Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[CH2:16]([O:23][C:24]1[CH:38]=[CH:37][C:36]([O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[CH:35][C:25]=1[C:26]([NH:28][CH2:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[O:27])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[C:47]([NH:50][C:51]1[CH:60]=[CH:59][C:54]([O:55][CH2:56][CH2:57]O)=[CH:53][CH:52]=1)(=[O:49])[CH3:48]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:16]([O:23][C:24]1[CH:38]=[CH:37][C:36]([O:39][CH2:40][C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)=[CH:35][C:25]=1[C:26]([NH:28][CH2:29][CH2:30][CH2:31][C:32]([O:34][CH2:57][CH2:56][O:55][C:54]1[CH:59]=[CH:60][C:51]([NH:50][C:47](=[O:49])[CH3:48])=[CH:52][CH:53]=1)=[O:33])=[O:27])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(=O)Nc1ccc(OCCO)cc1
Reactant: O=C(O)CCCNC(=O)c1cc(OCc2ccccc2)ccc1OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(=O)Nc1ccc(OCCOC(=O)CCCNC(=O)c2cc(OCc3ccccc3)ccc2OCc2ccccc2)cc1
Yield: 55 %

Procedure:
0.57 g (2.75 mmol) of dicyclohexylcarbodiimide was portionwise added to a solution of 1.05 g (2.5 mmol) of 4-{N-[2,5-di(benzyloxy)benzoyl]amino}butyric acid (compound of Example 1) in 16 ml of anhydrous methylene chloride at room temperature under stirring. After stirring the solution at the same temperature for 10 minutes 0.54 g (2.75 mmol) of 2-[4-(acetylamino)phenoxy]ethanol and 0.03 g (0.25 mmol) of 4-(N,N-dimethyl-amino)pyridine were added. The reaction mixture was stirred at room temperature for 4 hours, then diluted with methylene chloride and the solid product was filtered. The filtrate was successively washed with 5% acetic acid, 5% sodium hydrogen carbonate solution and water, then dried and evaporated under reduced pressure. The residue was separated by chromatography on a silica gel column by eluating with a 95:5 mixture of chloroform and methanol to obtain 0.82 g (55%) of the aimed product, m.p.: 141°-143° C.
Reaction SMILES: [O:1]1[CH2:5][C@@H:4]([NH2:6])[C@H:3]([NH2:7])[CH2:2]1.C([Li])CCC.[C:13](OC([O-])=O)([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].[Cl-].[Na+]>O1CCCC1>[C:16]([O:15][C:13](=[O:14])[NH:6][C@@H:4]1[CH2:5][O:1][CH2:2][C@H:3]1[NH2:7])([CH3:19])([CH3:18])[CH3:17]
Reactant: N[C@@H]1COC[C@H]1N
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H]1COC[C@H]1N
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 26.2 %

Procedure:
A flame-dried round bottom flask under nitrogen was charged with dry tetrahydrofuran (17 mL) and ((3S,4S)-tetrahydro-3,4-furandiamine (170 mg, 1.70 mmol) prepared according to the procedures of Skarzewski, J., et al. Tetrahedron: Asymmetry 1997, 8 (11), 1861. The solution was cooled to −78° C., and 2.5 M n-butyl lithium in hexanes (700 μL, 1.75 mmol) was added. The resulting cloudy white suspension was warmed to 23° C., and the suspension became orange. After 10 min, tert-butyl dicarbonate (371 mg, 1.70 mmol) was added in one portion. An additional 100 mg-portion of tert-butyl dicarbonate was added after 10 min. The reaction was then poured into saturated aqueous sodium chloride (50 mL), and the aqueous layer was washed with ethyl acetate (4×20 mL). The combined organic layers were dried over sodium sulfate, concentrated, and the resulting residue was purified by flash chromatography (5–10% methanol in dichloromethane) to yield the desired amine (90 mg, 26%) as a yellow oil. MS (ESI) 203 (M+H).
Reaction SMILES: [CH3:1][C:2]([CH3:29])([CH3:28])[C:3]([C:5]1[CH:27]=[CH:26][C:8]([C:9]([NH:11][C:12](=[O:25])[C:13]2[CH:18]=[CH:17][C:16]([C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:15][CH:14]=2)=[O:10])=[CH:7][CH:6]=1)=[O:4].[CH3:30]C(C)(C)C(C1C=CC(C(NC)=O)=CC=1)=O>>[CH3:1][C:2]([CH3:29])([CH3:28])[C:3]([C:5]1[CH:27]=[CH:26][C:8]([C:9]([N:11]([CH3:30])[C:12](=[O:25])[C:13]2[CH:18]=[CH:17][C:16]([C:19](=[O:24])[C:20]([CH3:21])([CH3:22])[CH3:23])=[CH:15][CH:14]=2)=[O:10])=[CH:7][CH:6]=1)=[O:4]
Reactant: CC(C)(C)C(=O)c1ccc(C(=O)NC(=O)c2ccc(C(=O)C(C)(C)C)cc2)cc1
Reactant: CNC(=O)c1ccc(C(=O)C(C)(C)C)cc1
Product: CN(C(=O)c1ccc(C(=O)C(C)(C)C)cc1)C(=O)c1ccc(C(=O)C(C)(C)C)cc1

