Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])[CH:3]=1.[CH3:21][P:22]([C:25]1[N:30]=[C:29]([O:31][CH3:32])[C:28]([NH2:33])=[CH:27][CH:26]=1)([CH3:24])=[O:23].Cl>COCCO.C(O)C>[CH3:24][P:22]([C:25]1[N:30]=[C:29]([O:31][CH3:32])[C:28]([NH:33][C:2]2[CH:3]=[C:4]([NH:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])[N:5]=[CH:6][N:7]=2)=[CH:27][CH:26]=1)([CH3:21])=[O:23]
Reactant: CC(C)S(=O)(=O)c1ccccc1Nc1cc(Cl)ncn1
Reactant: COc1nc(P(C)(C)=O)ccc1N
Agent: Cl
Solvent: CCO
Solvent: COCCO
Product: COc1nc(P(C)(C)=O)ccc1Nc1cc(Nc2ccccc2S(=O)(=O)C(C)C)ncn1

Procedure:
To a solution of 6-chloro-N-[2-(propan-2-ylsulfonyl)phenyl]pyrimidin-4-amine (0.250 mmol) in 1 mL of 2-methoxyethanol is added 6-(dimethylphosphoryl)-2-methoxypyridin-3-ylamine (50.0 mg, 0.250 mmol) and 0.15 mL of 2.5 M HCl in ethanol. The mixture is heated in a sealed tube at 90° C. until formation of the desired compound. The mixture is basified with 1N NaOH solution, and extracted with ethyl acetate. The organic layers can be combined, washed with saturated sodium chloride solution, dried with sodium sulfate, filtered and concentrated. The crude residue can be purified by silica gel chromatography.
Reaction SMILES: [CH2:1]([N:8]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:9]1[CH2:14][CH2:13][CH2:12][CH:11]([C:15](OC)=[O:16])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC1C=CC=CC=1)C1CCCC(C(OCC2C=CC=CC=2)=O)C1)C1C=CC=CC=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C(OCC)C>[CH2:19]([N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH:9]1[CH2:14][CH2:13][CH2:12][CH:11]([CH2:15][OH:16])[CH2:10]1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: COC(=O)C1CCCC(N(Cc2ccccc2)Cc2ccccc2)C1
Agent: O=C(OCc1ccccc1)C1CCCC(N(Cc2ccccc2)Cc2ccccc2)C1
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Product: OCC1CCCC(N(Cc2ccccc2)Cc2ccccc2)C1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
At 0° C., 23 g of a 1:3.5 mixture of methyl 3-dibenzylaminocyclohexanoate and benzyl 3-dibenzylaminocyclohexanoate were added dropwise to a suspension of 4.4 g of LiAlH4 in 250 ml of diethyl ether. The suspension was stirred at 0° C. for 2 h and then quenched using 2 ml of EtOAc, and 10 ml of 10N KOH were added. 50 g of MgSO4 were then added and the suspension was filtered. The residue was digested with EtOAc for 2 h and filtered again. The filtrate was concentrated, giving the product as an oil. C21 H27NO (309.46), LCMS (ESI): 310.2 (MH+).
Reaction SMILES: C(OC(N1[CH2:12][CH2:11][CH:10]([NH:13][C:14]([C:16]2[S:17][CH:18]=[CH:19][C:20]=2[NH:21][C:22]2[CH:27]=[CH:26][N:25]=[C:24]3[NH:28][CH:29]=[CH:30][C:23]=23)=[O:15])C1)=O)(C)(C)C.[Cl:31][C:32]1[CH:33]=C(CCN)[CH:35]=[CH:36][CH:37]=1>>[Cl:31][C:32]1[CH:33]=[C:12]([CH2:11][CH2:10][NH:13][C:14]([C:16]2[S:17][CH:18]=[CH:19][C:20]=2[NH:21][C:22]2[CH:27]=[CH:26][N:25]=[C:24]3[NH:28][CH:29]=[CH:30][C:23]=23)=[O:15])[CH:35]=[CH:36][CH:37]=1
Reactant: NCCc1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)c2sccc2Nc2ccnc3[nH]ccc23)C1
Product: O=C(NCCc1cccc(Cl)c1)c1sccc1Nc1ccnc2[nH]ccc12

