Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC(C)C)(C)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:27]1([CH2:33][CH2:34][OH:35])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.O[C:37]1[C:38]([CH:60]2[CH2:64][CH2:63][CH2:62][N:61]2[C:65](=[O:67])[CH3:66])=[CH:39][C:40]2[N:44]([CH2:45][O:46][CH2:47][CH2:48][Si:49]([CH3:52])([CH3:51])[CH3:50])[C:43]([C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][N:54]=3)=[N:42][C:41]=2[CH:59]=1.C(=O)(O)[O-].[Na+]>O1CCCC1>[CH2:34]([O:35][C:37]1[C:38]([CH:60]2[CH2:64][CH2:63][CH2:62][N:61]2[C:65](=[O:67])[CH3:66])=[CH:39][C:40]2[N:44]([CH2:45][O:46][CH2:47][CH2:48][Si:49]([CH3:52])([CH3:51])[CH3:50])[C:43]([C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][N:54]=3)=[N:42][C:41]=2[CH:59]=1)[CH2:33][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: OCCc1ccccc1
Reactant: CC(=O)N1CCCC1c1cc2c(cc1O)nc(-c1ccccn1)n2COCC[Si](C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(=O)N1CCCC1c1cc2c(cc1OCCc1ccccc1)nc(-c1ccccn1)n2COCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 6 h

Procedure:
0.019 ml of diisopropylamine, 27.6 mg of triphenyl phosphine and 0.011 ml of 2-phenyl-ethanol were added in order to a tetrahydrofuran (1 ml) solution of 29.2 mg of 1-(2-(6-hydroxy-2-pyridin-2-yl-3-(2-trimethylsilanyl-ethoxymethyl)-3H-benzimidazol-5-yl)pyrrolidin-1-yl)-ethanone obtained in Example 121 (step 10), and the reaction liquid was stirred for 6 hours at room temperature. 0.040 ml of diisopropylamine, 53.2 mg of triphenyl phosphine and 0.023 ml of 2-phenyl-ethanol were added in order to the reaction liquid, and the reaction liquid was stirred overnight at room temperature. Aqueous saturated sodium bicarbonate was added to the reaction liquid, and this was extracted with ethyl acetate, and dried with anhydrous magnesium sulfate. The solvent was evaporated away under reduced pressure, and the resulting residue was purified through partitioning thin-layer chromatography (Kieselgel™ 60F254, Art 5744 (by Merck), ethyl acetate) to obtain the entitled compound as a brown oily substance.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH3:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][CH:25]=1)[NH2:22]>>[ClH:1].[CH3:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][CH:25]=1)[NH:22][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: Cc1cccc(N)c1
Reactant: Clc1ncnc2ccc(N3CCOCC3)cc12
Product: Cc1cccc(Nc2ncnc3ccc(N4CCOCC4)cc23)c1
Product: Cl
Yield: 76 %

Procedure:
Using an analogous procedure to that described in Example 1, 4-chloro-6-morpholinoquinazoline was reacted with 3-methylaniline to give 4-(3'-methylanilino)-6-morpholinoquinazoline hydrochloride in 76% yield, m.p. 276°-278° C. NMR Spectrum: (CD3SOCD3) 2.38 (s, 3H), 3.41 (m, 4H), 3.82 (m, 4H), 7.18 (d, 1H), 7.38 (m, 1H), 7.48 (s, 1H), 7.50 (d, 1H), 7.87 (s, 2H), 8.08 (s, 1H), 8.75 (s, 1H); Elemental Analysis: Found C, 63.9; H, 6.0; N, 15.4; C19H20N4O 1HCl requires C, 64.1; H, 5.9; N, 15.8%.
Reaction SMILES: [Br:1][C:2]1[C:6]2[CH:7]=[N:8][C:9]([N+:12]([O-])=O)=[C:10]([OH:11])[C:5]=2[O:4][CH:3]=1.[C:15]1([CH2:21][CH:22](O)[CH3:23])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.ClC1C(F)=CC=C(Cl)C=1[C@H](OC1C2OC=CC=2C=NC=1[N+]([O-])=O)C>[Fe].Cl>[Br:1][C:2]1[C:6]2[CH:7]=[N:8][C:9]([NH2:12])=[C:10]([O:11][CH:22]([CH3:23])[CH2:21][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:5]=2[O:4][CH:3]=1
Reactant: CC(O)Cc1ccccc1
Reactant: O=[N+]([O-])c1ncc2c(Br)coc2c1O
Agent: [Fe]
Agent: C[C@@H](Oc1c([N+](=O)[O-])ncc2ccoc12)c1c(Cl)ccc(F)c1Cl
Agent: Cl
Product: CC(Cc1ccccc1)Oc1c(N)ncc2c(Br)coc12