Procedure:
Following the above procedure, but using in place of the 4-(2,2-dimethyl-1-oxopropyl)-benzamide an equivalent amount of 4-(2,2-dimethyl-1-oxopropyl)-N-methylbenzamide, there is obtained 4-(2,2-dimethyl-1-oxopropyl)-N-methyl-N-[4-(2,2-dimethyl-1-oxopropyl)-benzoyl]-benzamide (m.p. 121.5°-122.5° C.).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[N:3][N:2]=1.[H][H]>[Pd].[Ni].CO>[C:5]1([CH2:4][NH2:3])[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=1[CH2:1][NH2:2]
Reactant: [H][H]
Reactant: c1ccc2cnncc2c1
Agent: [Ni]
Agent: [Pd]
Solvent: CO
Product: NCc1ccccc1CN

Procedure:
Phthalazine (21.5 g, 0.165 mol), 10% palladium on carbon (2 g), and methanol (125 mL) were combined in a pressure bottle and shaken at room temperature under 60 psi of hydrogen for 5 days. Raney-nickel® slurry (6.42 g) and 10% palladium on carbon (0.50 g) were added, and the mixture was shaken at 50° C. under 60 psi of hydrogen for 16 hours. The mixture was filtered through a nylon membrane and concentrated to give the titled compound: 1H NMR (300 MHz, DMSO-d6) δ ppm 7.32 (dd, J=5.4, 3.5 Hz, 2H), 7.17 (dd, J=5.6, 3.4 Hz, 2H), 3.74 (s, 4H); MS (DCI/NH3) m/z 137 (M+H)+.
Reaction SMILES: [C:1]([CH:3]([C:5]1[CH:6]=[CH:7][C:8]([O:15][CH3:16])=[C:9]([CH:14]=1)[C:10]([O:12][CH3:13])=[O:11])O)#[N:2].S(Cl)([Cl:19])=O>C(Cl)(Cl)Cl.CN(C=O)C>[Cl:19][CH:3]([C:5]1[CH:6]=[CH:7][C:8]([O:15][CH3:16])=[C:9]([CH:14]=1)[C:10]([O:12][CH3:13])=[O:11])[C:1]#[N:2]
Reactant: COC(=O)c1cc(C(O)C#N)ccc1OC
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C(Cl)C#N)ccc1OC

Procedure:
To a suspension of methyl 5-(1-cyano-1-hydroxymethyl)-2-methoxybenzoate (2.15 g) in chloroform (40 ml) were added thionyl chloride (2.0 ml) and DMF (2 drops), and the mixture was refluxed for 30 minutes under heat. After cooling, the reaction mixture was washed with water, aqueous solution of sodium hydrogencarbonate and saturated brine in sequence and dried over anhydrous sodium sulfate. This was concentrated under reduced pressure to obtain 2.37 g of aimed compound as an oily product.
Reaction SMILES: CN(C)[C:3]([C:5]1[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[O:7][N:6]=1)=[O:4].C[Mg]Br.Cl.[O:21]1CC[CH2:23][CH2:22]1>C1(C)C=CC=CC=1>[C:10]1([C@@H:8]2[O:7][N:6]=[C:5]([C:3]([C:22](=[O:21])[CH3:23])=[O:4])[CH2:9]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CN(C)C(=O)C1=NO[C@@H](c2ccccc2)C1
Reactant: C1CCOC1
Agent: C[Mg]Br
Agent: Cl
Solvent: Cc1ccccc1
Product: CC(=O)C(=O)C1=NO[C@@H](c2ccccc2)C1
Temperature: -15 °C