Procedure:
This compound was prepared in an analogous manner as 3-{[3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carbonyl]-amino}-pyrrolidine-1-carboxylic acid tert-butyl ester using 2-(3-chlorophenyl)ethylamine instead of 1-BOC-3-aminopyrrolidine. LCMS (ESI) 396 (M+H) 1H NMR (400 MHz, DMSO-d6) δ ppm 11.59 (1H, br. s.) 10.29 (1H, s) 8.19 (1H, t, J=5.71 Hz) 8.03 (1H, d, J=5.47 Hz) 7.78 (1H, d, J=5.42 Hz) 7.47 (1H, d, J=5.37 Hz) 7.32 (2H, td, J=3.77, 1.93 Hz) 7.27 (1H, d, J=7.27 Hz) 7.22 (1H, t, J=1.83 Hz) 7.17 (1H, t, J=1.56 Hz) 6.81 (1H, d, J=5.52 Hz) 6.45 (1H, dd, J=3.49, 1.68 Hz) 3.43-3.51 (2H, m) 2.84 (2H, t, J=7.32 Hz)
Reaction SMILES: [CH3:1][N:2]([CH3:21])[C:3]([C:5]1[N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:8]2[N:9]=[C:10](Cl)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].[C:22]([O:26][C:27]([N:29]1[CH:35]2[CH2:36][CH2:37][CH:30]1[CH2:31][N:32]([C:39]1[CH:40]=[N:41][C:42]([NH2:45])=[CH:43][CH:44]=1)[C:33](=[O:38])[CH2:34]2)=[O:28])([CH3:25])([CH3:24])[CH3:23]>>[C:22]([O:26][C:27]([N:29]1[CH:35]2[CH2:36][CH2:37][CH:30]1[CH2:31][N:32]([C:39]1[CH:40]=[N:41][C:42]([NH:45][C:10]3[N:11]=[CH:12][C:7]4[CH:6]=[C:5]([C:3](=[O:4])[N:2]([CH3:21])[CH3:1])[N:14]([C:15]5[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=5)[C:8]=4[N:9]=3)=[CH:43][CH:44]=1)[C:33](=[O:38])[CH2:34]2)=[O:28])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)N1C2CCC1CN(c1ccc(N)nc1)C(=O)C2
Reactant: CN(C)C(=O)c1cc2cnc(Cl)nc2n1-c1ccccc1
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CC5CCC(CC4=O)N5C(=O)OC(C)(C)C)cn3)nc2n1-c1ccccc1
Yield: 89 %

Procedure:
Following general N—C coupling procedure 1, 2-chloro-7-phenyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (181 mg, 0.602 mmol) was combined with 3-(6-amino-pyridin-3-yl)-4-oxo-3,9-diaza-bicyclo[4.2.1]nonane-9-carboxylic acid tert-butyl ester (200 mg, 0.602 mmol), which gave 3-[6-(6-dimethylcarbamoyl-7-phenyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-4-oxo-3,9-diaza-bicyclo[4.2.1]nonane-9-carboxylic acid tert-butyl ester (320 mg, 0.536 mmol) in 86% yield.
Reaction SMILES: [C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23](I)=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:26][C:27]([F:38])([F:37])[C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1>>[C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23]([C:31]5[CH:32]=[CH:33][C:28]([C:27]([F:38])([F:37])[F:26])=[CH:29][CH:30]=5)=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[C@H](Nc1nccc(-n2cnc3cc(I)ccc32)n1)c1ccccc1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Product: C[C@H](Nc1nccc(-n2cnc3cc(-c4ccc(C(F)(F)F)cc4)ccc32)n1)c1ccccc1