Procedure:
3-Bromo-6-nitrofuro[3,2-c]pyridin-7-ol (Intermediate 10) was reacted with racemic 1-phenylpropan-2-ol following the procedure described for Intermediate 8. The resulting intermediate was reacted with iron/HCl as described in Example 2 to give the title compound. MS (ES+): m/z 347.22/349.23 (100/99) [MH+]. HPLC: tR=0.81 min (HPLC-ACQUITY, Analytical). 1H NMR (400 MHz, CD3OD): δ=1.32 (d, J=6.1 Hz, 3H), 2.93 (dd, J=13.5, 6.2 Hz, 1H), 3.10 (dd, J=13.6, 6.6 Hz, 1H), 4.98 (m, 1H), 7.13-7.21 (m, 1H), 7.25 (d, J=4.3 Hz, 4H), 7.70 (s, 1H), 7.82 (s, 1H).
Reaction SMILES: [Ti:1].[S:2](=[O:6])(=[O:5])([OH:4])[OH:3]>>[S:2]([O-:6])([O-:5])(=[O:4])=[O:3].[Ti+4:1].[S:2]([O-:6])([O-:5])(=[O:4])=[O:3]
Reactant: O=S(=O)(O)O
Reactant: [Ti]
Product: O=S(=O)([O-])[O-]
Product: [Ti+4]

Procedure:
A titanium ore was reacted with sulfuric acid to obtain a titanium sulfate solution, which was then subjected to thermal hydrolysis to obtain an agglomerated metatitanic acid. An aqueous slurry of 30% by weight in terms of TiO 2 was prepared therefrom and this slurry was adjusted to pH 7 with aqueous ammonia, then filtered and washed to remove sulfate. To the resulting dehydrated cake was added 35% hydrochloric acid to carry out peptization to obtain a titania sol of pH 1.5 and containing 1.5% by weight of HCl.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(Cl)(Cl)=O.[CH3:16]O>>[Cl:1][C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:16])=[O:5]
Reactant: CO
Reactant: O=C(O)c1ccc(Cl)nc1Cl
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(Cl)nc1Cl

Procedure:
To a solution of 2,6-dichloronicotinic acid (50 g, 0.26 mol) in methanol (250 mL) was added thionyl chloride (22.7 mL, 0.312 mol) slowly. The mixture was refluxed for 4 hours and concentrated to give methyl 2,6-dichloronicotinate as a white solid in quantitative yield.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[C:13]([C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=1[F:24])=[N:12][C:11]([NH:25][C:26]1[CH:30]=[C:29]([CH3:31])[NH:28][N:27]=1)=[CH:10]2)(=O)=O.[NH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1.N12CCCNC1CCCC=C2.[O:51]1CCC[CH2:52]1>CC([O-])=O.CC([O-])=O.[Pd+2]>[F:24][C:18]1[CH:19]=[C:20]([F:23])[CH:21]=[CH:22][C:17]=1[C:13]1[C:14]2[C:9](=[CH:8][C:7]([C:52]([N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[O:51])=[CH:16][CH:15]=2)[CH:10]=[C:11]([NH:25][C:26]2[CH:30]=[C:29]([CH3:31])[NH:28][N:27]=2)[N:12]=1
Reactant: Cc1cc(Nc2cc3cc(OS(=O)(=O)C(F)(F)F)ccc3c(-c3ccc(F)cc3F)n2)n[nH]1
Reactant: C1CCOC1
Reactant: C1COCCN1
Agent: [Pd+2]
Agent: C1=CN2CCCNC2CCC1
Agent: CC(=O)[O-]
Product: Cc1cc(Nc2cc3cc(C(=O)N4CCOCC4)ccc3c(-c3ccc(F)cc3F)n2)n[nH]1
Temperature: 150 °C