Procedure:
A solution of (5R)-4,5-dihydro-N,N-dimethyl-5-phenyl-3-isoxazole-carboxamide (i.e. the product of Example 12, Step D) (3.5 g, 16.0 mmol) in a mixture of tetrahydrofuran (5 mL) and toluene (10 mL) was cooled to −15° C., and methyl magnesium bromide (3.0 M solution in tetrahydrofuran, 8.8 mL, 26.4 mmol) was added over 1 h at −15° C. Then the reaction mixture was poured over a mixture of 20 g of concentrated hydrochloric acid and 80 g of ice, and the organic phase was separated. The aqueous phase was extracted with ethyl acetate (100 mL), and the combined extract was washed with brine (40 mL) and concentrated under reduced pressure to give 3.2 g of 1-[(5R)-4,5-dihydro-5-phenyl-3-isoxazoyl]ethanone.
Reaction SMILES: [CH:1]([NH:3][CH2:4][C@@H:5]([C:7]([O:9]C=O)=[O:8])[OH:6])=[O:2].N1C=CC=CC=1>CO>[CH:1]([NH:3][CH2:4][C@@H:5]([C:7]([OH:9])=[O:8])[OH:6])=[O:2]
Reactant: O=CNC[C@H](O)C(=O)OC=O
Solvent: c1ccncc1
Solvent: CO
Product: O=CNC[C@H](O)C(=O)O

Procedure:
A stock solution of N-formyl-(S)-isoserine was prepared by stirring 20 g (124.2 mmoles) of N,O-diformyl-(S)-isoserine in a mixture of methanol (85 ml) and pyridine (15 ml, 1.5 equiv.) at room temperature for 14-16 hrs. The completion of the reaction was judged by 1HNMR.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[NH:13]1[C:21]2[C:16](=[CH:17][C:18]([O:22][C:23]3[C:32]4[C:27](=[CH:28][C:29]([O:34][CH3:35])=[C:30]([OH:33])[CH:31]=4)[N:26]=[CH:25][N:24]=3)=[CH:19][N:20]=2)[CH:15]=[CH:14]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:55][S:56]([N:59]1[CH2:64][CH2:63][N:62]([CH2:65][CH2:66][CH2:67]O)[CH2:61][CH2:60]1)(=[O:58])=[O:57]>CN(C=O)C>[NH:13]1[C:21]2[C:16](=[CH:17][C:18]([O:22][C:23]3[C:32]4[C:27](=[CH:28][C:29]([O:34][CH3:35])=[C:30]([O:33][CH2:67][CH2:66][CH2:65][N:62]5[CH2:63][CH2:64][N:59]([S:56]([CH3:55])(=[O:58])=[O:57])[CH2:60][CH2:61]5)[CH:31]=4)[N:26]=[CH:25][N:24]=3)=[CH:19][N:20]=2)[CH:15]=[CH:14]1
Reactant: COc1cc2ncnc(Oc3cnc4[nH]ccc4c3)c2cc1O
Reactant: CS(=O)(=O)N1CCN(CCCO)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: COc1cc2ncnc(Oc3cnc4[nH]ccc4c3)c2cc1OCCCN1CCN(S(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 40 %

Procedure:
Diethyl azodicarboxylate (0.09 g, 0.518 mmol) was added dropwise to a solution of 4-(7-azaindol-5-yloxy)-6-hydroxy-7-methoxyquinazoline (0.133 g, 0.432 mmol), triphenylphosphine (0.17 g, 0.647 mmol) and 3-(4-methylsulphonylpiperazin-1-yl)propan-1-ol (0.115 g, 0.519 mmol) in DMF (4 ml) and the mixture was stirred at ambient temperature for 1 hour. The volatiles were removed under vacuum and the residue was purified by column chromatography using increasingly polar mixtures of ethyl acetate and methylene chloride followed by methylene chloride and methanol. The fractions containing the expected product were combined and evaporated. The solid was then repurified by preparative LC/MS eluting with acetonitrile/water (containing 1% acetic acid). The fractions containing the expected product were combined and evaporated. The residue was dissolved in aqueous sodium hydrogen carbonate and methylene chloride. The organic phase was separated and dried over magnesium sulphate and evaporated. The residue was triturated under diethyl ether, filtered, washed with ether and dried under vacuum over P2O5 to give 4-(7-azaindol-5-yloxy)-7-methoxy-6-(3-(4-methylsulphonylpiperazin-1-yl)propoxy)quinazoline (0.09, 40%).
Reaction SMILES: [C:1]1(=O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](=[O:10])[O:2]1.O.[NH2:13][NH2:14]>>[C:3]1(=[O:10])[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:1](=[O:2])[N:14]=[N:13]1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: NN
Solvent: O
Product: O=C1N=NC(=O)c2ccccc21