Procedure:
The title compound was prepared according to the procedure described in EXAMPLE 397, starting from 2-[(S)-1-Phenylethylamino]-4-[5-iodobenzimidazol-1-yl]pyrimidine and 4-trifluoromethylphenyl boronic acid. Mass spectrum (ESI) 460.4 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][N:8]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1)[C:9]2=[O:14])([O-])=O.CO>[Pd]>[NH2:1][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][N:8]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1)[C:9]2=[O:14]
Reactant: O=c1c2cccc([N+](=O)[O-])c2ccn1Cc1ccccn1
Agent: [Pd]
Solvent: CO
Product: Nc1cccc2c(=O)n(Cc3ccccn3)ccc12
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
Into a round bottom flask was combined 5-nitro-2-(pyridin-2-ylmethyl)isoquinolin-1(2H)-one (0.7 g, 0.002 mol), palladium/C (0.05 g, 0.0005 mol) and methanol (200 mL, 5 mol). The reaction mixture was stirred under hydrogen balloon at room temperature for 40 mins. The mixture was filtered over celite, MeOH was removed and the solid was yield (0.46 mg). MS m/z=252.4 (M+1). 1H NMR (DMSO) δ 8.49 (d, J=4.3 Hz, 1H), 7.74 (td, J=7.7, 1.6 Hz, 1H), 7.42 (t, J=7.3 Hz, 2H), 7.27 (dd, J=6.9, 5.0 Hz, 1H), 7.22-7.12 (m, 2H), 6.88 (d, J=7.2 Hz, 1H), 6.80 (d, J=7.6 Hz, 1H), 5.69 (s, 2H), 5.23 (s, 2H).
Reaction SMILES: CO[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][N:4]=1.[CH3:9][N:10]([CH2:12][CH2:13][NH2:14])[CH3:11]>C1(C)C(C)=CC=CC=1>[CH3:9][N:10]([CH3:11])[CH2:12][CH2:13][NH:14][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][N:4]=1
Reactant: COc1ccncn1
Reactant: CN(C)CCN
Solvent: Cc1ccccc1C
Product: CN(C)CCNc1ccncn1

Procedure:
A solution of 4-methoxypyrimidine (12.9 g., 0.117 mole) and unsym-dimethylethylene diamine (20.7 g., 0.23 mole) in 40 ml of xylene is heated under reflux for 64 hours. The reaction is concentrated and the oil is distilled at 15 mm of Hg. 4-(2-Dimethylaminoethylamino)pyrimidine, boiling at 164°-169° C., is collected.
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:12][CH2:13][OH:14])=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH:9]=1)[C:7]#[N:8].CCN(CC)CC.CS(Cl)(=O)=O.[Cl-].[NH4+].C1CCN2C(=NCCC2)CC1.ClC1C=CC=C(C(OO)=O)C=1>ClCCl.O.C(=O)(O)[O-].[Na+]>[F:1][C:2]1[C:3]([CH:12]2[CH2:13][O:14]2)=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: COc1cc(CCO)c(F)cc1C#N
Agent: CS(=O)(=O)Cl
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Solvent: CCN(CC)CC
Product: COc1cc(C2CO2)c(F)cc1C#N
Reaction time: 2 h

Procedure:
To a solution of 5-fluoro-4-(2-hydroxyethyl)-2-methoxybenzonitrile (0.68 g, 3.5 mmol) and Et3N (0.82 mL, 5.9 mmol) in dichloromethane (5 mL) was added methanesulfonyl chloride (0.33 mL, 4.2 mmol) at 0° C. After 15 min. the reaction mixture was poured into saturated ammonium chloride and extracted with dichloromethane. The combined organics were washed with 1 N HCl, saturated sodium bicarbonate solution, and brine, then dried (MgSO4) and concentrated in vacuo. The residue was re-dissolved in dichloromethane (5 mL), treated with DBU (0.79 mL, 5.2 mmol) and stirred for 2 h. TLC monitoring showed conversion to the olefin. The reaction mixture was diluted with water and extracted with dichloromethane. The combined organics were washed with 1 N HCl, saturated sodium bicarbonate solution, and brine, then dried (MgSO4) and concentrated in vacuo. The resulting olefin was dissolved in dichloromethane (5 mL) and treated with meta-chloro perbenzoic acid (0.72 g, 4.2 mmol) at 0° C. After 3 h, the mixture was diluted with saturated sodium bicarbonate solution and extracted with dichloromethane (twice). The combined organic extracts were washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The crude epoxide was purified by silica gel column chromatography (5->80% EtOAc:hexane) to provide 5-fluoro-2-methoxy-4-oxiran-2-ylbenzonitrile. 1H NMR (500 MHz, CD3OD) δ 7.32 (d, J=5.3 Hz, 1H), 6.82 (d, J=5.4 Hz, 1H), 4.19 (m, 1H), 3.96 (s, 3H), 3.27 (m, 1H), 2.76 (m, 1H);
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[Cl:25][C:26]1[CH:31]=[CH:30][C:29](B2OC(C)(C)C(C)(C)O2)=[CH:28][C:27]=1[O:41][CH2:42][C:43]1[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][CH:44]=1>>[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([C:2]2[N:3]=[C:4]([N:19]3[CH2:20][CH2:21][O:22][CH2:23][CH2:24]3)[C:5]3[S:10][C:9]([CH2:11][N:12]4[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]4)=[CH:8][C:6]=3[N:7]=2)=[CH:28][C:27]=1[O:41][CH2:42][C:43]1[CH:44]=[CH:45][C:46]([O:49][CH3:50])=[CH:47][CH:48]=1
Reactant: CN1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Reactant: COc1ccc(COc2cc(B3OC(C)(C)C(C)(C)O3)ccc2Cl)cc1
Product: COc1ccc(COc2cc(-c3nc(N4CCOCC4)c4sc(CN5CCN(C)CC5)cc4n3)ccc2Cl)cc1

