Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]1[CH:12]=[CH:13][C:14]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)=[N:15][CH:16]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Br[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32].[O-]S([O-])(=S)=O.[Na+].[Na+]>CN(C=O)C.CCOC(C)=O>[CH2:34]([O:33][C:31](=[O:32])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][N:17]([C:14]1[CH:13]=[CH:12][C:11]([O:10][CH2:3][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)=[CH:16][N:15]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)[CH3:35]
Reactant: c1ccc(COc2ccc(Nc3ccccn3)nc2)cc1
Reactant: CCOC(=O)CCCCCCBr
Agent: O=S([O-])([O-])=S
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCCCN(c1ccccn1)c1ccc(OCc2ccccc2)cn1
Reaction time: 0.17 h
Yield: 56.4 %

Procedure:
NaH (48 mg, 1.26 6 mmol) was added to II (350 mg, 1.26 mmol) in DMF (6 mL) at rt. After 10 min, KI (314 mg, 1.89 mmol) and ethyl 7-bromoheptanoate (0.370 mL, 1.89 mmol) were added. The reaction mixture was stirred at 90° C. for 18 h30 after which 0.1 M Na2S2O3 (50 mL) and EtOAc (50 mL) were added, the phases were separated and the aqueous extracted with EtOAc (2×25 mL). The organic phases were combined then dried over MgSO4, filtered, and subsequently evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography eluting with hexane/EtOAc (80:20 then 70:30) to furnish III as a colourless oil (308 mg, 56%).
Reaction SMILES: [N:1]1([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]([OH:19])=O)=[CH:12][CH:11]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[CH3:20][N:21]([CH:33]1[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]1)[C:22]1[CH:27]=[CH:26][C:25]([NH2:28])=[CH:24][C:23]=1[C:29]([F:32])([F:31])[F:30]>C(Cl)Cl.CO>[N:1]1([C:10]2[CH:11]=[CH:12][C:13]([CH2:16][C:17]([NH:28][C:25]3[CH:26]=[CH:27][C:22]([N:21]([CH3:20])[CH:33]4[CH2:34][CH2:35][N:36]([CH3:39])[CH2:37][CH2:38]4)=[C:23]([C:29]([F:32])([F:30])[F:31])[CH:24]=3)=[O:19])=[CH:14][CH:15]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: CN1CCC(N(C)c2ccc(N)cc2C(F)(F)F)CC1
Reactant: O=C(O)Cc1ccc(-n2cnc3ccccc32)cc1
Solvent: ClCCl
Solvent: CO
Product: CN1CCC(N(C)c2ccc(NC(=O)Cc3ccc(-n4cnc5ccccc54)cc3)cc2C(F)(F)F)CC1

Procedure:
The title compound is prepared as described in Example 1 but using (4-benzoimidazol-1-yl-phenyl)-acetic acid (Step 20.1) and 4-[methyl-(1-methyl-piperidin-4-yl)-amino]-3-trifluoromethyl-phenylamine (Step 15.1). Title compound: ES-MS: 522.0 [M+H]+; single peak at tR=3.15 min (System 1); Rf=0.19 (CH2Cl2/MeOH+1% NH3aq, 9:1).
Reaction SMILES: Cl[P:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C1COCC1.CC(C)([O-])C.[K+].Cl[CH2:27][C:28]1[N:33]=[C:32]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=2)[CH:31]=[CH:30][CH:29]=1>CCOCC.O>[C:3]1([P:2]([CH2:27][C:28]2[N:33]=[C:32]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=3)[CH:31]=[CH:30][CH:29]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: ClP(c1ccccc1)c1ccccc1
Reactant: ClCc1cccc(-c2ccccn2)n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: c1ccc(P(Cc2cccc(-c3ccccn3)n2)c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 61 %