Procedure:
When R7 and R8 are cyclopentylene or cyclohexylene, the dichloro intermediate is conveniently prepared from a 4,5,6,7-tetrahydro-4,7-(methano or ethano)isobenzofuran-1,3-dione. Diels and Alder, Ann., 478, 149 (1930); Ann., 490, 236 (1931). The dione compound is reacted with excess hydrazine hydrate in an exothermic reaction to produce the corresponding hexahydro-5,8-(methano or ethano)phthalazine-1,4-dione. Additional heating at 100°-170° C. for 10-30 minutes may be useful to complete the reaction. The phthalazine-1,4-dione is then reacted with excess phosphorus oxychloride heated at reflux for about 2-4 hours, cooled and the product hydrolyzed by careful addition of ice and water to produce the dichloro intermediate.
Reaction SMILES: C([Li])CCC.[CH3:6][C:7]([OH:13])([CH2:9][CH2:10][CH2:11][CH3:12])[CH3:8].[C:14](Cl)(=[O:18])[C:15]([CH3:17])=[CH2:16]>O1CCCC1>[C:14]([O:13][C:7]([CH3:8])([CH2:9][CH2:10][CH2:11][CH3:12])[CH3:6])(=[O:18])[C:15]([CH3:17])=[CH2:16]
Reactant: C=C(C)C(=O)Cl
Reactant: CCCCC(C)(C)O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C=C(C)C(=O)OC(C)(C)CCCC
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 58.9 %

