Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:20][CH:2]1[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:12][CH:13]=[C:14]([C:16]([F:19])([F:18])[F:17])[N:15]=2)=[CH:7][CH:6]=1.[CH2:21]([NH:28][CH2:29][CH2:30][O:31][C:32]1[CH:40]=[C:36]([C:37]([NH2:39])=[O:38])[C:35]([OH:41])=[CH:34][CH:33]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(O)(C)C>[CH2:21]([N:28]([CH2:29][CH2:30][O:31][C:32]1[CH:33]=[CH:34][C:35]([OH:41])=[C:36]([C:37](=[O:38])[NH2:39])[CH:40]=1)[CH2:20][CH:2]([OH:1])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:12][CH:13]=[C:14]([C:16]([F:19])([F:18])[F:17])[N:15]=2)=[CH:7][CH:6]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: FC(F)(F)c1csc(-c2ccc(OCC3CO3)cc2)n1
Reactant: NC(=O)c1cc(OCCNCc2ccccc2)ccc1O
Solvent: CC(C)O
Product: NC(=O)c1cc(OCCN(Cc2ccccc2)CC(O)COc2ccc(-c3nc(C(F)(F)F)cs3)cc2)ccc1O

Procedure:
A solution of 7.0 g of 2-[4-(2,3-epoxypropoxy)-phenyl]-4-(trifluoromethyl)-thiazole and 6.01 g of 5-[2-(benzylamino)-ethoxy]-salicylamide in 150 ml of isopropanol is heated under reflux for 18 hours and the solvent is subsequently removed in a rotary evaporator. The 1-[N-benzyl-2-(3-carbamoyl-4-hydroxyphenoxy)-ethylamino]-3-[4-[4-(trifluoromethyl)-thiazol-2-yl]-phenoxy]-2-propanol, obtained in the form of an oil, is further processed in that form.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Br:19][C:20]1[CH:68]=[CH:67][C:23]([O:24][CH2:25][C:26]([NH:28][CH2:29][C@@H:30]([C:39]2[CH:44]=[CH:43][C:42]([O:45][CH2:46][O:47][CH2:48][CH2:49][Si:50]([CH3:53])([CH3:52])[CH3:51])=[C:41]([N:54]([S:63]([CH3:66])(=[O:65])=[O:64])[CH2:55][O:56][CH2:57][CH2:58][Si:59]([CH3:62])([CH3:61])[CH3:60])[CH:40]=2)[O:31][Si](CC)(CC)CC)=[O:27])=[CH:22][CH:21]=1>O1CCCC1>[Br:19][C:20]1[CH:21]=[CH:22][C:23]([O:24][CH2:25][C:26]([NH:28][CH2:29][C@H:30]([OH:31])[C:39]2[CH:44]=[CH:43][C:42]([O:45][CH2:46][O:47][CH2:48][CH2:49][Si:50]([CH3:53])([CH3:52])[CH3:51])=[C:41]([N:54]([S:63]([CH3:66])(=[O:65])=[O:64])[CH2:55][O:56][CH2:57][CH2:58][Si:59]([CH3:60])([CH3:61])[CH3:62])[CH:40]=2)=[O:27])=[CH:67][CH:68]=1
Reactant: CC[Si](CC)(CC)O[C@@H](CNC(=O)COc1ccc(Br)cc1)c1ccc(OCOCC[Si](C)(C)C)c(N(COCC[Si](C)(C)C)S(C)(=O)=O)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCOc1ccc([C@@H](O)CNC(=O)COc2ccc(Br)cc2)cc1N(COCC[Si](C)(C)C)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 83.6 %

Procedure:
A 1 mol/L solution of tetra-n-butylammonium fluoride (2.6 mL) was added to a solution of 2-(4-bromophenoxy)-N—((R)-2-{3-[methanesulfonyl(2-trimethylsilylethoxymethyl)amino]-4-(2-trimethylsilylethoxymethoxy)phenyl}-2-triethylsilyloxyethyl)acetamide (2.37 g) in tetrahydrofuran (8 mL), and the mixture was stirred at room temperature for 2.5 hrs. A 1 mol/L solution of tetra-n-butylammonium fluoride (0.67 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 12 hrs. The reaction mixture was concentrated in vacuo, and water was added to the residue. The mixture was extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by medium-pressure silica gel column chromatography (eluent: n-hexane/ethyl acetate=1/1) to afford the title compound (1.71 g).
Reaction SMILES: [CH2:1]([NH:4][C:5]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:6]=1[CH:7]=O)[CH2:2][CH3:3].[CH3:17][O:18][C:19]([CH:21]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:20]>C1(C)C=CC=CC=1>[CH3:17][O:18][C:19](=[O:20])[CH:21]=[CH:7][C:6]1[CH:9]=[CH:10][C:11]([C:13]([F:16])([F:15])[F:14])=[CH:12][C:5]=1[NH:4][CH2:1][CH2:2][CH3:3]
Reactant: CCCNc1cc(C(F)(F)F)ccc1C=O
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: CCCNc1cc(C(F)(F)F)ccc1C=CC(=O)OC
Yield: 69 %