Procedure:
Synthesis of the Ligand BPy-(Ph)PNN (10) An oven-dried 250 mL three-necked round bottom flask equipped with an argon inlet, a stirring bar, dropping funnel and one rubber septum was cooled under a stream of argon. The flask was then charged with chlorodiphenylphosphine (1.08 g, 6 mmol) in 30 mL dry ether. The solution was cooled to 0° C. and a THF solution (5 mL) of potassium tert-butoxide (74 mg, 6.6 mmol) was added dropwise via syringe during 10 min. The resulting brown coloured mixture was stirred for 1 hr at 0° C. and then a solution of 6-chloromethyl-2,2′-bipyridine (1.02 g, 5 mmol) in 20 mL dry ether was added dropwise (˜15 min) to it. The stirring was continued for a further 1 hr at the same temperature and the mixture was allowed to slowly warm up to room temperature and stirred overnight. To this reaction mixture was added 20 mL of degassed water and the ether phase was separated under N2 atmosphere. The aqueous phase was extracted with ether (2×20 mL). The combined ether solutions were dried over anhydrous Na2SO4, filtered under N2 pressure, and the solvent was removed under vacuum to get brownish-white solid. This was purified by column chromatography in the nitrogen glove box (basic alumina; hexane:ether (10:1) as eluent) to yield 1.08 g (61%) of 6-di-phenyphosphinomethyl-2,2′-bipyridine (BPy-(Ph)PNN) as a white crystalline solid.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3[CH:15]=[C:14]([CH2:16][CH2:17][C@@H:18]([NH:26]C(=O)OC(C)(C)C)[CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[O:13][N:12]=3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3[CH:15]=[C:14]([CH2:16][CH2:17][C@@H:18]([NH2:26])[CH2:19][C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)[O:13][N:12]=3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1
Reactant: CC(C)(C)OC(=O)N[C@H](CCc1cc(-c2ccc3cnccc3c2)no1)Cc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@H](CCc1cc(-c2ccc3cnccc3c2)no1)Cc1ccccc1
Reaction time: 0.5 h
Yield: 21.8 %

Procedure:
To a solution of tert-butyl(R)-4-(3-(isoquinolin-6-yl)isoxazol-5-yl)-1-phenylbutan-2-ylcarbamate (0.089 g, 0.20 mmol) in 5 mL of DCM was added 1 mL of TFA. After 30 minutes, the solvent was removed by rotary evaporation. The residue was taken up in 2 N NH3/MeOH to free base the amine. Concentration under reduced pressure, followed by flash chromatography on silica gel (5% to 10% MeOH/DCM) afforded (2R)-4-(3-(isoquinolin-6-yl)isoxazol-5-yl)-1-phenylbutan-2-amine (0.015 g, 22% yield) as a brown solid. MS m/z: 344 (M+1); 1H NMR (400 MHz, CD3OD) δ ppm 9.46 (s, 1H), 8.58-8.55 (m, 1H), 8.48 (s, 1H), 8.35-8.25 (m, 2H), 8.12 (d, J=6.2 Hz, 1H), 7.40-7.27 (m, 5H), 6.79 (s, 1H), 3.61-3.50 (m, 2H), 3.19-2.94 (m, 3H), 2.16-2.03 (m, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=4)=[CH:18][CH:17]=3)=[C:11]([CH2:30][CH2:31][CH3:32])[N:10]=[C:9]2[CH3:33])=[CH:4][CH:3]=1.Br[CH:35]1[CH2:38][CH2:37][CH2:36]1.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>CN(C)C=O.O>[CH:35]1([O:1][C:2]2[CH:3]=[CH:4][C:5]([N:8]3[C:13](=[O:14])[C:12]([CH2:15][C:16]4[CH:21]=[CH:20][C:19]([C:22]5[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=5)=[CH:18][CH:17]=4)=[C:11]([CH2:30][CH2:31][CH3:32])[N:10]=[C:9]3[CH3:33])=[CH:6][CH:7]=2)[CH2:38][CH2:37][CH2:36]1
Reactant: BrC1CCC1
Reactant: CCCc1nc(C)n(-c2ccc(O)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCCc1nc(C)n(-c2ccc(OC3CCC3)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 80 °C
Reaction time: 5 h

Procedure:
To a solution of 4′-{[1-(4-hydroxyphenyl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (1.0 g) and bromocyclobutane (1.1 mL) in N,N-dimethylformamide (10 mL) was added cesium carbonate (1.5 g), and the mixture was stirred at 80° C. for 5 hr. The reaction mixture was allowed to cool to room temperature, ethyl acetate and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography to give the title compound as a pale-yellow viscous substance (1.02 g, 91%).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:9]([O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:10]>N#[Zr]>[C:9](=[O:10])([O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccccc1
Reactant: O=C(Cl)Oc1ccccc1
Agent: N#[Zr]
Product: O=C(Oc1ccccc1)Oc1ccccc1