Procedure:
A 0.5-2.0 mL process vial was charged with 1-(2,4-difluoro-phenyl)-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinolin-6-yl trifluoromethanesulfonate (24.3 mg), Pd(OAc)2 (2 mg), Mo(CO)6 (13.2 mg), morpholine (13.0 mg), 1,8-Diazabicyclo[5.4.0]undecen (DBU) (22.9 mg), and dry tetrahydrofuran (THF) (1 mL). The vial was immediately capped under air and heated at 150° C. for 15 min under microwave irradiation. After cooling, the reaction mixture was filtered through a short silica gel column, and the solvent was removed under reduced pressure. The residue was sent to prep-HPLC to get 5 mg of [1-(2,4-difluoro-phenyl)-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinolin-6-yl]-morpholin-4-yl-methanone as a yellow solid. LC-MS m/e 450 MH+. 1H NMR (400 MHz, CDCl3) 7.74(s, 1H), 7.70(s, 1H), 7.66(m, 1H), 7.54(m, 1H), 7.24(m, 1H), 7.10(t, 1H), 7.02(t, 1H), 6.00(s, 1H), 3.83˜3.48(m, 8H), 2.33(s, 3H).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]([O:13][CH2:14][CH2:15][CH3:16])=[C:8]([CH:12]=1)[C:9]([NH2:11])=[NH:10].[O:17]=[C:18]1NC(C2C=CC=CC=2OCC=C)=N[CH:20]=[C:19]1[C:34]([O:36][CH2:37][CH3:38])=[O:35]>>[O:17]=[C:18]1[NH:11][C:9]([C:8]2[CH:12]=[C:4]([O:3][CH3:2])[CH:5]=[CH:6][C:7]=2[O:13][CH2:14][CH2:15][CH3:16])=[N:10][CH:20]=[C:19]1[C:34]([O:36][CH2:37][CH3:38])=[O:35]
Reactant: C=CCOc1ccccc1-c1ncc(C(=O)OCC)c(=O)[nH]1
Reactant: CCCOc1ccc(OC)cc1C(=N)N
Agent: Cl
Product: CCCOc1ccc(OC)cc1-c1ncc(C(=O)OCC)c(=O)[nH]1

Procedure:
The title compound was prepared from 5-methoxy-2 -n-propoxybenzamidine hydrochloride in a manner similar to that described for the preparation of ethyl 1,6-dihydro-6 -oxo-2-(2-allyloxyphenyl)pyrimidine-5-carboxylate in Preparation 29. The product had m.p. 124°-126°.
Reaction SMILES: [OH:1][CH:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12](=[O:14])[CH3:13])=[CH:9][CH:10]=2)[C:5]([CH3:16])([CH3:15])[CH2:4][CH2:3]1.[CH3:17][O:18][CH2:19]Cl.[CH2:21](N(CC)CC)C>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl>[CH3:17][O:18][CH2:19][CH2:21][O:1][CH:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12](=[O:14])[CH3:13])=[CH:9][CH:10]=2)[C:5]([CH3:16])([CH3:15])[CH2:4][CH2:3]1
Reactant: CCN(CC)CC
Reactant: COCCl
Reactant: CC(=O)c1ccc2c(c1)C(C)(C)CCC2O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: ClCCl
Product: COCCOC1CCC(C)(C)c2cc(C(C)=O)ccc21
Yield: 58.6 %

