Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[CH:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[CH2:16][OH:17].CNC1C=CC=C(NC)N=1.C(N(CC)CC)C.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>ClCCl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[CH:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[CH2:16][O:17][S:36]([CH3:35])(=[O:38])=[O:37]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(OC)c(C2CCCC2CO)c1
Agent: CNc1cccc(NC)n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(OC)c(C2CCCC2COS(C)(=O)=O)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 101.8 %

Procedure:
Dissolve [2-(2,5-dimethoxy-phenyl)-cyclopentyl]-methanol (3.6 g, 15 mmol) in dichloromethane (94 ml), add 2,6-dimethylaminopyridine (0.4 g, 0.31 mmol), add triethylamine (4.7 ml, 33.5 mmol), cool to 0° C., add methanesulfonyl chloride (1.9 g, 17 mmol), remove ice bath and stir 2 hours at room temperature. Quench with water and ethyl acetate, separate layers, wash with brine, dry and concentrate to give the title compound (4.8 g, 100%): 1H NMR (CDCl3) δ 6.78-6.69 (m, 3H), 3.86-3.82 (m, 1H), 3.79 (s, 3H), 3.76 (s, 3H), 3.68-3.64 (m,1H), 3.53-3.47 (m, 1H), 2.83-2.76 (m, 1H), 2.69 (s,3H), 1.97-1.88 (m, 3H), 1.67-1.60 (m,3H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:14]3[C:13]([C:22]4[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=4)=[N:12][NH:11][C:10]=3[C:9]2=[O:30])=[CH:4][CH:3]=1.[O:31]1[CH:35]=[CH:34][NH:33]N1[Sn](CCCC)(CCCC)CCCC.O1C=CC=[C:50]1P(C1OC=CC=1)C1OC=CC=1>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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[CH3:29][O:28][C:25]1[CH:24]=[CH:23][C:22]([C:13]2[C:14]3[CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[N:8]([C:5]4[CH:6]=[CH:7][C:2]([C:50]5[O:31][CH:35]=[CH:34][N:33]=5)=[CH:3][CH:4]=4)[C:9](=[O:30])[C:10]=3[NH:11][N:12]=2)=[CH:27][CH:26]=1
Reactant: CCCC[Sn](CCCC)(CCCC)N1NC=CO1
Reactant: COc1ccc(-c2n[nH]c3c2C(c2ccccc2)N(c2ccc(Br)cc2)C3=O)cc1
Reactant: c1coc(P(c2ccco2)c2ccco2)c1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: COc1ccc(-c2n[nH]c3c2C(c2ccccc2)N(c2ccc(-c4ncco4)cc2)C3=O)cc1
Temperature: 130 °C
Reaction time: 1.25 h
Yield: 44.6 %

Procedure:
A mixture of 5-(4-bromophenyl)-3-(4-methoxyphenyl)-4-phenyl-4,5-dihydro-1H-pyrrolo[3,4-c]pyrazol-6-one (0.138 g, 0.3 mmol), oxadiazol-2-yl tributyltin (0.134 g, 0.37 mmol), tris(2-furyl)phosphine (0.014 g, 0.06 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.027 g, 0.03 mmol) and dioxane (1.5 mL) was stirred at 130° C. under microwave radiation for 75 min. The reaction mixture was purified by silica gel column chromatography (ethyl acetate/n-hexane). The fraction was concentrated under reduced pressure and the precipitate was collected by filtration to give 3-(4-methoxyphenyl)-5-(4-oxazol-2-ylphenyl)-4-phenyl-4,5-dihydro-1H-pyrrolo[3,4-c]pyrazol-6-one (12 mg, 10%) as colorless crystals.
Reaction SMILES: [Cl:1][CH2:2][C@:3]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=1[F:21])([OH:13])[C@H:4]([O:6]C1CCCCO1)[CH3:5].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[Cl:1][CH2:2][C@:3]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=1[F:21])([OH:13])[C@H:4]([OH:6])[CH3:5]
Reactant: C[C@@H](OC1CCCCO1)[C@@](O)(CCl)c1ccc(F)cc1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: C[C@@H](O)[C@@](O)(CCl)c1ccc(F)cc1F
Yield: 107.9 %

