product: CCN1CCN(c2cc(C3CCCC3)c(OC(=O)OC)cc2N)CC1
Reaction time: 3 h
Yield: 80.4 %

Procedure:
A solution of 2-cyclopentyl-4-(4-ethylpiperazin-1-yl)-5-nitrophenyl methyl carbonate (675 mg, 1.79 mmol) in ethanol (7 mL) treated with 10% Pd/C (68 mg) was stirred under H2 atmosphere for 3 h. The reaction mixture filtered through a plug of silica and washed with methanol. The filtrate was concentrated in vacuo to yield 5-amino-2-cyclopentyl-4-(4-ethylpiperazin-1-yl)phenyl methyl carbonate (500 mg, 80% yield). 1H NMR (400.0 MHz, DMSO-d6) δ 6.83 (d, J=8.4 Hz, 1H), 6.57 (d, J=8.4 Hz, 1H), 4.86 (s, 2H), 3.83 (s, 3H), 2.93-2.82 (m, 5H), 2.62 (d, J=9.4 Hz, 2H), 2.36 (q, J=7.2 Hz, 2H), 2.23-2.20 (m, 2H), 1.82-1.81 (m, 2H), 1.69-1.66 (m, 2H), 1.58-1.55 (m, 2H), 1.42-1.39 (m, 2H), 1.01 (t, J=7.1 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([N:9]2[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]2)[N:5]=[CH:4][N:3]=1.[C:16](O)(=O)[C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1.N>O>[CH3:15][N:12]1[CH2:13][CH2:14][N:9]([C:6]2[N:5]=[CH:4][N:3]=[C:2]3[C:7]=2[NH:8][C:16]([C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)=[N:1]3)[CH2:10][CH2:11]1
Reactant: CN1CCN(c2ncnc(N)c2N)CC1
Reactant: O=C(O)c1ccncc1
Agent: N
Solvent: O
Product: CN1CCN(c2ncnc3nc(-c4ccncc4)[nH]c23)CC1
Reaction time: 4 h
Yield: 35.3 %

Procedure:
A mixture of 3 g of 4,5-diamino-6-(4-methyl-1-piperazinyl) pyrimidine, 1.8 g of isonicotinic acid and 45 g of polyphosphoric acid is stirred at 160°-170° C. for 4 hours under nitrogen atmosphere. To the resultant mixture is added 200 ml of water and the solution is neutralized with an ammonia solution. The crystals precipitated are filtered and washed with water, and then recrystallized from methanol to give 1.5 g of 6-(4- methyl-1-piperazinyl)-8-(4-pyridyl)purine, melting at 333°-335° C.
Reaction SMILES: [C:1]([C:4]1[CH:8]=[CH:7][S:6]C=1)(=O)[CH3:2].[S:9]1[CH:13]=[CH:12][C:11]([C:14]([CH2:16][C:17]#[N:18])=[O:15])=[CH:10]1.C1(=O)CCCC1.N1CCOCC1.[S]>>[NH2:18][C:17]1[S:6][C:7]2[CH2:2][CH2:1][CH2:4][C:8]=2[C:16]=1[C:14]([C:11]1[CH:12]=[CH:13][S:9][CH:10]=1)=[O:15]
Reactant: N#CCC(=O)c1ccsc1
Reactant: CC(=O)c1ccsc1
Agent: [S]
Solvent: C1COCCN1
Solvent: O=C1CCCC1
Product: Nc1sc2c(c1C(=O)c1ccsc1)CCC2
Yield: 71 %

Procedure:
The procedure of Example 1 was followed except that 3-acetylthiophene (Aldrich) was used in place of acetophenone to prepare the corresponding 2-(thiophene-3-carbonyl)acetonitrile (Steps A and B). Cyclopentanone (Aldrich), 2-(thiophene-3-carbonyl)acetonitrile, morpholine, and sulfur were reacted according to the procedure of Step C, Example 1, to afford the desired compound. Yield: 71%; IR (KBr) cm−1: 3330, 3117, 2846, 1569, 1448, 1435, 1265, 855, 836, 757, 715; 1H NMR (CDCl3):δ2.24 (m, 4H), 2.71 (m, 2H), 6.83 (bs, 2H), 7.33 (m, 2H), 7.56 (m, 1H); yellow solid, mp: 125-127° C. (petroleum ether).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:21])[C:9]=1[O:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([CH:18]([CH3:20])[CH3:19])[CH:12]=1)[CH2:5]O.B(Br)(Br)[Br:23]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:21])[C:9]=1[O:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([CH:18]([CH3:20])[CH3:19])[CH:12]=1)[CH2:5][Br:23]
Reactant: BrB(Br)Br
Reactant: CC(C)c1cc(Oc2c(Cl)cc(CO)cc2Cl)ccc1O
Solvent: ClCCl
Product: CC(C)c1cc(Oc2c(Cl)cc(CBr)cc2Cl)ccc1O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 3,5-dichloro-4-(4′-hydroxy-3′-iso-propylphenoxy)benzyl alcohol in CH2Cl2 (5.0 mL) at −78° C. is added BBr3. The reaction mixture is stirred at room temperature for 16 h, poured into ice water and extracted with ethyl acetate. The organic layer is dried over MgSO4, filtered and concentrated under reduced pressure. The crude product is purified by column chromatography on silica gel, eluting with acetone-hexanes to afford 3,5-dichloro-4-(4′-hydroxy-3′-iso-propylphenoxy)benzyl bromide.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[O:12].C(N=P1(N(CC)CC)N(C)CCCN1C)(C)(C)C.[CH3:31][C:32]1[CH:39]=[CH:38][CH:37]=[CH:36][C:33]=1[CH2:34]Br.C(Cl)Cl>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:31][C:32]1[CH:39]=[CH:38][CH:37]=[CH:36][C:33]=1[CH3:34])[C:6](=[O:11])[C:5]2=[O:12]
Reactant: O=C1Nc2ccc(Br)cc2C1=O
Reactant: Cc1ccccc1CBr
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Solvent: CC#N
Solvent: ClCCl
Product: Cc1ccccc1CN1C(=O)C(=O)c2cc(Br)ccc21
Yield: 53 %