Procedure:
A solution of (+/-) 1-hydroxy-6-acetyl-1,2,3,4-tetrahydro-4,4-dimethyl-naphthalene (Compound D25, 24.8 mg, 0.11 mmol), chloromethyl methyl ether (0.12 mmol), triethyl amine (0.02 ml, 0.13 mmol) and catalytic amount of tetrabutylammonium bromide in 2 ml of CH2Cl2 was stirred at room temperature for 5 h. Purification by column chromatography (silica) with ethyl acetate/hexane (1/10) afforded the title compound as an oil (17.8 mg).
Reaction SMILES: [Br:1][CH2:2][CH:3]([CH2:14][O:15]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:4][CH2:5][N:6]1[CH:11]=[CH:10][C:9](=[O:12])[NH:8][C:7]1=[O:13].CC1C=CC(S(O)(=O)=O)=CC=1.O.C(Cl)(Cl)Cl.CO>CO>[Br:1][CH2:2][CH:3]([CH2:14][OH:15])[CH2:4][CH2:5][N:6]1[CH:11]=[CH:10][C:9](=[O:12])[NH:8][C:7]1=[O:13]
Reactant: O=c1ccn(CCC(CBr)COC(c2ccccc2)(c2ccccc2)c2ccccc2)c(=O)[nH]1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: O
Product: O=c1ccn(CCC(CO)CBr)c(=O)[nH]1

Procedure:
A solution of compound 37 (22 g, 0.042 mol) in methanol (100 mL) was treated with PTSA. H2O (0.80 g, 0.0042 mol) and stirred for 6 h at RT. The reaction mixture was concentrated under vacuum and the crude compound was used for next reaction (10.5 g, crude product). TLC: Chloroform/Methanol, 1:1, Rf=0.2
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[O:4][C:3]=1[CH:13]([O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH3:14].C1(C)C=CC=CC=1.C([Sn](CCCC)(CCCC)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=1)CCC>>[Si:16]([O:15][CH:13]([C:3]1[O:4][C:5](=[O:12])[C:6]2[C:11]([C:2]=1[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH3:14])([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]
Reactant: CC(O[Si](C)(C)C(C)(C)C)c1oc(=O)c2ccccc2c1Br
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Solvent: Cc1ccccc1
Product: CC(O[Si](C)(C)C(C)(C)C)c1oc(=O)c2ccccc2c1-c1ccccn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a degassed solution of 4-bromo-3-(1-((tert-butyldimethylsilyl)oxy)ethyl)-1H-isochromen-1-one (intermediate A8, 2 g, 5.22 mmol) in toluene (30 ml) PdCl2(PPh3)2 (0.183 g, 0.261 mmol) was added followed by 2-(tributylstannyl)pyridine (4.55 ml, 10.44 mmol) and the resulting mixture was heated to reflux overnight. The mixture was allowed to cool to RT and then and filtered through a celite pad. The solvent was removed in vacuo, the crude was dissolved in AcOEt and an aqueous sat. sol of KF was added and the mixture was stirred for 2 hrs. The organic phase was separated, dried over sodium sulfate and evaporated to dryness. The crude was purified by flash chromatography on silica gel Biotage cartridge (cyclohexane to cyclohexane:EtOAc=20:80) to afford 3-(1-((tert-butyldimethylsilyl)oxy)ethyl)-4-(pyridin-2-yl)-1H-isochromen-1-one as a pale yellow oil (Intermediate B58.1, 0.508 g, 1.33 mmol).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:13]=1[OH:14])[C:8]([OH:10])=[O:9])([CH3:4])([CH3:3])[CH3:2].[N+:19]([C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH2:29]O)=[CH:24][CH:23]=1)([O-:21])=[O:20].C1(N=C=NC2CCCCC2)CCCCC1>C1COCC1>[CH3:2][C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:13]=1[OH:14])[C:8]([O:10][CH2:29][CH2:28][C:25]1[CH:24]=[CH:23][C:22]([N+:19]([O-:21])=[O:20])=[CH:27][CH:26]=1)=[O:9])([CH3:4])[CH3:3]
Reactant: O=[N+]([O-])c1ccc(CCO)cc1
Reactant: CC(C)(C)c1cc(C(=O)O)cc(C(C)(C)C)c1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(C(=O)OCCc2ccc([N+](=O)[O-])cc2)cc(C(C)(C)C)c1O
Temperature: 20 °C
Reaction time: 15 h