Procedure:
Example 1 was repeated with 14.1 g of a powdered zirconium nitride from H. C. Starck at 140° C. After 2 hours' reaction time, phenol conversion was 9.4%, wherein 2.2 g of phenyl chloroformate and 12.5 g of diphenyl carbonate were formed. Selectivity for carbonates was 92.4%.
Reaction SMILES: [C:1]([O:4]C(=O)C)(=[O:3])[CH3:2].S(=O)(=O)(O)O.[CH3:13][O:14][C:15](=[O:26])[C:16](=[CH2:25])[CH:17](O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH3:13][O:14][C:15](=[O:26])[C:16](=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:25][O:4][C:1](=[O:3])[CH3:2]
Reactant: C=C(C(=O)OC)C(O)c1ccccc1
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Product: COC(=O)C(=Cc1ccccc1)COC(C)=O
Temperature: 100 °C
Reaction time: 4 h

Procedure:
The product (108.8 g) in Reference Example 1, namely 3-hydroxy-2-methylene-3-phenylpropionate methyl ester, is dissolved in acetic anhydride (113 ml; 1.20 mol), to which sulfuric acid (0.2 ml) is added, and the resulting mixture is stirred at 100° C. for 4 hours. The reaction solution is concentrated under reduced pressure, to give a crude product of the title compound at a yield of 143.9 g. 1H-NMR analysis reveals that the compound is a mixture of the E form and the Z form at a ratio of 87:13.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[C:8]1[CH:23]=[CH:22][C:11]([O:12][CH2:13][CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[CH:10][CH:9]=1.Cl[CH2:25][CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>CN(C=O)C.O>[N:28]1([CH2:27][CH2:26][CH2:25][N:3]2[CH:7]=[CH:6][CH:5]=[C:4]2[C:8]2[CH:23]=[CH:22][C:11]([O:12][CH2:13][CH2:14][CH2:15][N:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)=[CH:10][CH:9]=2)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: c1c[nH]c(-c2ccc(OCCCN3CCCCC3)cc2)c1
Reactant: ClCCCN1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: c1cc(-c2ccc(OCCCN3CCCCC3)cc2)n(CCCN2CCCCC2)c1
Reaction time: 0.33 h
Yield: 89.2 %

Procedure:
To a stirred suspension of sodium hydride (0.051 g) in DMF (3 mL) at RT was added dropwise the product of Example 18 (0.2 g) in DMF (4 mL). After 20 min, 1-(3-chloro-propyl)-piperdine (0.139 g) was added dropwise and the mixture stirred for 12 h. The mixture was diluted with water and extracted several times with diethyl ether. The combined organic layers were washed with brine, dried (sodium sulfate), filtered and concentrated under reduced pressure, giving the title compound as a dark red oil (0.257 g). 1H NMR (400 MHz, C6D6): 7.35 (d, J=8.8 Hz, 2H), 6.90 (d, J=8.8 Hz, 2H), 6.72 (t, J=2.5 Hz, 1H), 6.44 (d, J=2.5 Hz), 3.82 (m, 4H), 2.37-2.16 (m, 8H), 2.06 (br s, 4H), 1.96 (t, J=6.6 Hz, 2H), 1.87-1.81 (m, 2H), 1.59-1.22 (m, 16H).
Reaction SMILES: [OH-:1].[Na+].[CH:3]1[C:13]2[CH2:12][CH2:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[CH:8]([CH2:18][N:19]3[CH2:24][CH2:23][C:22](=O)[CH2:21][CH2:20]3)[C:7]=2[CH:6]=[CH:5][CH:4]=1.Cl.[NH2:27]O>C(O)C.O>[CH:3]1[C:13]2[CH2:12][CH2:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[CH:8]([CH2:18][N:19]3[CH2:24][CH2:23][C:22](=[N:27][OH:1])[CH2:21][CH2:20]3)[C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: NO
Reactant: O=C1CCN(CC2c3ccccc3CCc3ccccc32)CC1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: ON=C1CCN(CC2c3ccccc3CCc3ccccc32)CC1