Procedure:
N-Methoxy-N-methyl-2-propylamino-4-trifluoromethyl-benzamide (98.3 mg, 0.339 mmol) was reacted with 1M lithium aluminum hydride (0.6 ml) in THF (20 ml) at −40° C. for 1 hr. The reaction mixture was quenched by adding saturated potassium hydrogen sulfate solution. The mixture was stirred for 30 min. The reactions solvent was removed in vacuo. Water (30 ml) was added to the resulting residue, which was extracted with CH2Cl2 (30 ml×3). The combined organic layer was dried over MgSO4 and concentrated in vacuo to yield 2-propylamino-4-trifluoromethyl-benzaldehyde (78 mg). 2-Propylamino-4-trifluoromethyl-benzaldehyde in toluene was reacted with methyl (triphenylphosphoranylidene) acetate (137 mg) at 100° C. overnight. The reaction solvent was removed in vacuo. Water (30 ml) was added to the resulting residue, which was extracted with ethyl acetate (30 ml×3). The combined organic layer was dried over MgSO4 and filtered. The filterate was concentrated in vacuo and purified with column chromatography to yield title compound (67 mg, 69%).
Reaction SMILES: C[O:2][C:3](=[O:19])/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]Br.[OH:20][C:21]1[CH:31]=[CH:30][C:24]2[C:25](=[O:29])[CH2:26][CH2:27][O:28][C:23]=2[C:22]=1[CH2:32][CH2:33][CH3:34]>>[O:29]=[C:25]1[C:24]2[CH:30]=[CH:31][C:21]([O:20][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][O:12][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=3/[CH:5]=[CH:4]/[C:3]([OH:2])=[O:19])=[C:22]([CH2:32][CH2:33][CH3:34])[C:23]=2[O:28][CH2:27][CH2:26]1
Reactant: CCCc1c(O)ccc2c1OCCC2=O
Reactant: COC(=O)/C=C/c1ccccc1OCCCCCBr
Product: CCCc1c(OCCCCCOc2ccccc2/C=C/C(=O)O)ccc2c1OCCC2=O

Procedure:
Using the procedure of example 4, and starting with 0.5 g (1.5 mmol) of (E)-3-[2-[(5-bromopentyl)oxy]phenyl]-2-propenoic acid methyl ester and 0.3 g (1.45 mmol) of 2,3-dihydro-7-hydroxy-8-propyl-4H-1-benzopyran-4-one, (E)-3-[2-[5-[(3,4-dihydro-4-oxo-8-propyl-2H-1-benzopyran-7-yl)oxy]pentyloxy]phenyl]-2-propenoic acid was obtained in 24% overall yield after purification by flash chromatography (silica gel, chloroform-methanol-acetic acid) and recrystallization from acetonitrile as a colorless solid, mp 123°-126° C.
Reaction SMILES: CS(O[CH2:6][C@@H:7]1[CH2:9][C@@H:8]1[C:10]1[C:15]2[CH2:16][CH2:17][O:18][C:14]=2[CH:13]=[CH:12][CH:11]=1)(=O)=O.[N-:19]=[N+:20]=[N-:21].[Na+]>CN(C)C=O.C(Cl)Cl>[O:18]1[C:14]2[CH:13]=[CH:12][CH:11]=[C:10]([C@H:8]3[CH2:9][C@H:7]3[CH2:6][N:19]=[N+:20]=[N-:21])[C:15]=2[CH2:16][CH2:17]1
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)OC[C@@H]1C[C@@H]1c1cccc2c1CCO2
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: [N-]=[N+]=NC[C@@H]1C[C@@H]1c1cccc2c1CCO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 102.2 %