Procedure:
Combine 5-bromoisatin (90 mg, 0.4 mmol), 2-tert-butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-diazaphosphorine on polysteyrene (270-290 mg, 0.60-0.64 mmol, 2.2 mmol/g, Fluka) and 2-methylbenzyl bromide (0.054 mL, 0.4 mmol) in acetonitrile (4 mL) in a 20 dram scintillation vial and shake on a rotator for 2.5 days. Dilute with and a small amount of CH2Cl2 as needed to soluabilize solids. Filter off beads, washing with MeOH, and concentrate in vacuo. Triturate the resulting solid with diethyl ether (about 4 mL) and pipet off the liquid. Dry the solid to obtain approximately 70 mg of the title compound as crude material and use without further purification.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][C:5]([CH3:9])([OH:8])[CH2:4][CH2:3]1.[F:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=1[C@H:18]1[CH2:22][CH2:21][CH2:20][N:19]1[C:23]1[CH:28]=[CH:27][N:26]2[N:29]=[CH:30][C:31]([C:32](O)=[O:33])=[C:25]2[N:24]=1>>[F:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=1[C@H:18]1[CH2:22][CH2:21][CH2:20][N:19]1[C:23]1[CH:28]=[CH:27][N:26]2[N:29]=[CH:30][C:31]([C:32]([NH:1][CH:2]3[CH2:7][CH2:6][C:5]([OH:8])([CH3:9])[CH2:4][CH2:3]3)=[O:33])=[C:25]2[N:24]=1
Reactant: CC1(O)CCC(N)CC1
Reactant: O=C(O)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)nc12
Product: CC1(O)CCC(NC(=O)c2cnn3ccc(N4CCC[C@@H]4c4cc(F)ccc4F)nc23)CC1
Yield: 48 %

Procedure:
The minor isomer from Step A (45.1 mg, 0.197 mmol) was dissolved in DCM (1.0 mL) and 4N HCl in dioxane (492 μL, 1.97 mmol) was added. The reaction mixture was stirred at ambient temperature for 1 hour and was concentrated to afford 4-amino-1-methylcyclohexanol (minor isomer). The 4-amino-1-methylcyclohexanol was reacted with (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (Preparation C) according to the procedure outlined in Example 1 to provide the title product as a white solid (14 mg, 48% yield). MS (apci) m/z=456.1 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.[NH2:44][C:45]1[S:46][C:47]2[C:53]([N:54]([CH3:58])[C:55](=[O:57])[CH3:56])=[CH:52][CH:51]=[C:50]([O:59][CH3:60])[C:48]=2[N:49]=1>C1COCC1>[C:55]([N:54]([CH3:58])[C:53]1[C:47]2[S:46][C:45]([NH:44][C:6](=[O:8])[C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:10][CH:9]=3)=[N:49][C:48]=2[C:50]([O:59][CH3:60])=[CH:51][CH:52]=1)(=[O:57])[CH3:56]
Reactant: O=C(O)c1ccc(F)cc1
Reactant: COc1ccc(N(C)C(C)=O)c2sc(N)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(N(C)C(C)=O)c2sc(NC(=O)c3ccc(F)cc3)nc12
Reaction time: 2 h
Yield: 24.3 %

Procedure:
To a stirred solution of 31 mg (0.22 mmol) 4-fluoro-benzoic acid in 2 ml THF were added 89 mg (0.23 mmol) HATU and 0.07 ml (0.44 mmol) N-ethyldiisopropylamine and stirring continued at room temperature for 2 h. 28 mg (0.11 mmol) N-(2-amino-4-methoxy-benzothiazol-7-yl)-N-methyl-acetamide was then added and stirring continued at 50° C. for 16 h. The reaction mixture was then concentrated in vacuo. Flash chromatography (dichloromethane/methanol 50/1) followed by trituration in ether afforded 10 mg (24%) N-[7-(acetyl-methyl-amino)-4-methoxy-benzothiazol-2-yl]-4-fluoro-benzamide as a white crystalline solid. ES-MS m/e (%o): 374 (M+H+, 100).