Procedure:
A mixed solution of 0.15 g (0.47 mmol) of (2R,3R)-1-chloro-2-(2,4-difluorophenyl)-3-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)butan-2-ol, 5 mL of methanol, and 0.02 g of p-toluenesulfonic acid monohydrate was stirred at room temperature for 30 minutes. Concentration was performed under reduced pressure to obtain a crude product. The resulting product was purified by column on silica gel to obtain 0.12 g of the title compound (yield: 97%).
Reaction SMILES: ClC1C=C(Cl)C=CC=1C1C(N2C=CN=C2)=CN=C(CCN)N=1.Cl[C:24]1[N:29]=[C:28]([O:30][CH2:31][CH2:32][N:33]([CH3:35])[CH3:34])[C:27]([N+:36]([O-:38])=[O:37])=[CH:26][CH:25]=1.[Cl:39][C:40]1[CH:45]=[C:44]([Cl:46])[CH:43]=[CH:42][C:41]=1[C:47]1[C:52]([C:53]2[NH:54][CH:55]=[CH:56][N:57]=2)=[CH:51][N:50]=[C:49]([NH:58][CH2:59][CH2:60][NH:61]C2C=CC([N+]([O-])=O)=C(OC)N=2)[N:48]=1>>[Cl:39][C:40]1[CH:45]=[C:44]([Cl:46])[CH:43]=[CH:42][C:41]=1[C:47]1[C:52]([C:53]2[NH:57][CH:56]=[CH:55][N:54]=2)=[CH:51][N:50]=[C:49]([NH:58][CH2:59][CH2:60][NH:61][C:24]2[N:29]=[C:28]([O:30][CH2:31][CH2:32][N:33]([CH3:35])[CH3:34])[C:27]([N+:36]([O-:38])=[O:37])=[CH:26][CH:25]=2)[N:48]=1
Reactant: COc1nc(NCCNc2ncc(-c3ncc[nH]3)c(-c3ccc(Cl)cc3Cl)n2)ccc1[N+](=O)[O-]
Reactant: CN(C)CCOc1nc(Cl)ccc1[N+](=O)[O-]
Agent: NCCc1ncc(-n2ccnc2)c(-c2ccc(Cl)cc2Cl)n1
Product: CN(C)CCOc1nc(NCCNc2ncc(-c3ncc[nH]3)c(-c3ccc(Cl)cc3Cl)n2)ccc1[N+](=O)[O-]

Procedure:
(2-{6-[(2-{[4-(2,4-dichlorophenyl)-5-imidazolylpyrimidin-2-yl]amino}ethyl)-amino]-3-nitro(2-pyridyloxy)}ethyl)dimethylamine was prepared from [4-(2,4-dichlorophenyl)-5-imidazol-1-ylpyrimidin-2-ylethylamine and [2-(6-chloro-3-nitro(2-pyridyloxy))ethyl]dimethylamine in accordance with the procedure described above for the preparation of [4-(2,4-dichlorophenyl)-5-imidazol-2-ylpyrimidin-2-yl]{2-[(6-methoxy-5-nitro(2-pyridyl))amino]ethyl}amine.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[C:9]([O:12][CH2:13][CH2:14]Br)(=[O:11])[CH3:10].C([O-])([O-])=O.[Cs+].[Cs+]>CC#N.CCOC(C)=O>[CH2:13]([O:12][C:9](=[O:11])[CH2:10][O:8][C:5]1[CH:6]=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH3:14]
Reactant: Oc1ccc(Cl)nc1
Reactant: CC(=O)OCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCOC(=O)COc1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.1 %