Procedure:
2-Chloro-6-(4-methyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine was reacted with 2-[4-chloro-3-(4-methoxy-benzyloxy)-phenyl]-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane in general procedure A. Purification on silica yielded 2-[4-chloro-3-(4-methoxy-benzyloxy)-phenyl]-6-(4-methyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine. This was then reacted with trifluoroacetic acid in dichloromethane to yield the desired compound.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:11][C:10]1([C:41]1[S:42][C:43]([Cl:58])=[C:44]([CH2:46][O:47][Si:48]([CH:55]([CH3:57])[CH3:56])([CH:52]([CH3:54])[CH3:53])[CH:49]([CH3:51])[CH3:50])[CH:45]=1)O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([SiH](CC)CC)C.B(F)(F)F.CCOCC.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[Cl:58][C:43]1[S:42][C:41]([CH:10]2[C@H:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C@@H:14]([O:15][CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:13]([O:23][CH2:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[O:11]2)=[CH:45][C:44]=1[CH2:46][O:47][Si:48]([CH:55]([CH3:56])[CH3:57])([CH:49]([CH3:50])[CH3:51])[CH:52]([CH3:53])[CH3:54]
Reactant: CC(C)[Si](OCc1cc(C2(O)O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)sc1Cl)(C(C)C)C(C)C
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Agent: O=C([O-])[O-]
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)[Si](OCc1cc(C2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)sc1Cl)(C(C)C)C(C)C
Temperature: -20 °C
Yield: 98.3 %

Procedure:
To a solution of alcohol 33 (8.53 g, 10.1 mmol) in CH2Cl2 (50 mL) were added triethylsilane (3.3 mL, 20.2 mmol) and boron trifluoride diethyl etherate (2.6 mL, 20.2 mmol) at −60° C. The mixture was allowed to slowly warm to −20° C. To a mixture was added aq. saturated K2CO3 solution (50 mL) to quench the reaction. The mixture was evaporated under reduced pressure to remove CH2Cl2 and extracted with EtOAc (100 mL). The combined organic layer was dried over MgSO4, filtered, and concentrated in vacuo to yield the title compound 34 (8.22 g), which was carried on to the next step without further purification.
Reaction SMILES: [C:1]1([C:11](=[O:23])[CH2:12][C:13](=[O:22])[CH2:14][C:15](=O)[C:16]([O:18]CC)=[O:17])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Cl>O1CCOCC1>[C:1]1([C:11]2[O:23][C:15]([C:16]([OH:18])=[O:17])=[CH:14][C:13](=[O:22])[CH:12]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)C(=O)CC(=O)CC(=O)c1cccc2ccccc12
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O)c1cc(=O)cc(-c2cccc3ccccc23)o1