Procedure:
A solution of (cis)-[2-(2,3-dihydrobenzofuran-4-yl)cycloprop-1-yl]methyl methane sulfonate (5.0 mmol) and sodium azide (10.0 mmol) in 100 mL of dimethylformamide was heated at 70° C. for 1 h. The reaction mixture was allowed to cool to room temperature and stirred overnight. The crude reaction mixture was then diluted with CH2Cl2 (100×mL) and washed sequentially with water (3×100 mL) and then brine (1×100 mL). The organic phase was separated, dried over magnesium sulfate, filtered and concentrated in vacuo to provide 1.1 g of the desired product as an oil (quantitative yield).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[NH:4][CH:5]=[N:6]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[O:42]([C@:50]([C@@H:58]([CH:60]([O:62][Si:63]([C:66]([CH3:69])([CH3:68])[CH3:67])([CH3:65])[CH3:64])[OH:61])[OH:59])([OH:57])[C:51]([F:56])([F:55])[C:52](O)=[O:53])[Si:43]([C:46]([CH3:49])([CH3:48])[CH3:47])([CH3:45])[CH3:44]>O1CCCC1>[Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C:52]([C:51]([F:56])([F:55])[C@@:50]([O:42][Si:43]([C:46]([CH3:49])([CH3:48])[CH3:47])([CH3:45])[CH3:44])([C@@H:58]([CH:60]([O:62][Si:63]([C:66]([CH3:69])([CH3:68])[CH3:67])([CH3:65])[CH3:64])[OH:61])[OH:59])[OH:57])=[O:53]
Reactant: CC(C)(C)[Si](C)(C)OC(O)[C@@H](O)[C@](O)(O[Si](C)(C)C(C)(C)C)C(F)(F)C(=O)O
Reactant: Clc1ncnc2nc[nH]c12
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OC(O)[C@@H](O)[C@](O)(O[Si](C)(C)C(C)(C)C)C(F)(F)C(=O)n1cnc2c(Cl)ncnc21
Temperature: 25 °C
Reaction time: 60 h
Yield: 34.3 %

Procedure:
To a solution of 0.77 g (5.0 mmol) of 6-chloropurine in 50 ml of tetrahydrofuran was added 1.31 g (5.0 mmol) of triphenylphosphine and 0.87 g (5.0 mmol) of diethyl azodicarboxylate. To this solution was added a solution of 1.99 g (5.0 mmol) of 3,5-bis(t-butyldimethylsiloxy)-1-hydroxy-2-desoxy-2,2-difluororibose in tetrahydrofuran. The reaction mixture was stirred at room temperature for approximately 60 hours and an additional 0.66 g (1.7 mmol) of 3,5-bis(t-butyldimethylsiloxy)-1-hydroxy-2-desoxy-2,2-difluororibose was added to the reaction mixture. The mixture was stirred for an additional 6 hours at room temperature. The solvent was evaporated under vacuum and the residue was stirred in a small amount of diethyl ether overnight. The precipitated solid was removed by vacuum filtration and the filtrate was concentrated under vacuum to dryness. The residue was chromatographed over 70 g of silica and eluted with chloroform. Fractions containing the major component were combined and the solvent was evaporated therefrom to provide 1.0 g of 1-(6-chloro-9H-purin-9-yl)-3,5-bis(t-butyldimethylsiloxy)-2-desoxy-2,2-difluororibose. The structure of the product was verified by NMR. Mass spec.=477 [534-(t-butyl)]
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[C:17]([N:18]2[CH:22]=[CH:21][CH:20]=[N:19]2)=[CH:16][CH:15]=[C:14]([CH3:23])[N:13]=1)=[O:11].Br[C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][N:26]=1>>[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([NH:1][CH2:2][C@@H:3]2[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]2[C:10]([C:12]2[C:17]([N:18]3[CH:22]=[CH:21][CH:20]=[N:19]3)=[CH:16][CH:15]=[C:14]([CH3:23])[N:13]=2)=[O:11])=[N:26][CH:27]=1
Reactant: Clc1ccc(Br)nc1
Reactant: Cc1ccc(-n2cccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)n1
Product: Cc1ccc(-n2cccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ccc(Cl)cn2)n1