Procedure:
To a flame-dried, nitrogen-purged 500 mL 3-neck roundbottom flask with 250 mL pressure-equalizing addition funnel and magnetic stirbar was charged 81 mL n-butyl lithium (129 mmol, 1 equiv., 1.6 M in hexanes). A degassed solution of 15.0 g 2-methyl-2-hexanol (129 mmol, 1 eq.) in 100 mL anhydrous tetrahydrofuran was charged to the addition funnel and added to the reaction mixture dropwise at 0° C. over 60 minutes. The reaction mixture was warmed for 15 minutes on hot water bath to ensure the reaction was complete. The reaction vessel was cooled to 0° C. and 14.2 g methacryloyl chloride (135 mmol, 1.05 eq.) was added dropwise and allowed to stir for 15 minutes. The addition funnel was replaced with a reflux condenser and the reaction heated to reflux for 20 hours. After the reaction was complete, it was cooled to 0° C. and quenched aqueous sodium bicarbonate. The product was extracted into ethyl ether and the organic phase washed sequentially with aqueous sodium bicarbonate, water, and brine and then dried over magnesium sulfate, filtered, concentrated in vacuo, and stored over a small amount of sodium bicarbonate. The crude product mixture was vacuum distilled through a vacuum-jacketed short-path distillation head to afford 14 g (59%) of 2-methylhexan-2-yl methacrylate (XIII) as a colorless liquid.
Reaction SMILES: [CH2:1]([NH:5][CH3:6])[CH2:2][CH2:3][CH3:4].[Cl:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][S:13](Cl)(=[O:15])=[O:14].C(N(CC)CC)C.Cl>C(Cl)Cl>[CH2:1]([N:5]([CH3:6])[S:13]([CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][Cl:7])(=[O:15])=[O:14])[CH2:2][CH2:3][CH3:4]
Reactant: O=S(=O)(Cl)CCCCCCl
Reactant: CCCCNC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCN(C)S(=O)(=O)CCCCCCl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.47 ml of N-butylmethylamine were added under an inert gas atmosphere to a solution of 410 mg of 5-chloropentane sulfonyl chloride in 10 ml of methylene chloride. The temperature rose from 13° C. to 26° C., and then after cooling to 0° to 5° C., 0.55 ml of triethylamine were added. The mixture was stirred at ambient temperature for 2 hours and the reaction medium was poured into an aqueous solution of 1M hydrochloric acid, extracted with methylene chloride, washed with water, then with a saturated aqueous solution of sodium chloride, dried and evaporated to dryness under reduced pressure to obtain 486 mg of the expected product.
Reaction SMILES: [NH2:1][C:2]1[C:17]([O:18][CH3:19])=[CH:16][C:5]2[N:6]([CH2:14][CH3:15])[C:7](=[O:13])[CH2:8][CH2:9][C:10]([CH3:12])([CH3:11])[C:4]=2[CH:3]=1.Cl[C:21]1[N:26]=[C:25]([NH:27][C@@H:28]2[C@@H:33]3[CH2:34][C@@H:30]([CH:31]=[CH:32]3)[C@@H:29]2[C:35]([NH2:37])=[O:36])[C:24]([Cl:38])=[CH:23][N:22]=1>>[Cl:38][C:24]1[C:25]([NH:27][C@@H:28]2[C@@H:33]3[CH2:34][C@@H:30]([CH:31]=[CH:32]3)[C@@H:29]2[C:35]([NH2:37])=[O:36])=[N:26][C:21]([NH:1][C:2]2[C:17]([O:18][CH3:19])=[CH:16][C:5]3[N:6]([CH2:14][CH3:15])[C:7](=[O:13])[CH2:8][CH2:9][C:10]([CH3:12])([CH3:11])[C:4]=3[CH:3]=2)=[N:22][CH:23]=1
Reactant: CCN1C(=O)CCC(C)(C)c2cc(N)c(OC)cc21
Reactant: NC(=O)[C@@H]1[C@H](Nc2nc(Cl)ncc2Cl)[C@H]2C=C[C@@H]1C2
Product: CCN1C(=O)CCC(C)(C)c2cc(Nc3ncc(Cl)c(N[C@H]4[C@@H](C(N)=O)[C@@H]5C=C[C@H]4C5)n3)c(OC)cc21
Yield: 69.9 %

Procedure:
Following a procedure analogous to 101b, 7-Amino-1-ethyl-8-methoxy-5,5-dimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (88 mgs) and (1S,2S,3R,4R)-3-(2,5-Dichloro-pyrimidin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (84 mgs) gave the title compound as white solid 103 mgs (70%); 1H-NMR (CDCl3, 400 MHz) δ 8.43 (s, 1H), 7.94 (s, 1H), 7.39 (s, 1H), 6.76 (s, 1H), 6.47 (d, J=9.0 Hz, 1H), 6.29 (s, 2H), 5.54 (broad s, 1H), 5.32 (broad s, 1H), 4.56 (t, J=8.6 Hz, 1H), 3.92 (s, 3H), 3.83 (broad m, 2H), 3.09 (s, 1H), 2.83 (s, 1H), 2.51 (d, J=8.2 Hz, 1H), 2.29-2.25 (m, 3H), 2.09-2.05 (m, 2H), 1.68 (d, J=9.3 Hz, 1H), 1.34 (s, 6H), 0.91-0.85 (m, 3H); LC/MS:, found (M+H)+=525.28; MP:156-166° C.
Reaction SMILES: [N:1]1[N:5]2[CH:6]=[CH:7][CH:8]=[N:9][C:4]2=[C:3]([C:10](Cl)=[O:11])[CH:2]=1.[Si:13]([O:20][C:21]([CH3:39])([CH3:38])[CH2:22][C:23]1[S:24][C:25]([NH2:37])=[C:26]([C:28]2[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:29]=2[O:35][CH3:36])[N:27]=1)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].N1C=CC=CC=1>C(Cl)Cl>[Si:13]([O:20][C:21]([CH3:39])([CH3:38])[CH2:22][C:23]1[S:24][C:25]([NH:37][C:10]([C:3]2[CH:2]=[N:1][N:5]3[CH:6]=[CH:7][CH:8]=[N:9][C:4]=23)=[O:11])=[C:26]([C:28]2[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:29]=2[O:35][CH3:36])[N:27]=1)([C:16]([CH3:18])([CH3:19])[CH3:17])([CH3:15])[CH3:14]
Reactant: COc1ccc(Cl)cc1-c1nc(CC(C)(C)O[Si](C)(C)C(C)(C)C)sc1N
Reactant: O=C(Cl)c1cnn2cccnc12
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(Cl)cc1-c1nc(CC(C)(C)O[Si](C)(C)C(C)(C)C)sc1NC(=O)c1cnn2cccnc12
Reaction time: 72 h
Yield: 66 %