Procedure:
This crude ester was dissolved in dioxan (50 ml) and concentrated hydrochloric acid (50 ml), and the solution was heated under reflux for 11/2 hours then concentrated under vacuum to give a brown solid. The solid was recrystallised from ethanol and from ethanol-water to give the title product (mp 248-249° C. with decomposition).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[Si:34]([O:51][CH2:52][CH:53]([OH:58])[C:54]([O:56][CH3:57])=[O:55])([C:47]([CH3:50])([CH3:49])[CH3:48])([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.[C:59](O)(=[S:61])[CH3:60]>C1COCC1>[Si:34]([O:51][CH2:52][CH:53]([O:58][C:59](=[S:61])[CH3:60])[C:54]([O:56][CH3:57])=[O:55])([C:47]([CH3:50])([CH3:49])[CH3:48])([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: COC(=O)C(O)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reactant: CC(O)=S
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)C(CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)OC(C)=S
Temperature: 0 °C
Reaction time: 1 h
Yield: 61.6 %

Procedure:
To a solution of triphenylphosphine (101 g, 385 mmol, 2 eq) in THF (1.5 L) was added diisopropylazodicarboxylate (76 mL, 386 mmol, 2 eq) at 0° C. The mixture was stirred at 0° C. for 1 hr and was followed by the addition of a solution of methyl 3-t-butyldiphenylsilyloxy-2-hydroxypropionate (example 39) (68.89 g, 192 mmol) and thioacetic acid (27.6 mL, 386 mmol, 2 eq.) in THF, to the same temperature. The mixture was stirred at 0° C. for 1 hr and at room temperature for 18 hr. The solution was concentrated to dryness and the solid was washed with hexane (5×300 mL). The organic solution was filtered and evaporated under reduced pressure. The crude material was purified by flash chromatography with a mixture of hexane and ethyl acetate (95:5) to give the pure compound (49.3 g) in 62% yield.
Reaction SMILES: N#N.[F:3][C:4]([F:14])([F:13])[C:5]([NH:7][CH2:8][CH2:9][CH2:10][NH:11][CH3:12])=[O:6].CN1CCOCC1.Cl[C:23]([O:25][CH:26]([CH3:28])[CH3:27])=[O:24]>C(OCC)(=O)C.C1(C)C=CC=CC=1>[CH:26]([O:25][C:23](=[O:24])[N:11]([CH3:12])[CH2:10][CH2:9][CH2:8][NH:7][C:5](=[O:6])[C:4]([F:13])([F:14])[F:3])([CH3:28])[CH3:27]
Reactant: CC(C)OC(=O)Cl
Reactant: CNCCCNC(=O)C(F)(F)F
Agent: N#N
Solvent: CN1CCOCC1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)OC(=O)N(C)CCCNC(=O)C(F)(F)F
Temperature: 0 °C

Procedure:
To a rapidly stirred, 0° C., N2 blanketed, solution of 2,2,2-trifluoro-N-(3-methylamino-propyl)-acetamide (6.0 g, 32.4 mmol) and N-methylmorpholine [109-02-4] (7.1 mL, 64.6 mmol) in ethyl acetate (65 mL) was steadily added a 1.0M solution of isopropyl chloroformate in toluene (32.4 mL) over the course of 10 minutes. The reaction was allowed to stir and warm to ambient temperature over night at which time it was washed with brine, dried (MgSO4) and evaporated to provide 9.0 g of clear yellow oil. LRMS (ESI) m/z 271.1 [(M+H)]+, calc'd for C10H17F3N2O3: 270.25.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[C:19]2[N:23]([CH3:24])[N:22]=[CH:21][CH:20]=2)=[CH:4][C:5]([F:10])=[C:6]([CH:9]=1)[C:7]#[N:8].OO.C(=O)([O-])[O-:28].[K+].[K+]>CS(C)=O>[Cl:1][C:2]1[C:3]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[C:19]2[N:23]([CH3:24])[N:22]=[CH:21][CH:20]=2)=[CH:4][C:5]([F:10])=[C:6]([CH:9]=1)[C:7]([NH2:8])=[O:28]
Reactant: Cn1nccc1-c1cc(Cl)ccc1Oc1cc(F)c(C#N)cc1Cl
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: Cn1nccc1-c1cc(Cl)ccc1Oc1cc(F)c(C(N)=O)cc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 105.1 %