Procedure:
The title compound was prepared following the same general protocol as described for Example A44 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(6-methyl-3-(1H-pyrazol-1-yl)pyridin-2-yl)methanone and 2-bromo-5-chloropyridine. MS (ESI) 425 (M+H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH3:12][C:13]([C:15]1[CH:16]=[CH:17][C:18]([OH:21])=[CH:19][CH:20]=1)=[O:14].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([O:21][C:18]2[CH:19]=[CH:20][C:15]([C:13](=[O:14])[CH3:12])=[CH:16][CH:17]=2)=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1Br
Reactant: CC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)c1ccc(Oc2ccc(Cl)cc2[N+](=O)[O-])cc1
Temperature: 80 °C
Yield: 78 %

Procedure:
1-Bromo-4-chloro-2-nitrobenzene (5 g, 21.2 mmol) was added to a solution of 4-hydroxyacetophenone (2.87 g, 21.1 mmol), and K2CO3 (7.28 g, 0.052 mol) in DMF (50 mL). The mixture was heated at 80° C. for 15 h. The reaction was poured into water. The aqueous phase was extracted with ethyl acetate (2×) and the combined phases were washed with water, brine, and dried over sodium sulfate, filtered and concentrated under vacuum giving the crude title compound. The crude product was purified by flash chromatography eluting with (hexanes/ethyl acetate 70:30) to give the title compound (4.8 g, 77.8%).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[CH:8]#[C:9][CH:10]([OH:13])[CH2:11][CH3:12]>C(N(CC)CC)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CSC.[Cu]Br>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:8]#[C:9][CH:10]([OH:13])[CH2:11][CH3:12])[CH:3]=1
Reactant: C#CC(O)CC
Reactant: Brc1cccnc1
Agent: [Cu]Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CSC
Product: CCC(O)C#Cc1cccnc1
Temperature: 70 °C
Yield: 100.1 %

Procedure:
To a solution of 3-bromopyridine (12.0 g, 75.6 mmol) and 1-pentyn-3-ol (7.0 mL, 83.2 mmol) in triethylamine (150 mL) were added Pd(PPh3)4 (88 mg, 0.076 mmol) and copper(I) bromide dimethylsulfide (31 mg, 0.15 mmol). The mixture was heated at 70° C. for 5 hr, cooled to room temperature and filtered. The filter cake was washed with EtOAc (30 mL). The combined filtrate was concentrated to give 1-(3-pyridinyl)-1-pentyn-3-ol (12.2 g, 99%) as a dark oil.
Reaction SMILES: [C:1]1([C:7]2[O:11][N:10]=[C:9]([C:12]3[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=3[CH2:14][OH:15])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C)=[O:22].S(=O)(=O)(O)O>O.[O-2].[O-2].[O-2].[Cr+6]>[C:1]1([C:7]2[O:11][N:10]=[C:9]([C:12]3[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=3[C:14]([OH:22])=[O:15])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)=O
Reactant: OCc1ccccc1-c1cc(-c2ccccc2)on1
Agent: [Cr+6]
Agent: O=S(=O)(O)O
Agent: [O-2]
Solvent: O
Product: O=C(O)c1ccccc1-c1cc(-c2ccccc2)on1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 6.3 g. (0.025 mole) o-(5-phenyl-3-isoxazolyl)benzyl alcohol in 125 ml. acetone is added dropwise at room temperature to 50 ml. (0.1 mole) of a reagent prepared by dissolving 100 g. (1.0 mole) chromium trioxide in 160 g. of concentrated sulfuric acid and diluting with water to form a 500 ml. solution. The mixture is stirred for 3 hours at room temperature and then filtered. The acetone is evaporated in vacuo and the residue partitioned between ether and water. The resulting layers are separated and the ether washed with water, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo. The resulting solid is triturated with cold ether and filtered to give o-(5-phenyl-3-isoxazolyl) benzoic acid; m.p. 144.5° to 146.5° C.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[O:6][CH2:7][C:8](=[O:12])[NH:9][C:10]=2[N:11]=1.[O:19]1[CH2:23][CH:20]1[CH2:21][OH:22]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1C=CC=CC=1>[OH:19][CH:20]([CH2:21][OH:22])[CH2:23][N:9]1[C:8](=[O:12])[CH2:7][O:6][C:5]2[C:4]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:3][C:2]([CH3:1])=[N:11][C:10]1=2
Reactant: OCC1CO1
Reactant: Cc1nc2c(c(N3CCOCC3)n1)OCC(=O)N2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: c1ccccc1
Product: Cc1nc(N2CCOCC2)c2c(n1)N(CC(O)CO)C(=O)CO2
Reaction time: 7 h
Yield: 80.2 %