Procedure:
In a 250 ml flask containing 80 ml of THF, under an argon atmosphere, 2.45 g (9.8 mmoles) of 3,5-di-tert-butyl-4-hydroxybenzoic acid, 1.8 g (10.8 mmoles) of 4-nitrobenzene-ethanol and 2.2 g (10.8 mrnmoles) of dicyclohexylcarbodiimide are introduced successively, under agitation. The reaction medium is agitated for 15 hours at 20° C. and the precipitate which appears is filtered out. The filtrate is washed with 2×30 ml of a saturated NaCl solution, the organic phase is dried over magnesium sulphate, filtered and concentrated under vacuum. The residue is then crystallized using di-isopropyl ether. The solid is recovered by filtration and 2.4 g (62%) of white crystals are obtained after drying. Melting point: 123.5-124.5 ° C.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:17][CH2:18][O:19][CH2:20][C:21]#[C:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH2:15])[C:8]=2[N:16]=1)[CH3:2].[ClH:29]>C(OCC)C>[ClH:29].[CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:17][CH2:18][O:19][CH2:20][CH2:21][CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH2:15])[C:8]=2[N:16]=1)[CH3:2]
Reactant: CCOCc1nc2c(N)nc(C)c(C)c2n1CCOCC#Cc1ccccc1
Agent: Cl
Solvent: CCOCC
Product: CCOCc1nc2c(N)nc(C)c(C)c2n1CCOCCCc1ccccc1
Reaction time: 18 h

Procedure:
The general method described in Example 112 was used to hydrogenate 2-ethoxymethyl-6,7-dimethyl-1-{2-[(3-phenylprop-2-ynyl)oxy]ethyl}-1H-imidazo[4,5-c]pyridin-4-amine (1.17 g, 3.09 mmol), prepared as described in Example 122. The reaction was complete after 18 hours. The crude product, isolated as an oil, was dissolved with diethyl ether (20 mL) and treated with a 1 M solution of hydrochloric acid in diethyl ether. The resulting salt was isolated by filtration, dried under reduced pressure, and recrystallized from ethyl acetate. The crystals, obtained in two crops, were dried for three hours under high vacuum at 60° C. to provide 0.777 g of 2-ethoxymethyl-6,7-dimethyl-1-[2-(3-phenylpropoxy)ethyl]-1H-imidazo[4,5-c]pyridin-4-amine hydrochloride as a white powder, mp 128–130° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8](=[O:15])OCC(Cl)(Cl)Cl)[N:2]=1.[F:16][C:17]1[CH:18]=[C:19]([C:23]2[N:24]=[C:25]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)[S:26][CH:27]=2)[CH:20]=[CH:21][CH:22]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[F:16][C:17]1[CH:18]=[C:19]([C:23]2[N:24]=[C:25]([N:28]3[CH2:29][CH2:30][N:31]([C:8]([NH:7][C:3]4[N:2]=[N:1][CH:6]=[CH:5][CH:4]=4)=[O:15])[CH2:32][CH2:33]3)[S:26][CH:27]=2)[CH:20]=[CH:21][CH:22]=1
Reactant: Fc1cccc(-c2csc(N3CCNCC3)n2)c1
Reactant: O=C(Nc1cccnn1)OCC(Cl)(Cl)Cl
Solvent: O
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cccnn1)N1CCN(c2nc(-c3cccc(F)c3)cs2)CC1
Temperature: 70 °C
Reaction time: 72 h
Yield: 28.1 %