Procedure:
To a solution of 5-chloro-4-[4-chloro-2-(1-methyl-1H-pyrazol-5-yl)phenoxy]-2-fluorobenzonitrile (Preparation 19, 290 mg, 0.801 mmol) in DMSO (0.8 mL) was added hydrogen peroxide (545 μL, 16 mmol) followed by potassium carbonate (221 mg, 1.60 mmol). The reaction was stirred at room temperature for 18 hours. The reaction was then purified directly using trilution reverse phase chromatography to furnish the title compound (320 mg, 105%).
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Br:14][C:15]1[CH:22]=[C:21]([Br:23])[CH:20]=[C:17]([CH:18]=O)[C:16]=1[OH:24]>>[Br:14][C:15]1[C:16]([OH:24])=[C:17]([CH:20]=[C:21]([Br:23])[CH:22]=1)[CH2:18][N:4]1[CH2:5][CH2:6][N:1]([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:2][CH2:3]1
Reactant: O=Cc1cc(Br)cc(Br)c1O
Reactant: O=c1cc(N2CCNCC2)nc[nH]1
Product: O=c1cc(N2CCN(Cc3cc(Br)cc(Br)c3O)CC2)nc[nH]1

Procedure:
6-[4-(3,5-Dibromo-2-hydroxy-benzyl)-piperazin-1-yl]-3H-pyrimidin-4-one was prepared using Procedure B from 6-piperazin-1-yl-3H-pyrimidin-4-one (Intermediate 4) and 3,5-dibromosalicylaldehyde (available from Aldrich). 1H NMR (400 MHz, CDCl3) δ 2.62-2.66 (m, 4H), 3.48 (s, 1H), 3.58-3.65 (m, 4H), 3.72 (s, 2H), 5.40 (s, 1H), 7.07 (s, 1H), 7.58 (s, 1H), 7.84 (s, 1H), 11.90 (br s, 1H). Mass spectrum (ES) MH+=445.
Reaction SMILES: C([NH:4][C:5]1[S:6][C:7]([S:10]([C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=2)=[O:11])=[CH:8][N:9]=1)(=O)C.Cl.C(O)(=O)C.C(=O)([O-])[O-].[Na+].[Na+]>O>[NH2:4][C:5]1[S:6][C:7]([S:10]([C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=2)=[O:11])=[CH:8][N:9]=1
Reactant: CC(=O)Nc1ncc(S(=O)c2ccc(N)cc2)s1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Nc1ccc(S(=O)c2cnc(N)s2)cc1
Yield: 105.8 %

Procedure:
A mixture of 2-acetylamino-5-(4-aminophenylsulfinyl)thiazole (5.0 g) in a mixture of aqueous 6N-hydrochloric acid (10 ml) and acetic acid (35 ml) was refluxed for 3.5 hours with stirring. The reaction mixture was diluted with water and adjusted to pH 8 using aqueous sodium carbonate under ice cooling. The precipitates were collected by filtration, washed with water and dried in vacuo to give 2-amino-5-(4-aminophenylsulfinyl)thiazole (4.5 g, yield: 100%). mp: 205°-208° C. (dec.)
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([CH2:7][OH:8])=[N:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH:38]1([CH:41]([C:47]2[CH:52]=[CH:51][CH:50]=[C:49](O)[CH:48]=2)[CH2:42][C:43]([O:45][CH3:46])=[O:44])[CH2:40][CH2:39]1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.C1(C)C=CC=CC=1>[Br:1][C:2]1[S:6][C:5]([CH2:7][O:8][C:51]2[CH:52]=[C:47]([CH:41]([CH:38]3[CH2:39][CH2:40]3)[CH2:42][C:43]([O:45][CH3:46])=[O:44])[CH:48]=[CH:49][CH:50]=2)=[N:4][C:3]=1[C:9]1[CH:10]=[CH:11][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:13][CH:14]=1
Reactant: OCc1nc(-c2ccc(C(F)(F)F)cc2)c(Br)s1
Reactant: COC(=O)CC(c1cccc(O)c1)C1CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COC(=O)CC(c1cccc(OCc2nc(-c3ccc(C(F)(F)F)cc3)c(Br)s2)c1)C1CC1
Yield: 22.9 %