Procedure:
A solution of pyrazolo[1,5-a]pyrimidine-3-carbonyl chloride (52.0 mg, 0.29 mmol), 2-(2-(tert-butyldimethylsilyloxy)-2-methylpropyl)-4-(5-chloro-2-methoxyphenyl)thiazol-5-amine (103 mg, 0.24 mmol) and pyridine (2 mL) was stirred at 60° C. for 2 hours, then at room temperature for an additional 72 hours. DCM was added, the organics washed with water, sodium hydrogen carbonate (sat. aq.) and brine, then evaporated to dryness. The residues were purified by flash chromatography on silica gel (0 to 20% ethyl acetate in dichloromethane) to yield 90.6 mg (66%) of N-(2-(2-(tert-butyldimethylsilyloxy)-2-methylpropyl)-4-(5-chloro-2-methoxyphenyl)thiazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide as a yellow solid. LCMS (ESI) m+H=572.1; 1H NMR (400 MHz, DMSO-d6): δ 10.45 (s, br, 1H); 9.38 (dd, 1H); 8.76 (s, 1H); 8.73-8.72 (m, 1H); 7.51 (dd, 1H); 7.45 (d, 1H); 7.35 (d, 1H); 7.31 (d, 1H); 3.79 (s, 3H); 3.06 (s, 2H); 1.32 (s, 6H); 0.90 (s, 9H); 0.11 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]([OH:25])[CH2:9][NH:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH:13]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23]C)[CH:18]=3)[CH2:12]2)[CH:5]=[CH:6][CH:7]=1.B(Br)(Br)Br.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]([OH:25])[CH2:9][NH:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH:13]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([OH:23])[CH:18]=3)[CH2:12]2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cccc(C2CCCC(NC[C@H](O)c3cccc(Cl)c3)C2)c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Oc1cccc(C2CCCC(NC[C@H](O)c3cccc(Cl)c3)C2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81 %

Procedure:
A solution of the (1R)-1-(3-chlorophenyl)-2-[3-(3-methoxyphenyl) cyclohexylamino]ethanol (trans-H) obtained in Example 3 (2.21 g) in methylene chloride (100 ml) was cooled to -10° C. After slowly adding dropwise a solution of 1 M boron tribromide in methylene chloride thereto, the mixture was stirred for 2 hours while gradually heating it to room temperature. The reaction solution was poured a portion at a time into an aqueous sodium bicarbonate solution while cooling on ice in order to terminate the reaction, and the extraction was performed with a mixed solvent of chloroform:ethanol=5:1. After washing the organic layer with saturated saline, it was dried with anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to produce a crude product which was then separated and purified by silica gel column chromatography (chloroform-chloroform:methanol=20:1) to give 1.72 g of (1R)-1-(3-chlorophenyl)-2-[3-(3-hydroxyphenyl)cyclohexylamino]ethanol (trans-H) (81.1% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C(O)C.[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]([N:35]=[C:36]=[S:37])=[O:34])=[CH:29][CH:28]=1>C1(C)C=CC=CC=1>[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]([NH:35][C:36]([NH:20][C:19]2[CH:21]=[CH:22][C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][CH:7]=3)=[CH:17][CH:18]=2)=[S:37])=[O:34])=[CH:29][CH:28]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: O=C(N=C=S)c1ccc(Cl)cc1
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccc(Cl)cc4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. Commercially available 4-chloro-1-benzenecarbonyl isothiocyanate (50 μl) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (77 mg, yield 92%).
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].C[Al](C)C.[F:10][C:11]1[CH:22]=[CH:21][C:14]([CH:15]([OH:20])[C:16](OC)=[O:17])=[CH:13][CH:12]=1>C1(C)C=CC=CC=1>[CH3:2][N:3]([O:4][CH3:5])[C:16](=[O:17])[CH:15]([OH:20])[C:14]1[CH:13]=[CH:12][C:11]([F:10])=[CH:22][CH:21]=1
Reactant: CNOC
Reactant: COC(=O)C(O)c1ccc(F)cc1
Agent: C[Al](C)C
Agent: Cl
Solvent: Cc1ccccc1
Product: CON(C)C(=O)C(O)c1ccc(F)cc1
Temperature: 3.5 °C
Reaction time: 1.5 h
Yield: 94.6 %