Procedure:
To a suspension of 6-chloro-pyridin-3-ol (1000 mg, 7.72 mmol) and bromoethyl acetate (1933 mg, 11.57 mmol) in CH3CN was added Cs2CO3 (3772 mg, 11.57 mmol). The mixture was stirred for overnight at room temperature. The reaction mixture was diluted with EtOAc, then washed three times with H2O and brine, and then dried. MgSO4, filtered and concentrated under reduced pressure. The obtained residue was column-chromatographed to yield the (6-chloro-pyridin-3-yloxy)-acetic acid ethyl ester (1.5 g, 90%).
Reaction SMILES: [OH-].[K+].C([O:6][CH2:7][C@H:8]1[C@H:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:9]1([Cl:18])[Cl:17])(=O)C.O1CCCC1.Cl>CO.O>[Cl:17][C:9]1([Cl:18])[C@@H:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C@@H:8]1[CH2:7][OH:6]
Reactant: CC(=O)OC[C@H]1[C@H](c2ccccc2)C1(Cl)Cl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: OC[C@H]1[C@H](c2ccccc2)C1(Cl)Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of KOH (3.36 g, 60 mmol) and the product of Step 1, above, (10.36 g, 40 mmol) in a mixture of methanol (30 ml), tetrahydrofuran (30 ml) and water (90 ml) was stirred for 3 hours at room temperature. The reaction mixture was neutralized with 1N aqueous hydrochloric acid and extracted with diethyl ether (100 ml+2×50 ml). The combined organic phases were washed with saturated aqueous sodium bicarbonate (2×50 ml) and brine (50 ml), then dried over MgSO4. Evaporation of the solvent afforded (2,2-dichloro-trans-3-phenylcyclopropyl)methanol in quantitative yield. To a stirred solution of the alcohol thus prepared (4.34 g, 20 mmol), N,O-di-tert-butoxycarbonylhydroxylamine (5.83 g, 25 mmol), and triphenylphosphine (6.56 g, 25 mmol) in toluene (40 ml), cooled to −42° C. was added dropwise a solution of diethyl azodicarboxylate (4.35 g, 25 mmol) in toluene (5 ml) over 15 minutes under a nitrogen atmosphere. The reaction mixture was allowed to warm to room temperature overnight, insolubles were removed by filtration and the filtrate concentrated under reduced pressure. The resultant residue was purified by column chromatography (SiO2, 300 g; 8% ethyl acetate in n-hexane) affording the title compound (8.09 g, 94% yield).
Reaction SMILES: C(O[C:4]([C:6]1[CH:15]=[N:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1)=[O:5])C.[CH:16]1([C:19]([CH3:21])=[O:20])[CH2:18][CH2:17]1.C[O-].[Na+]>C1C=CC=CC=1>[CH:16]1([C:19](=[O:20])[CH2:21][C:4]([C:6]2[CH:15]=[N:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]=2)=[O:5])[CH2:18][CH2:17]1
Reactant: CC(=O)C1CC1
Reactant: CCOC(=O)c1cnc2ccccc2n1
Agent: C[O-]
Agent: [Na+]
Solvent: c1ccccc1
Product: O=C(CC(=O)C1CC1)c1cnc2ccccc2n1

Procedure:
A mixture of 3.0 g. of ethyl-2-quinoxalate, 1.7 g. of cyclopropylmethyl ketone and 0.9 g. of sodium methoxide in 100 ml. of benzene is heated under reflux for 4 hours. The mixture is diluted with 100 ml. of water and the benzene phase is separated. The aqueous solution is made weakly acidic with dilute hydrochloric acid and extracted with chloroform. The chloroform solution is dried over magnesium sulfate and concentrated under reduced pressure to yield straw-colored crystals, which are recrystallized from acetonitrile to provide cream-colored crystals, melting point 113°-115°C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:12][CH3:13])[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10].[OH2:14].C[OH:16].OOS([O-])=O.[K+]>CC(C)=O.CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:12]([CH3:13])(=[O:16])=[O:14])[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10]
Reactant: O
Reactant: CO
Reactant: COc1cc(SC)ccc1[N+](=O)[O-]
Agent: O=S([O-])OO
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: COc1cc(S(C)(=O)=O)ccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 83 %