Procedure:
A mixture containing 1 g of 2-methyl-4-(4-morpholinyl)-6,7-dihydro-8H-pyrimido[5,4-b][1,4]oxazin-7-one, 0.59 g of 2,3-epoxypropanol, 0.128 g of tetra(n-butyl)ammonium bromide and 60 ml of abs. benzene is refluxed under stirring for 7 hours. After filtering, the precipitate is washed with benzene and ether and dried to give 1.04 g (77%) of the product, m.p.: 153°-155° C.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([NH:18][C:19]([C:21]2[NH:22][N:23]=[C:24]([CH:26]3[CH2:28][CH2:27]3)[CH:25]=2)=[O:20])[CH:13]=1)[CH2:9][CH2:10][OH:11])(C)(C)C.Cl>O1CCOCC1>[NH2:7][CH:8]([C:12]1[CH:13]=[C:14]([NH:18][C:19]([C:21]2[NH:22][N:23]=[C:24]([CH:26]3[CH2:28][CH2:27]3)[CH:25]=2)=[O:20])[CH:15]=[CH:16][CH:17]=1)[CH2:9][CH2:10][OH:11]
Reactant: CC(C)(C)OC(=O)NC(CCO)c1cccc(NC(=O)c2cc(C3CC3)n[nH]2)c1
Agent: Cl
Solvent: C1COCCO1
Product: NC(CCO)c1cccc(NC(=O)c2cc(C3CC3)n[nH]2)c1
Reaction time: 8 h

Procedure:
1.5 g (0.3.1 mmol) (1-{3-[(5-Cyclopropyl-2H-pyrazole-3-carbonyl)-amino]-phenyl}-3-hydroxy-propyl)-carbamic acid tert-butyl ester were dissolved in 40 ml dioxane and 15 ml 4 N HCl in dioxane were added. The mixture was stirred overnight, filtered and washed with dioxane. To this residue, 0.1 N NaOH and ethyl acetate was added, the aqueus phase was washed with ethyl acetate twice, the organic layer was dried over Na2SO4 and evaporated to dryness.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH3:14])[NH:11][N:10]=2)[N:5]2[CH:15]=[CH:16][N:17]=[C:4]2[CH:3]=1.[CH3:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>CN(C=O)C>[CH3:18][N:19]1[CH2:24][CH2:23][N:22]([C:2]2[N:7]=[C:6]([NH:8][C:9]3[CH:13]=[C:12]([CH3:14])[NH:11][N:10]=3)[N:5]3[CH:15]=[CH:16][N:17]=[C:4]3[CH:3]=2)[CH2:21][CH2:20]1
Reactant: CN1CCNCC1
Reactant: Cc1cc(Nc2nc(Cl)cc3nccn23)n[nH]1
Solvent: CN(C)C=O
Product: Cc1cc(Nc2nc(N3CCN(C)CC3)cc3nccn23)n[nH]1
Temperature: 175 °C

Procedure:
Referring to Scheme 6, (7-Chloro-imidazo[1,2-c]pyrimidin-5-yl)-(5-methyl-1H-pyrazol-3-yl)-amine (0.12 mol) and 1-methyl-piperazine (1.2 mol) were dissolved in DMF (0.3 mL) This solution was heated at between 150-200° C. for 1-25 minutes using a microwave reactor. Purification by preparative HPLC afforded the product as a solid. 1H NMR (400 MHz, DMSO-D6) δ ppm 2.27 (s, 3H) 2.84 (s, 3H) 3.13 (bs, 2H) 3.32-3.49 (m, 4H) 4.41 (bs, 2H) 6.31 (s, 1H) 6.38 (s, 1H) 7.78 (d, J=2.53 Hz, 1H) 8.29 (d, J=2.27 Hz, 1H) 10.83 (s, 1H) 12.41 (s, 1H); ESI-MS: m/z 313.3 (M+H)+
Reaction SMILES: [CH:1]12[NH:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][CH:3]([C:9]1[N:13]=[C:12]([NH:14][C:15]3[C:20]([O:21][C:22]4[C:23]([CH3:28])=[N:24][CH:25]=[CH:26][CH:27]=4)=[CH:19][C:18]([S:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=4)=[CH:17][N:16]=3)[S:11][N:10]=1)[CH2:2]2.C(N(CC)CC)C.[C:43](OC(=O)C)(=[O:45])[CH3:44].[ClH:50]>C(Cl)Cl>[ClH:50].[CH3:28][C:23]1[C:22]([O:21][C:20]2[C:15]([NH:14][C:12]3[S:11][N:10]=[C:9]([CH:3]4[CH2:4][CH:5]5[N:8]([C:43](=[O:45])[CH3:44])[CH:1]([CH2:7][CH2:6]5)[CH2:2]4)[N:13]=3)=[N:16][CH:17]=[C:18]([S:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=3)[CH:19]=2)=[CH:27][CH:26]=[CH:25][N:24]=1
Reactant: Cc1ncccc1Oc1cc(Sc2ccccn2)cnc1Nc1nc(C2CC3CCC(C2)N3)ns1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1C2CCC1CC(c1nsc(Nc3ncc(Sc4ccccn4)cc3Oc3cccnc3C)n1)C2
Reaction time: 0.08 h
Yield: 82.4 %