Procedure:
2.6 Parts of finely ground sodium hydroxide is added to a suspension of 3 parts of 1-[(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-yl)methyl]-4-piperidinone and 1.5 part of hydroxylamine hydrochloride in 50 parts by volume of ethanol-water (4:1) solution. The resultant mixture is heated on a steam bath for about 5 hours and then partitioned between water and ethyl acetate. The aqueous layer is separated and extracted with a second portion of ethyl acetate. The ethyl acetate extracts are combined, dried, and concentrated to give 1-[(10,11-dihydro-5H-dibenzo[a,d]-cyclohepten-5-yl)methyl]-4-piperidinone oxime, as a white solid which melts at about 199°-202° C. after recrystallization from dioxane. This compound is represented by the following structural formula ##STR33##
Reaction SMILES: Br[CH:2]([C:6]([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)=[O:7])[CH2:3][CH2:4][Cl:5].[F-:15].[K+].C1OCCOCCOCCOCCOCCOC1.C1C=CC=CC=1>O>[F:15][CH:2]([C:6]([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)=[O:7])[CH2:3][CH2:4][Cl:5]
Reactant: O=C(c1ccc(Cl)cc1)C(Br)CCCl
Reactant: [F-]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: c1ccccc1
Solvent: O
Product: O=C(c1ccc(Cl)cc1)C(F)CCCl
Yield: 52.8 %

Procedure:
A mixture of 68 g of 4-chlorophenyl 1-bromo-3chloropropyl ketone, 27.5 g of dry potassium fluoride, 11 g of 18-crown-6 and 200 ml of dry benzene is heated under reflux for 8 hours. Thereafter, 200 ml of water are added, and the organic phase is separated off, washed several times with water, dried over sodium sulphate and evaporated down in vacuo. The residue is stirred with light benzine, with the addition of a small amount of toluene. After the resulting solid has been filtered off under suction and drying has been carried out, 28.5 g (53% of theory) of 4-chlorophenyl 1-fluoro-3-chloropropyl ketone of melting point 53° C. are obtained. ##STR217##
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:13]([CH2:14][CH3:15])[C:12]2[CH:16]=[CH:17][C:18]([N:20]([C:22]3[CH:27]=[CH:26][N:25]=[C:24]([Cl:28])[N:23]=3)[CH3:21])=[CH:19][C:11]=2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:29][C:30]1[CH:31]=[C:32]([S:36]([NH2:39])(=[O:38])=[O:37])[CH:33]=[CH:34][CH:35]=1>>[ClH:28].[CH2:1]([NH:8][C:9]1[N:13]([CH2:14][CH3:15])[C:12]2[CH:16]=[CH:17][C:18]([N:20]([CH3:21])[C:22]3[CH:27]=[CH:26][N:25]=[C:24]([NH:29][C:30]4[CH:31]=[C:32]([S:36]([NH2:39])(=[O:37])=[O:38])[CH:33]=[CH:34][CH:35]=4)[N:23]=3)=[CH:19][C:11]=2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1cccc(S(N)(=O)=O)c1
Reactant: CCn1c(NCc2ccccc2)nc2cc(N(C)c3ccnc(Cl)n3)ccc21
Product: CCn1c(NCc2ccccc2)nc2cc(N(C)c3ccnc(Nc4cccc(S(N)(=O)=O)c4)n3)ccc21
Product: Cl

Procedure:
The title compound was prepared following the procedure of example one with N2-Benzyl-N5-(2-chloro-pyrimidin-4-yl)-1-ethyl-N5-methyl-1H-benzoimidazole-2,5-diamine (98 mg, 0.25 mmol) and 3-amino-benzenesulfonamide (43 mg, 0.25 mmol) as a white solid (34 mg, 24%). 1H NMR (300 MHz, d6-DMSO+NaHCO3) δ 9.61 (s, 1H), 8.56 (s, 1H), 7.75-7.84 (m, 2H), 7.23-7.45 (m, 11H), 7.04 (d, J=7.2 Hz, 1H), 5.71 (d, J=5.7 Hz, 1H), 4.68 (d, J=5.1 Hz, 2H), 4.21 (m, 2H), 3.46 (s, 3H), 1.28 (m, 3H). MS (ESI) m/z=529 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][C:20]4[O:24][C:23]([C:25]5([NH:33]C(=O)OC(C)(C)C)[CH2:30][O:29]C(C)(C)[O:27][CH2:26]5)=[CH:22][C:21]=4[CH:41]=3)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][CH3:11].CCO>C(Cl)Cl>[NH2:33][C:25]([C:23]1[O:24][C:20]2[CH:19]=[CH:18][C:17]([C:14]3[N:13]=[C:12]([C:4]4[CH:5]=[CH:6][C:7]([O:8][CH2:9][CH2:10][CH3:11])=[C:2]([Cl:1])[CH:3]=4)[O:16][N:15]=3)=[CH:41][C:21]=2[CH:22]=1)([CH2:26][OH:27])[CH2:30][OH:29]
Reactant: CCCOc1ccc(-c2nc(-c3ccc4oc(C5(NC(=O)OC(C)(C)C)COC(C)(C)OC5)cc4c3)no2)cc1Cl
Solvent: ClCCl
Solvent: CCO
Product: CCCOc1ccc(-c2nc(-c3ccc4oc(C(N)(CO)CO)cc4c3)no2)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.4 %