Procedure:
To a suspension of (3-methoxy-4-nitrophenyl)(methyl)sulfane (0.58 g, 2.9 mmol) in acetone (10 mL) was added water (10 mL), methanol (1.0 mL). The mixture was cooled in an ice-bath for 10 minutes before adding Oxone (2.90 g, 4.72 mmol) in four portions over 4 minutes. The reaction was stirred at 0° C. for 15 minutes and then allowed to warm up to room temperature. The reaction was stirred at room temperature for 2 hours before being diluted with EtOAc (50 mL). The suspension was filtered, concentrated to ⅓ of its volume and diluted with water (40 mL). The mixture was then extracted with EtOAc. The combined extracts were washed with brine, dried over sodium sulfate, filtered and concentrated to give 2-methoxy-4-(methylsulfonyl)-1-nitrobenzene (0.67 g, 83%).
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:8][O:9][C:10]1[CH:11]=[C:12]([CH2:18][CH2:19]Cl)[CH:13]=[CH:14][C:15]=1[O:16][CH3:17].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:8][O:9][C:10]1[CH:11]=[C:12]([CH2:18][CH2:19][N:1]2[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)[CH:13]=[CH:14][C:15]=1[O:16][CH3:17]
Reactant: C1CNCCNC1
Reactant: COc1ccc(CCCl)cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(CCN2CCCNCC2)cc1OC
Yield: 77.1 %

Procedure:
32.27 g of homopiperazine, 13.2 g of 2-(3,4-dimethoxyphenyl)ethyl chloride and 71.3 g of potassium carbonate were added to 500 ml of acetonitrile. The obtained mixture was heated under reflux for 20 hours, cooled and filtered. The filtrate was concentrated under a reduced pressure to obtain a residue. This residue was extracted with ether thrice. The extracts were combined, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under a reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent: chloroform/methanol/isopropylamine (100:10:1)) to obtain 13.40 g of the title compound as a yellow oil (yield: 77%).
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH3:7])=[O:5])#[N:2].[CH:8](=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(O)(=O)C.O>C1C=CC=CC=1.NCCC(O)=O>[C:1](/[C:3](=[CH:8]\[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)/[C:4]([O:6][CH3:7])=[O:5])#[N:2]
Reactant: O=Cc1ccccc1
Reactant: COC(=O)CC#N
Agent: NCCC(=O)O
Solvent: c1ccccc1
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)/C(C#N)=C/c1ccccc1
Yield: 91.3 %

Procedure:
A mixture containing 2.0 mL (22.7 mmoles) of methyl cyanoacetate, 2.38 g (22.4 mmoles) of benzaldehyde, 18 mg of β-alanine, and 1.00 mL of glacial acetic acid in 35 mL of benzene was heated at reflux for 2 hours with continuous azeotropic removal of water by means of a Dean-Stark trap. The product was isolated as described in the procedure of Example I, affording 3.83 g (91% yield) of crystalline cyanoester 2: mp 90°-91° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH:15]3[CH:19]([C:20]4[CH:24]=[CH:23][S:22][CH:21]=4)[CH2:18][NH:17][CH2:16]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:32][C:33]1[N:41]=[CH:40][CH:39]=[CH:38][C:34]=1[C:35](Cl)=[O:36]>C(Cl)Cl>[Cl:32][C:33]1[C:34]([C:35]([N:17]2[CH2:18][CH:19]([C:20]3[CH:24]=[CH:23][S:22][CH:21]=3)[CH:15]([CH2:14][N:11]3[CH2:10][CH2:9][CH:8]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)[CH2:13][CH2:12]3)[CH2:16]2)=[O:36])=[CH:38][CH:39]=[CH:40][N:41]=1
Reactant: O=C(Cl)c1cccnc1Cl
Reactant: Fc1ccc(C2CCN(CC3CNCC3c3ccsc3)CC2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1cccnc1Cl)N1CC(CN2CCC(c3ccc(F)cc3)CC2)C(c2ccsc2)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 82.6 %

Procedure:
A mixture of 0.105 g (0.3 mmol) of 3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(RS)-(3-thienyl)pyrrolidine, 0.082 mL (0.6 mmol) of triethylamine and 0.054 g (0.3 mmol) of 2-chloronicotinoyl chloride (Aldrich) in 6 mL of CH2Cl2 was stirred at rt for 4 h. The reaction mixture was concentrated and the residue was purified by chomatography (silica, hexanes: acetone=3:1) to afford 0.12 g of the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH:9]([N:12]=[CH:13]C)([CH3:11])[CH3:10].[Cl-].[NH4+].O1CCC[CH2:18]1>C([Li])CCC.CCCCCC>[OH:8][C:7]1[C:2]([CH:1]([CH3:18])[CH2:13][NH:12][CH:9]([CH3:11])[CH3:10])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: C1CCOC1
Reactant: Cc1ncccc1O
Reactant: CC=NC(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Product: CC(C)NCC(C)c1ncccc1O