Procedure:
3-(8-azabicyclo[3.2.1]octan-3-yl)-N-(3-(2-methylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-yl)-1,2,4-thiadiazol-5-amine (100 mg, 0.199 mmol) was dissolved in CH2Cl2 (3 mL) and triethylamine (41.5 μL, 0.298 mmol) and acetic anhydride (22.5 μL, 0.238 mmol) were added and the reaction stirred for 5 minutes. The reaction was partitioned between saturated aqueous NaHCO3 and CH2Cl2, dried over sodium sulfate, filtered, concentrated and purified on silica gel (10% methanol in EtOAc) to afford 1-(3-(5-(3-(2-methylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)-8-azabicyclo[3.2.1]octan-8-yl)ethanone hydrochloride (95.2 mg, 0.164 mmol, 82.4% yield) as a solid after HCl salt formation. Mass spectrum (apci) m/z=546.0 (M+H—HCl).
Reaction SMILES: [F:1][C:2]1([CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([S:16]([NH2:19])(=[O:18])=[O:17])=[CH:12][C:11]=2[N+:20]([O-:22])=[O:21])[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[O:23]1[CH2:28][CH2:27][C:26](=O)[CH2:25][CH2:24]1.C([BH3-])#N.[Na+].C(O)(=O)C>O1CCCC1>[F:1][C:2]1([CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([S:16]([NH2:19])(=[O:18])=[O:17])=[CH:12][C:11]=2[N+:20]([O-:22])=[O:21])[CH2:7][CH2:6][N:5]([CH:26]2[CH2:27][CH2:28][O:23][CH2:24][CH2:25]2)[CH2:4][CH2:3]1
Reactant: O=C1CCOCC1
Reactant: NS(=O)(=O)c1ccc(OCC2(F)CCNCC2)c([N+](=O)[O-])c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: NS(=O)(=O)c1ccc(OCC2(F)CCN(C3CCOCC3)CC2)c([N+](=O)[O-])c1

Procedure:
A mixture of EXAMPLE 173A (0.4 g), dihydro-2H-pyran-4(3H)-one (0.179 g), sodium cyanoborohydride (0.112 g), and acetic acid (0.5 mL) in tetrahydrofuran (3 mL) was stirred overnight. The solvents were removed under reduced pressure. The residue was purified with flash column chromatography on silica gel eluting with 100:5:0.5 ethyl acetate/methanol/NH4OH to give the desired product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]3[N:29]=[CH:28][S:27][C:14]=3[N:15]=[C:16]([N:18]3[CH2:23][CH2:22][CH2:21][CH:20]([C:24](O)=[O:25])[CH2:19]3)[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[NH2:30][C:31]1[CH:40]=[CH:39][C:34]([C:35]([O:37][CH3:38])=[O:36])=[C:33]([O:41][CH3:42])[CH:32]=1.CN1C=CN=C1.CCN=C=NCCCN(C)C>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]3[N:29]=[CH:28][S:27][C:14]=3[N:15]=[C:16]([N:18]3[CH2:23][CH2:22][CH2:21][CH:20]([C:24]([NH:30][C:31]4[CH:40]=[CH:39][C:34]([C:35]([O:37][CH3:38])=[O:36])=[C:33]([O:41][CH3:42])[CH:32]=4)=[O:25])[CH2:19]3)[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COC(=O)c1ccc(N)cc1OC
Reactant: COc1ccc(Nc2nc(N3CCCC(C(=O)O)C3)nc3scnc23)cc1OC
Agent: CCN=C=NCCCN(C)C
Agent: Cn1ccnc1
Solvent: ClCCl
Product: COC(=O)c1ccc(NC(=O)C2CCCN(c3nc(Nc4ccc(OC)c(OC)c4)c4ncsc4n3)C2)cc1OC
Temperature: 25 °C
Reaction time: 15 h
Yield: 80.6 %