Procedure:
To a stirred solution of product of Step D (0.1 g, 0.17 mmol) in CH2Cl2 (0.5 ml) TFA (1 ml) was added. After stirring for 1 h at room temperature, EtOH (2 ml) was added and stirring was continued for additional 1 h. The mixture was evaporated to dryness and the residue was purified by FCC (SiO2, CH2Cl2 saturated with concentrated NH4OH/MeOH; 98:2) to give the title product (0.035 g, 46%) as colourless solid. 1H-NMR (DMSO-d6) 8.3 (d, 1H, J=1.11 Hz); 8.15 (d, 1H, J=2.01 Hz); 8.09 (dd, 1H, J=8.67, 2.04 Hz); 7.94 (dd, 1H, J=8.58, 1.53 Hz); 7.68 (d, 1H, J=8.61 Hz); 7.37 (d, 1H, J=8.76 Hz); 6.92 (s, 1H); 4.91 (b, 2H); 4.14 (t, 2H, J=6.36 Hz); 3.69 (d, 2H, J=10.6 Hz); 3.59 (d, 2H, J=10.6 Hz); 1.83-1.72 (m, 2H); 0.97 (t, 3H, J=7.41 Hz).
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:15])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[Si:11]([CH3:14])([CH3:13])[CH3:12])[CH3:2].[N+:16]([O-])([OH:18])=[O:17].S(=O)(=O)(O)O>C(Cl)Cl>[CH2:1]([NH:3][C:4](=[O:15])[C:5]1[CH:10]=[C:9]([N+:16]([O-:18])=[O:17])[CH:8]=[CH:7][C:6]=1[Si:11]([CH3:14])([CH3:13])[CH3:12])[CH3:2]
Reactant: CCNC(=O)c1ccccc1[Si](C)(C)C
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: CCNC(=O)c1cc([N+](=O)[O-])ccc1[Si](C)(C)C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 60 %

Procedure:
To a solution of the amide of example 49 (1.10 g, 5 mmol) in CH2Cl2 (50 mL) at 0° C. was added dropwise over 2 min, a cold mixture of 70% nitric acid (0.95 mL, 15 mmol) and concentrated sulfuric acid (5 mL) dropwise. The mixture was stirred at 0° C. for 10 min and was poured onto ice. The mixture was extracted with ethyl acetate, the combined organic layers washed with brine, sat NaHCO3, brine, dried (MgSO4) and concentrated to a solid (2.68 g, 101%) consisting of a 2:1 ratio of 5-nitro and 3-nitro isomers. The title compound was obtained by RC (ethyl acetate/hexanes) in 60% yield as a white solid. m.p. 100-102° C.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[C:8]([CH3:10])[N:7]=[C:6]([S:11][CH3:12])[N:5]=1)[CH3:2].[I:13]Cl>CO>[CH2:1]([NH:3][C:4]1[C:9]([I:13])=[C:8]([CH3:10])[N:7]=[C:6]([S:11][CH3:12])[N:5]=1)[CH3:2]
Reactant: ClI
Reactant: CCNc1cc(C)nc(SC)n1
Solvent: CO
Product: CCNc1nc(SC)nc(C)c1I
Reaction time: 8 h
Yield: 67 %