Procedure:
To the solution of 10.9 g of 2-methyl-3-hydroxypyridine in 400 ml of tetrahydrofuran, 88 ml of 2.5 molar n-butyllithium in hexane are added dropwise while stirring under nitrogen and keeping the temperature at about 0°. Stirring is continued for 2 hours at 0°-5°, whereupon 0.2 g of isopropyliminoethane are added rapidly and the temperature is maintained at 0°-5°. After stirring the resulting mixture 2 more hours at said temperature, it is poured into 200 ml of saturated aqueous ammonium chloride. The organic layer is separated, evaporated, redissolved in 100 ml of water and the solution extracted 5 times with 50 ml of diethyl ether. The aqueous phase is saturated with sodium chloride, extracted 5 times with 200 ml of methylene chloride, the combined extracts dried, filtered and evaporated. The residue is dissolved in ethanol and the solution neutralized with ethanolic fumaric acid. The resulting suspension is filtered and the residue recrystallized from ethanol, to yield the hemi-fumarate of N-[2-(3-hydroxy-2-pyridyl)propyl]-isopropylamine of Formula II, with R=H, R'=OH and CpH2p±1 =CH(CH3)2, melting at 199°-199.5°.
Reaction SMILES: [I:1][C:2]1[N:3]=[C:4]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)=[CH:12][CH:11]=2)[NH:5][C:6]=1I.S([O-])([O-])=O.[Na+].[Na+]>C(O)C.O>[I:1][C:2]1[N:3]=[C:4]([CH2:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)=[CH:14][CH:15]=2)[NH:5][CH:6]=1
Reactant: Ic1nc(CCc2ccc(-c3ccccn3)cc2)[nH]c1I
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Ic1c[nH]c(CCc2ccc(-c3ccccn3)cc2)n1

Procedure:
A solution of 2-{4-[2-(4,5-diiodo-1H-imidazol-2-yl)ethyl]phenyl}pyridine (11.2 g, 22.4 mmol) and sodium sulfite (3.1 g, 24.7 mmol) in ethanol (200 mL) and water (200 mL) was heated at 100° C. for 2 days. The reaction mixture was concentrated to half its original volume and partitioned between ethyl acetate and water. The organic phase was separated and concentrated in vacuo to afford 2-{4-[2-(4-iodo-1H-imidazol-2-yl)ethyl]phenyl}pyridine, which was used without further purification.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]2[N:11]=[C:10]([CH2:12][N:13]3[CH2:18][CH2:17][CH:16]([C:19]([OH:22])([CH3:21])[CH3:20])[CH2:15][CH2:14]3)[CH:9]=[CH:8][C:6]=2[N:7]=1.[NH:29]1[C:37]2[C:32](=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30]1>>[NH:29]1[C:37]2[C:32](=[C:33]([C:2]3[N:3]=[C:4]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)[C:5]4[N:11]=[C:10]([CH2:12][N:13]5[CH2:18][CH2:17][CH:16]([C:19]([OH:22])([CH3:21])[CH3:20])[CH2:15][CH2:14]5)[CH:9]=[CH:8][C:6]=4[N:7]=3)[CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30]1
Reactant: OB(O)c1cccc2[nH]ccc12
Reactant: CC(C)(O)C1CCN(Cc2ccc3nc(Cl)nc(N4CCOCC4)c3n2)CC1
Product: CC(C)(O)C1CCN(Cc2ccc3nc(-c4cccc5[nH]ccc45)nc(N4CCOCC4)c3n2)CC1