Procedure:
A mixture of 2,2,2-trichloroethyl pyridazin-3-ylcarbamate (226 mg, 0.835 mmol), 4-[4-(3-fluorophenyl)-1,3-thiazol-2-yl]piperazine (200 mg, 0.760 mmol) and diisopropylethylamine (0.265 ml, 1.52 mmol) in dimethylsulfoxide (2.5 ml) was stirred at 70° C. for 3 days. Water was poured into the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) and recrystallized from a mixed solvent of hexane and tetrahydrofuran to give the desired product (92.7 ml, 28.1%) as a solid. mp 176-177° C.
Reaction SMILES: OC(C(F)(F)F)=O.[C:8]1([N:14]2[CH2:19][CH2:18][N:17]([CH2:20][C:21]3[N:22]=[C:23]([NH:26]C(=O)C)[S:24][CH:25]=3)[CH2:16][CH2:15]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl>C1COCC1>[C:8]1([N:14]2[CH2:19][CH2:18][N:17]([CH2:20][C:21]3[N:22]=[C:23]([NH2:26])[S:24][CH:25]=3)[CH2:16][CH2:15]2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC(=O)Nc1nc(CN2CCN(c3ccccc3)CC2)cs1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: Nc1nc(CN2CCN(c3ccccc3)CC2)cs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
To a solution of N-(4-((4-phenylpiperazin-1-yl)methyl) thiazol-2-yl)acetamide TFA salt (30 mg, 0.07 mmol) in THF (2 ml) was added 6N hydrochloric acid (2 ml). The reaction was heated at reflux for 2.5 hours, and then stirred at room temperature overnight. The reaction mixture was concentrated under vacuum to give the hydrochloride salt of 4-((4-phenylpiperazin-1-yl)methyl)thiazol-2-amine 94a as a tan solid, 20 mg (92% yield). LC/MS m/z 275.24 (M+H)+); HPLC Rt: 0.77 min.
Reaction SMILES: NC1C(O)=NC=C([Br:8])C=1.[Sn](Cl)Cl.[N+:13]([C:16]1[C:17](O)=[N:18][CH:19]=[CH:20][CH:21]=1)([O-])=O.[CH:23]([OH:25])=O>>[Br:8][C:19]1[N:18]=[C:17]2[O:25][CH:23]=[N:13][C:16]2=[CH:21][CH:20]=1
Reactant: Nc1cc(Br)cnc1O
Reactant: O=[N+]([O-])c1cccnc1O
Reactant: O=CO
Agent: Cl[Sn]Cl
Product: Brc1ccc2ncoc2n1

Procedure:
5-Bromooxazolo[5,4-b]pyridine, isomeric by orientation of ring fusion to the previously described 6-bromooxazolo[4,5-b]pyridine, can also be used in the Heck coupling with N-methyl-N-(tert-butoxycarbonyl)-4-penten-2-amine. Subsequent removal of the tert-butoxycarbonyl protecting group provides (4E)-N-methyl-5-(5-oxazolo[5,4-b]pyridinyl)-4-penten-2-amine. The required 5-bromooxazolo[5,4-b]pyridine is synthesized from 3-amino-5-bromo-2-pyridinol (3-amino-5-bromo-2-pyridone) by the condensation with formic acid (or a derivative thereof) as described above. 3-Amino-5-bromo-2-pyridinol can be made by bromination (using techniques described by T. Batkowski, Rocz. Chem. 41: 729-741 (1967)) and subsequent tin(II) chloride reduction (according to the method described by S. X. Cai et al., J. Med. Chem. 40(22): 3679-3686 (1997)) of commercially available 3-nitro-2-pyridinol (Aldrich Chemical Company).
Reaction SMILES: [CH2:1]([O:8][CH:9]1[CH2:14][C:13]([CH3:16])([CH3:15])[NH:12][C:11]([CH3:18])([CH3:17])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]>C(O)C>[CH2:1]([O:8][CH:9]1[CH2:14][C:13]([CH3:16])([CH3:15])[N:12]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:11]([CH3:18])([CH3:17])[CH2:10]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CBr
Reactant: CC1(C)CC(OCc2ccccc2)CC(C)(C)N1
Solvent: CCO
Product: CCOC(=O)CN1C(C)(C)CC(OCc2ccccc2)CC1(C)C

Procedure:
A mixture of 4-benzyloxy-2,2,6,6-tetramethylpiperidine and 1.67 parts of ethyl α-bromoacetate in 30 parts of ethyl alcohol was heated under reflux conditions for 115 hours. The ethyl alcohol solvent was removed by distillation under reduced pressure and the residue fractionally distilled to give 4-benzyloxy-1-ethoxycarbonylmethyl-2,2,6,6-tetramethylpiperidine having a boiling point of 145°-6° C at 0.2 m.m. of Hg. and the following elemental analysis by weight:
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][C:2]=1[CH2:11][C:12](=O)[CH3:13].[C-:15]#[N:16].[K+].[NH4+:18].[Cl-]>CO.O>[NH2:18][C:12]([CH3:13])([CH2:11][C:2]1[CH2:3][CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1)[C:15]#[N:16]
Reactant: CC(=O)CC1=Cc2ccccc2CC1
Reactant: [NH4+]
Reactant: [C-]#N
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC(N)(C#N)CC1=Cc2ccccc2CC1
Temperature: 20 °C
Reaction time: 72 h