Procedure:
To the solution of N-ethyl-6-methyl-2-(methylthio)pyrimidin-4-amine (20 g, 121.6 mmol) in methanol was added iodine monochloride (26.58 g, 163.7 mmol) in small portions at 0° C. Then the reaction mixture was stirred overnight. After evaporation of solvent, the residue was triturated with acetone. The product N-ethyl-5-iodo-6-methyl-2-(methylthio)pyrimidin-4-amine (25.2 g, 75% yield) was collected by filtration. 1H NMR (400 MHz, CDCl3): δ 5.37 (bs, 1H), 3.52 (q, J=7.2 Hz, 1H), 2.50 (s, 3H), 1.26 (t, J=7.2 Hz, 3H).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]([C:8]1[C:12]([CH3:13])=[C:11]([CH3:14])[NH:10][CH:9]=1)=[O:7])[CH3:4].Cl[C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]=[CH:18][CH:17]=1.O>CN(C)C=O>[CH2:3]([O:5][C:6]([C:8]1[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]([C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]=[CH:18][CH:17]=2)[CH:9]=1)=[O:7])[CH3:4]
Reactant: CCOC(=O)c1c[nH]c(C)c1C
Reactant: Clc1ccnc2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cn(-c2ccnc3ccccc23)c(C)c1C
Temperature: 40 °C
Reaction time: 0.3 h

Procedure:
0.285 g (8.9 mmol) of sodium hydride, at 75% by weight in liquid petroleum jelly, is added at a temperature in the region of 20° C. under an argon atmosphere to a solution of 1.35 g (8.1 mmol) of 3-ethoxycarbonyl-4,5-dimethyl-1H-pyrrole in 8 mL of dimethylformamide. After stirring at a temperature in the region of 40° C. for 0.3 hour, 1.45 g (8.9 mmol) of 4-chloroquinoline and 2 mL of dimethylformamide are added. After stirring at a temperature in the region of 140° C. for 6 hours, the reaction mixture is poured into 100 mL of salt water and then extracted with twice 50 mL of ethyl acetate. The combined organic phases are washed with 15 mL of water, carefully separated by settling and then concentrated to dryness under reduced pressure (2.7 kPa) to give a brown oil which is purified by silica gel chromatography [eluent: cyclohexane/ethyl acetate (75/25 by volume)]. After concentrating the fractions under reduced pressure (2.7 kPa), 1.32 g of 3-ethoxycarbonyl-4,5-dimethyl-1-(quinol-4-yl)-1H-pyrrole are obtained in the form of a yellowish oil. 1H NMR spectrum (300 MHz, d6-(CD3)2SO, δ in ppm): 1.27 (t, J=7 Hz, 3H), 1.87 (s, 3H), 2.27 (s, 3H), 4.21 (mt, 2H), 7.37 (dd, J=8 and 1 Hz, 1H), 7.55 (s, 1H), 7.62 (d, J=5 Hz, 1H), 7.70 (ddd, J=8, 7 and 1 Hz, 1H), 7.89 (ddd, J=8, 7 and 1 Hz, 1H), 8.19 (broad d, J=8 Hz, 1H), 9.07 (d, J=5 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:13]([C:15]3[C:16]([O:34][CH2:35][CH3:36])=[C:17]([C:23]4[CH:24]=[CH:25][C:26]([C:29]([N:31]([CH3:33])[CH3:32])=[O:30])=[N:27][CH:28]=4)[C:18]([CH3:22])=[C:19]([Cl:21])[CH:20]=3)[CH3:14])[N:9]=C(C=C)[C:3]=12.C[N+]1([O-])CC[O:41]CC1.[C:45]([OH:49])([CH3:48])([CH3:47])C>O.[Os](=O)(=O)(=O)=O>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:13]([C:15]3[C:16]([O:34][CH2:35][CH3:36])=[C:17]([C:23]4[CH:24]=[CH:25][C:26]([C:29]([N:31]([CH3:33])[CH3:32])=[O:30])=[N:27][CH:28]=4)[C:18]([CH3:22])=[C:19]([Cl:21])[CH:20]=3)[CH3:14])[N:9]=[C:47]([CH:45]([OH:49])[CH2:48][OH:41])[C:3]=12
Reactant: CC(C)(C)O
Reactant: C[N+]1([O-])CCOCC1
Reactant: C=Cc1nn(C(C)c2cc(Cl)c(C)c(-c3ccc(C(=O)N(C)C)nc3)c2OCC)c2ncnc(N)c12
Agent: O=[Os](=O)(=O)=O
Solvent: O
Product: CCOc1c(C(C)n2nc(C(O)CO)c3c(N)ncnc32)cc(Cl)c(C)c1-c1ccc(C(=O)N(C)C)nc1
Reaction time: 3 h
Yield: 95 %