Procedure:
2-(1-((2-chloro-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)propan-2-ol from Example 8 (88 mg) was reacted with 1H-indol-4-ylboronic acid via General Procedure A to produce 22.8 mg of 109 following reverse phase HPLC purification.
Reaction SMILES: N1([CH:10]=[O:11])C2C=CC=CC=2N=N1.[C:12]1([CH2:18][O:19][NH:20][CH2:21][C@@H:22]([CH2:26][CH2:27][CH2:28][CH3:29])[C:23]([OH:25])=[O:24])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C([O-])([O-])=O.[Na+].[Na+].CC(OC(OC(OC(C)(C)C)=O)=O)(C)C>C1COCC1.O>[CH:10]([N:20]([CH2:21][C@@H:22]([CH2:26][CH2:27][CH2:28][CH3:29])[C:23]([OH:25])=[O:24])[O:19][CH2:18][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:11]
Reactant: CCCC[C@H](CNOCc1ccccc1)C(=O)O
Reactant: O=Cn1nnc2ccccc21
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCCC[C@H](CN(C=O)OCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.3 %

Procedure:
To a solution of 1H-1,2,3-benzotriazole-1-carbaldehyde (26 g, 0.18 mol) in THF (200 ml) at 0° C. was added dropwise a solution of (2R)-2-({[(phenylmethyl)oxy]amino}methyl)hexanoic acid (8) (40 g, 0.16 mol) in THF (200 mL). The reaction mixture was warmed up to rt and stirred overnight. LC/MS indicated completion of the reaction. To the reaction mixture at 0° C. was added water (400 mL), Na2CO3 (36 g), and Boc2O (43.6 g, 0.36 mol). The mixture was stirred for 3 h. THF was removed under vacuum. The aqueous mixture was washed with ether and then acidified to pH ˜2.0 with acetic acid, and extracted with ethyl acetate. The extracts were dried and concentrated to provide the title compound (36.8 g, 80%). LCMS: (M+H)+: 280.2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:20]3[CH:25]=[CH:24][C:23]([S:26][CH3:27])=[CH:22][CH:21]=3)=[N:10][N:11]([CH2:17][C:18]#[CH:19])[C:12]=2[C:13]([F:16])([F:15])[F:14])=[CH:4][CH:3]=1.OO.[OH2:30].C(O)(=[O:33])C>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:20]3[CH:21]=[CH:22][C:23]([S:26]([CH3:27])(=[O:33])=[O:30])=[CH:24][CH:25]=3)=[N:10][N:11]([CH2:17][C:18]#[CH:19])[C:12]=2[C:13]([F:15])([F:16])[F:14])=[CH:4][CH:3]=1
Reactant: CC(=O)O
Reactant: C#CCn1nc(-c2ccc(SC)cc2)c(-c2ccc(F)cc2)c1C(F)(F)F
Reactant: O
Agent: OO
Product: C#CCn1nc(-c2ccc(S(C)(=O)=O)cc2)c(-c2ccc(F)cc2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 72 h
Yield: 21 %

Procedure:
To a solution of 0.066 mmol of 4-(4-fluorophenyl)-3-[4-(methylthio)phenyl-]1-propargyl-5-(trifluoromethyl)pyrazole from step 2 in 5 mL of glacial acetic acid was added 13 mmol of 30% hydrogen peroxide. The reaction mixture was stirred at room temperature for 72 hours and poured into water. The crude product was purified by HPLC (40% ethyl acetate-hexane) followed by recrystallization from methylene chloride-hexane to give 4-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]-1-propargyl-5-(trifluoromethyl)-1H-pyrazole as white needles (21%): mp 158°-159.5° C.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:7]([OH:9])=[O:8])=[CH:5][N:6]=1.[CH2:10]([Li])CCC.[CH2:15]([C:19]1[C:23]([CH:24]=[O:25])=[C:22]([CH3:26])[O:21][N:20]=1)[CH2:16][CH2:17][CH3:18]>C1COCC1.CCCCCC>[CH3:10][O:8][C:7]([C:4]1[S:3][C:2]([CH2:1][CH:24]([C:23]2[C:19]([CH2:15][CH2:16][CH2:17][CH3:18])=[N:20][O:21][C:22]=2[CH3:26])[OH:25])=[N:6][CH:5]=1)=[O:9]
Reactant: [Li]CCCC
Reactant: CCCCc1noc(C)c1C=O
Reactant: Cc1ncc(C(=O)O)s1
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCCc1noc(C)c1C(O)Cc1ncc(C(=O)OC)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 10 %