Procedure:
To a solution of 1-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)piperidine-3-carboxylic acid (110 mg, 0.27 mmol) and methyl 4-amino-2-methoxybenzoate (48 mg, 0.27 mmol) in dichloromethane (15 mL) were added the solution of 1-methyl-1H-imidazole (87 mg, 1.1 mmol) and EDCI (203 mg, 1.1 mmol) in dichloromethane (5 mL), the reaction mixture was stirred at room temperature for 15 hours, the solvent was removed in vacuo, then methanol (5 mL) was added, the precipitate was collected by filtration and washed with methanol (5 mL) to afford methyl 4-(1-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)piperidine-3-carboxamido)-2-methoxybenzoate (126 mg, 80.8%) as an orange solid. LC-MS: 579 [M+H]+, tR=1.58 min.
Reaction SMILES: [Cl-].[Zn+2:2].[Cl-].[C-:4]#[N:5].[C-]#N.[C-]#N.[C-]#N.[C-]#N.[C-]#N.[Co:16]>O>[C-:4]#[N:5].[C-:4]#[N:5].[C-:4]#[N:5].[C-:4]#[N:5].[C-:4]#[N:5].[C-:4]#[N:5].[C-:4]#[N:5].[C-:4]#[N:5].[C-:4]#[N:5].[C-:4]#[N:5].[C-:4]#[N:5].[C-:4]#[N:5].[Co+3:16].[Co+3:16].[Zn+2:2].[Zn+2:2].[Zn+2:2]
Reactant: [Co]
Agent: [C-]#N
Agent: [Cl-]
Agent: [Zn+2]
Solvent: O
Product: [Co+3]

Procedure:
A solution of zinc chloride (26.65 g; 0.1956 mole) in water (26.65 g) was added rapidly to an agitated solution of potassium hexacyanocobaltate (13.00 g, 0.0391 mole) in water (263.35 g). The potassium hexacyanocobaltate solution was maintained at 40° C. during addition of the zinc chloride solution. A colorless precipate of zinc hexacyanocobaltate particles formed immediately upon addition. After stirring for 15 minutes at 40° C., dimethoxyethane (84.00 g; 0.9321 mole) was added to the aqueous catalyst slurry. The resulting mixture was stirred for an additional 30 minutes and the zinc hexacyanocobaltate zinc chloride dimethoxyethane water complex catalyst recovered by filtration using a horizontal basket centrifugal filter and a light weight nylon fabric filter medium. After washing with 300 mL dimethoxyethane and drying in air at ambient temperature and pressure, the filter cake obtained was quite soft and could be easily crushed to a fine powder.
Reaction SMILES: C(OC([NH:11][C@H:12]([CH2:22][CH3:23])/[CH:13]=[CH:14]/[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=O)C1C=CC=CC=1.C(O)(=O)C>CO.[C].[Pd]>[C:15]([OH:17])(=[O:16])[CH3:14].[NH2:11][C@H:12]([CH2:22][CH3:23])[CH2:13][CH2:14][C:15]([O:17][C:18]([CH3:20])([CH3:19])[CH3:21])=[O:16]
Reactant: CC[C@H](/C=C/C(=O)OC(C)(C)C)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: CC[C@@H](N)CCC(=O)OC(C)(C)C
Reaction time: 7 h

Procedure:
To a solution of tert-butyl (2E, 4R)-4-{[(benzyloxy)carbonyl]amino}-2-hexenoate (9.73 g, 30.5 mmol) in methanol (200 ml) were added acetic acid (3.5 ml, 61 mmol) and 10% Palladium carbon (3.2 g). The mixture was stirred under hydrogen atmosphere for 7 hours. Catalyst was filtered off under a nitrogen atomosphere and the filtrate was condensed with an evaporator to give tert-butyl (4R)-4-aminohexanoate acetic acid salt (7.5 g, quantitatively).