Procedure:
To a solution of 5-{3-[1-(4-amino-3-vinyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-methylphenyl}-N,N-dimethylpyridine-2-carboxamide (80 mg, 0.16 mmol, from Example 81, Step 1) in tert-butyl alcohol (1 mL) was added N-methylmorpholine N-oxide (20 mg, 0.17 mmol) and water (0.50 mL). To this solution was then added 4% osmium tetraoxide (5.0 μL, 0.00079 mmol). After stirring for 3 h, another equivalent of N-methylmorpholine N-oxide was added. The reaction was stirred at room temperature overnight. The solution was diluted with water, and extracted with EtOAc. The combined organic layers were dried over MgSO4 and filtered, concentrated to give the desired product (0.64 g, 95%). LCMS calculated for C26H31ClN7O4 (M+H)+: m/z=540.2; Found: 540.2.
Reaction SMILES: C(=O)(O)[O-:2].[Na+].Cl.NO.[Cl:9][C:10]1[C:11]([C:24]#[N:25])=[N:12][CH:13]=[C:14]([Cl:23])[C:15]=1[O:16][CH:17]([CH3:22])[C:18]([F:21])([F:20])[F:19]>C(O)C>[Cl:9][C:10]1[C:11]([C:24]([NH2:25])=[O:2])=[N:12][CH:13]=[C:14]([Cl:23])[C:15]=1[O:16][CH:17]([CH3:22])[C:18]([F:21])([F:19])[F:20]
Reactant: O=C([O-])O
Reactant: CC(Oc1c(Cl)cnc(C#N)c1Cl)C(F)(F)F
Agent: Cl
Agent: NO
Agent: [Na+]
Solvent: CCO
Product: CC(Oc1c(Cl)cnc(C(N)=O)c1Cl)C(F)(F)F
Yield: 91.2 %

Procedure:
To 5 ml of ethanol were added 0.4 g of sodium bicarbonate and 0.33 g of hydroxylamine hydrochloride, and the mixture was heated to reflux for 1 hour. After allowing to cool, 0.67 g of 3,5-dichloro-4-(2,2,2-trifluoro-1-methylethoxy)pyridine-2-carbonitrile at room temperature, and the mixture was stirred for 4 hours, and concentrated. To the residue was added water, the resultant solution was extracted with ethyl acetate three times, and the organic layers were combined, washed with an aqueous saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was washed with hexane three times to obtain 0.65 g of 3,5-dichloro-4-(2,2,2-trifluoro-1-methylethoxy)pyridine-2-carboxamide=oxime.
Reaction SMILES: [CH3:1][C:2](C)([CH2:6][C:7]1[S:8][CH:9]=[CH:10][CH:11]=1)[C:3](O)=O.C1(P([N:27]=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(CC)CC)C.O>C(O)(C)(C)C>[CH3:1][C:2]([CH3:3])([NH2:27])[CH2:6][C:7]1[S:8][CH:9]=[CH:10][CH:11]=1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CC(C)(Cc1cccs1)C(=O)O
Solvent: CC(C)(C)O
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(N)Cc1cccs1

Procedure:
A solution of 2,2-dimethyl-3-(2-thienyl)propanoic acid (11.2 g, 0.06 mole), diphenylphosphorylazide (16.7 g, 0.06 mole) (Aldrich Chemical Company), and triethylamine (6.14 g, 0.06 mole) in t-butanol (100 mL) was heated at reflux for 5 hrs. The solution was poured into water (300 mL) and the crude material extracted with ether. The combined extracts were washed with brine, dried (MgSO4) and evaporated to 11.9 g of an oil. This oil was added to a mixture of ethylene glycol (50 mL), H2O (20 drops) and KOH (10 g). The mixture was heated at reflux for 5 hr, cooled to 25°, diluted with H2O (300 mL) and acidified to pH 1 with conc HCl. Acid insoluble material was removed by washing with ether. The aqueous solution was then made basic with 50% NaOH solution and the product was extracted with ether. The ether extracts were combined, washed with brine, dried (MgSO4) and concentrated in vacuo to 6.9 g (74%) of product. The NMR spectrum is consistent with the structure of this intermediate compound.