Procedure:
To a solution of 6.50 g (35 mmol) of 1-(3,4-dihydronaphth-2-yl)propan-2-one in a mixture of 41 ml of CH3OH and 20 ml of water there are added, in succession, all at once, 2.34 g (36 mmol) of KCN and 1.93 g (36 mmol) of NH4Cl. After stirring for 72 hours at 20° C., the mixture is diluted with H2O and extracted with CH2Cl2 (4×50 ml). The solvents are evaporated off; the residue is taken up in Et2O and extracted again with 1N HCl (3×40 ml). The combined aqueous phases are rendered alkaline with 6N NaOH and then extracted with CH2Cl2 (3×50 ml). After drying and concentrating the organic phases, the title compound is obtained in the form of a yellow oil, which is used directly for the following reaction.
Reaction SMILES: [CH2:1]1[O:5][C@@H:4]2[C@H:6]([OH:9])[CH2:7][O:8][C@@H:3]2[C@@H:2]1[OH:10].[C:11]1([CH3:21])[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1.[OH-:22].[K+]>C(Cl)(Cl)(Cl)Cl.ClCCl.O>[CH3:21][C:11]1[CH:16]=[CH:15][C:14]([S:17]([O:10][C@@H:2]2[CH2:1][O:5][C@@H:4]3[C@H:6]([O:9][S:17]([C:14]4[CH:15]=[CH:16][C:11]([CH3:21])=[CH:12][CH:13]=4)(=[O:18])=[O:22])[CH2:7][O:8][C@H:3]23)(=[O:19])=[O:18])=[CH:13][CH:12]=1
Reactant: [OH-]
Reactant: O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [K+]
Solvent: ClCCl
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1ccc(S(=O)(=O)O[C@@H]2CO[C@H]3[C@@H]2OC[C@H]3OS(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 0 °C
Yield: 48.2 %

Procedure:
Isomannide (40) (50 g, 342.5 mmol) and p-toluenesulphonyl chloride (143.6 g, 753.2 mmol) were dissolved in a mixture of carbon tetrachloride (300 mL), dichloromethane (30 mL) and water (250 mL). The flask was cooled to 0° C. and a solution of potassium hydroxide (42.0 g, 750.0 mmol) in water (42 mL) added dropwise over 2 hours with stirring under argon. The resulting biphasic mixture was stirred vigorously at 0° C. for 24 hours. The resulting off-white precipitate, comprising a mixture of mono- and bistosylates (approximately 1:1), was collected by filtration in vacuo. The filter cake was washed with water then triturated with methanol (500 mL). The solid was isolated by filtration in vacuo to obtain ditosylate (39) as an off-white powder (75 g, 48%). [α]D18+96.7° (c=10.5, CHCl3).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[N:7]1[CH2:10][C:9]2([CH2:13][NH:12][CH2:11]2)[CH2:8]1.[Cl:14][C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=1[CH2:22][N:23]=[C:24]=[O:25]>>[Cl:14][C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=1[CH2:22][NH:23][C:24]([N:12]1[CH2:13][C:9]2([CH2:10][N:7]([C:2]3[N:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[CH2:8]2)[CH2:11]1)=[O:25]
Reactant: O=C=NCc1ccc(Cl)cc1Cl
Reactant: c1cnc(N2CC3(CNC3)C2)nc1
Product: O=C(NCc1ccc(Cl)cc1Cl)N1CC2(C1)CN(c1ncccn1)C2
Yield: 62 %

Procedure:
In analogy to the experimental procedure of example 1a) 2-Pyrimidin-2-yl-2,6-diaza-spiro[3.3]heptane instead of 6-(tert-butoxycarbonyl)-2,6-diaza-spiro[3.3]heptane oxalate was converted using 2,4-dichloro-1-(isocyanatomethyl)benzene into the title compound (32 mg, 62%) which was obtained as a colorless solid. MS (EI) m/e: 378.1 (M+H)+.