Procedure:
To a stirred solution of 2-methyl-thiazole-5-carboxylic acid (215 mg, 1.50 mmol) in THF (10 mL) at −78° C. and under argon was added n-butyllithium (1.88 mL of a 1.60M solution in hexane, 3.0 mmol) dropwise. After 1 h, a solution of 3-butyl-5-methyl-isoxazole-4-carbaldehyde (251 mg, 1.50 mmol) in THF (10 mL) was added dropwise. After 2 h the reaction mixture was quenched with 10% aqueous citric acid (10 mL) then warmed to room temperature. The reaction mixture was extracted with ethyl acetate then the combined extracts were dried, filtered and concentrated. The resultant oil was redissolved in methanol (15 mL) and ether (7 mL) then (trimethylsilyl)diazomethane (2.25 mL of a 2M solution in ether, 4.5 mmol) was added dropwise. After 30 min, further (trimethylsilyl)diazomethane (2.25 mL of a 2M solution in ether, 4.5 mmol) was added. After 30 min, the reaction mixture was quenched with acetic acid (3 drops) then was concentrated and the residue redissolved in ethyl acetate and washed with NaOH (2 N). The organic phase was dried, filtered and concentrated then purified by chromatography (silica, 0 to 4% methanol in dichloromethane) to give the title compound (49 mg, 10%) as a brown oil. MS: m/e=307.3 [M+H]+.
Reaction SMILES: [CH:1]1[C:7]([NH2:8])=[N:6][C:4](=[O:5])[N:3]([C@@H:9]2[O:13][C@H:12]([CH2:14][OH:15])[C@@H:11]([OH:16])[C:10]2([F:18])[F:17])[CH:2]=1.Cl.Cl[Si](C)(C)C.Cl[C:26]([O:28][CH2:29][CH:30]=[CH2:31])=[O:27].CCO>N1C=CC=CC=1.O>[CH2:29]([O:28][C:26]([NH:8][C:7]1[CH:1]=[CH:2][N:3]([C@H:9]2[C:10]([F:17])([F:18])[C@H:11]([OH:16])[C@@H:12]([CH2:14][OH:15])[O:13]2)[C:4](=[O:5])[N:6]=1)=[O:27])[CH:30]=[CH2:31]
Reactant: Nc1ccn([C@@H]2O[C@H](CO)[C@@H](O)C2(F)F)c(=O)n1
Reactant: C=CCOC(=O)Cl
Agent: C[Si](C)(C)Cl
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Solvent: CCO
Product: C=CCOC(=O)Nc1ccn([C@@H]2O[C@H](CO)[C@@H](O)C2(F)F)c(=O)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
To a solution of gemcitabine hydrochloride (1.2 g, 4 mmol) in 12 mL pyridine, chlorotrimethylsilane (2.54 mL, 20 mmol) was added at 0° C.; after stirring for 2 h, allyl chloroformate (0.43 mL, 4 mmol) was added at 0° C. The reaction mixture was allowed to warm to RT, and heated at 45° C. overnight, then cooled to 30-35° C. when 12 mL of absolute EtOH was added. The reaction mixture was reheated at 45° C. for 0.5 h, and following the addition of 6 mL of H2O, was heated at 45° C. for 5 h, then cooled to RT and concentrated in vacuo. The residue was partitioned between EtOAc and water; The organic layer was separated, and the aqueous layer was again extracted with EtOAc. The organic extracts were combined and washed with saturated aqueous CuSO4 solution, saturated aqueous NaHCO3 solution and brine, dried over Na2SO4 and concentrated in vacuo. Purification by flash column chromatography (5:1→10:1 EtOAc/Hexane) afforded 1 (white solid, 70% yield): 1H NMR (400 MHz, DMSO-d6) δ11.00 (s, 1H), 8.26-8.28 (d, 1H), 7.13-7.15 (d, 1H), 6.34-6.37 (d, 1H), 6.18-6.22 (t, 1H), 5.95-6.02 (m, 1H), 5.38-5.43 (d, 1H), 5.34 (t, 1H), 5.27-5.30 (d, 1H), 4.67-4.69 (d, 2H), 4.20-4.25 (m, 1H), 3.90-3.95 (m, 1H), 3.82-3.86 (m, 1H), 3.66-3.72 (m, 1H); MS (HR-ESI): m/z 346.0857 [M−H]−.