Procedure:
To a solution of (5-bromo-4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)methanol (300 mg) in THF (15 ml) were added triphenylphosphine (349 mg), methyl 3-cyclopropyl-3-(3-hydroxyphenyl)propanoate (293 mg), and a 40% solution of diethyl azodicarboxylate in toluene (520 μL), and the mixture was stirred at room temperature for 30 min. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (110 mg) as a colorless oil.
Reaction SMILES: F[C:2]1[CH:28]=[CH:27][C:5]2[N:6]=[C:7]([C:9]3[C:10]([NH2:26])=[N:11][CH:12]=[C:13]([C:15]4[CH:16]=[N:17][N:18]([CH:20]5[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]5)[CH:19]=4)[CH:14]=3)[S:8][C:4]=2[CH:3]=1.[Br:29]C1C2N=C(Cl)SC=2C=CC=1>>[Br:29][C:27]1[C:5]2[N:6]=[C:7]([C:9]3[C:10]([NH2:26])=[N:11][CH:12]=[C:13]([C:15]4[CH:16]=[N:17][N:18]([CH:20]5[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]5)[CH:19]=4)[CH:14]=3)[S:8][C:4]=2[CH:3]=[CH:2][CH:28]=1
Reactant: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1nc2ccc(F)cc2s1
Reactant: Clc1nc2c(Br)cccc2s1
Product: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1nc2c(Br)cccc2s1

Procedure:
Same procedure as 3-(6-fluorobenzothiazol-2-yl)-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-pyridin-2-ylamine except using 4-bromo-2-chloro-1,3-benzothiazole in place of 2-chloro-6-fluorobenzothiazole to afford the title compound as a yellow solid. 1H NMR (400 MHz, CD3OD): δ=8.81 (s, 1H), 8.44 (s, 1H), 8.41 (s, 1H), 8.11 (d, J=8.0 Hz, 1H), 8.08 (s, 1H), 7.84 (d, J=8.0 Hz, 1H), 7.47 (t, J=8.0 Hz, 1H), 4.68 (m, 1H), 3.59-3.63 (m, 2H), 2.38-2.41 (m, 4H). MS(ES+): m/z=455.01/456.92 [MH+]. HPLC: tR=1.59 min (polar—5 min, ZQ3).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][N:14]=[C:13]3[C:16]4[C:21]([CH2:22][CH2:23][C:12]=23)=[CH:20][C:19]([CH:24]=C)=[CH:18][CH:17]=4)=[C:7]([C:26]([F:29])([F:28])[F:27])[CH:6]=1)([CH3:3])[CH3:2].C[N+]1([O-])CC[O:34]CC1.I([O-])(=O)(=O)=O.[Na+]>C1COCC1.O.[Os](=O)(=O)(=O)=O>[CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][N:14]=[C:13]3[C:16]4[C:21]([CH2:22][CH2:23][C:12]=23)=[CH:20][C:19]([CH:24]=[O:34])=[CH:18][CH:17]=4)=[C:7]([C:26]([F:28])([F:27])[F:29])[CH:6]=1)([CH3:2])[CH3:3]
Reactant: C=Cc1ccc2c(c1)CCc1c-2noc1-c1ccc(OC(C)C)cc1C(F)(F)F
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)Oc1ccc(-c2onc3c2CCc2cc(C=O)ccc2-3)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 98.2 %

Procedure:
To 3-(4-isopropoxy-2-(trifluoromethyl)phenyl)-7-vinyl-4,5-dihydronaphtho[1,2-c]isoxazole (Preparation 17B, 0.225 g, 0.563 mmol) in THF (2 mL) was added N-methylmorpholine-N-oxide (50% in water) (0.3 mL, 0.563 mmol) followed by osmium tetroxide (4% in water) (0.088 mL, 0.011 mmol) at room temperature. The contents were stirred at room temperature for 14 h. Sodium periodate (0.181 g, 0.845 mmol) dissolved in 1 mL of water was added at room temperature. The contents were stirred at room temperature for 30 min. The reaction mixture was partitioned between ethyl acetate (10 mL) and brine (5 mL). The dichloromethane layer was dried over sodium sulfate and concentrated to yield 3-(4-isopropoxy-2-(trifluoromethyl)phenyl)-4,5-dihydronaphtho[1,2-c]isoxazole-7-carbaldehyde (0.222 g, 0.553 mmol, 98% yield). LC/MS M+1=402.1.