Procedure:
Cool a mixture of N-methyl-O-methyl hydroxylamine hydrochloride (118 mmol) and toluene (125 mL) to −5° C. Slowly add trimethylaluminum (2 M in heptane, 59.2 mL, 118 mmol) to the mixture over 20 minutes, maintaining the reaction temperature from −1 to 8° C. After about 5 minutes slowly warm the mixture to room temperature and stir for 1.5 hours. Add a solution of methyl p-fluoromandelate (11.1 g, 60 mmol) in 75 mL of toluene over 30 min without external cooling. Cool the reaction to 0° C. and quench with 10% hydrochloric acid. Extract with ethyl acetate (4×250 mL). Wash the combined ethyl acetate layers sequentially with water and saturated aqueous sodium chloride, dry over sodium sulfate and concentrate under reduced pressure to provide 12.1 g (82%) of the desired compound.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([NH2:12])=[S:11])[CH:5]=[C:6]([I:8])[CH:7]=1.BrBr.N>C(Cl)(Cl)Cl.O>[I:1][C:2]1[CH:7]=[C:6]([I:8])[C:5]2[S:11][C:10]([NH2:12])=[N:9][C:4]=2[CH:3]=1
Reactant: NC(=S)Nc1cc(I)cc(I)c1
Agent: BrBr
Agent: N
Solvent: ClC(Cl)Cl
Solvent: O
Product: Nc1nc2cc(I)cc(I)c2s1
Temperature: 2.5 °C
Reaction time: 0.25 h
Yield: 87.1 %

Procedure:
To a solution of (3,5-diiodo-phenyl)-thiourea (4.0 g, 0.01 mol) in CHCl3 (160 mL) at −55-60° C. was added dropwise a solution of Br2 (4.72 g, 0.02 mol, in 25 ml of CHCl3) over a period of 15 min. The reaction mixture was stirred at −55-60° C. for 15 min followed by refluxing at 70-75° C. for 3 h. The reaction mixture was cooled to room temperature and filtered to get the crude residue that was washed with hexane and diethyl ether. The solid thus obtained was dissolved in H2O, basified with aqueous ammonia solution to pH 10-12 and stirred for 30 min. The solid thus obtained was filtered and washed with water to get the desired product (3.50 g, 88%).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[N:19]=[C:9]2[N:10]=[C:11]([C:15]([O:17][CH3:18])=[O:16])[CH:12]=[C:13](Cl)[N:8]2[N:7]=1)(=[O:3])[CH3:2].O.[SH2:21].[Na]>CO>[C:1]([O:4][CH2:5][C:6]1[N:19]=[C:9]2[N:10]=[C:11]([C:15]([O:17][CH3:18])=[O:16])[CH:12]=[C:13]([SH:21])[N:8]2[N:7]=1)(=[O:3])[CH3:2]
Reactant: COC(=O)c1cc(Cl)n2nc(COC(C)=O)nc2n1
Reactant: S
Agent: [Na]
Solvent: O
Solvent: CO
Product: COC(=O)c1cc(S)n2nc(COC(C)=O)nc2n1
Temperature: 60 °C
Reaction time: 4 h
Yield: 98.1 %

Procedure:
Methyl 2-(acetoxymethyl)-7-chloro-s-triazolo[1,5-a]pyrimidine-5-carboxylate (370 mg) (1.3 mmol) are dissolved in 10 ml of methanol. After the addition of 289 mg (3.9 mmol) of sodium hydrogen sulphide hydrate the mixture is stirred at 60° C. for 4 hours. The yellow solution is concentrated in a vacuum. The residue is dissolved in water and the product is precipitated at pH 3 with 3N aqueous hydrochloric acid. The precipitate is filtered off under suction and crystallized from methanol. There are obtained 360 mg of methyl 2-(acetoxymethyl)-7-mercapto-s-triazolo[1,5-a]pyrimidine-5-carboxylate.