Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][NH2:2].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([CH2:13][C:14]2[N:18]=[CH:17][O:16][N:15]=2)(=[O:12])=[O:11])=[CH:6][CH:5]=1.[CH2:19]([OH:21])C>>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([CH2:13][C:14]2[N:18]=[C:17]([C:19]([NH:1][NH2:2])=[O:21])[O:16][N:15]=2)(=[O:12])=[O:11])=[CH:6][CH:5]=1
Reactant: NN
Reactant: CCO
Reactant: O=S(=O)(Cc1ncon1)c1ccc(Cl)cc1
Product: NNC(=O)c1nc(CS(=O)(=O)c2ccc(Cl)cc2)no1
Reaction time: 5 h

Procedure:
Five ml. of 95% hydrazine (.15 moles) in ethanol was added slowly, with stirring, to 3-[(4-chlorophenylsulfonyl)methyl]-1, 2,4-oxadiazole, 5-carboxylic acid ethyl ester suspended in ethanol at 5° C. This reaction mixture was stirred in ice for 5 hours and then overnight at room temperature. The product was filtered off and recrystallized from ethanol to give 8 g. of the product, with m.p. 177° C.
Reaction SMILES: [NH2:1][C:2]1[N:23]=[C:22](Cl)[CH:21]=[CH:20][C:3]=1[C:4]([NH:6][CH2:7][C:8]1[S:9][C:10]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:11][CH:12]=1)=[O:5].C1C=CC(CC(NCN[C@H](C(O)=O)CC2[CH:44]=[CH:43][C:42]([N+:45]([O-])=O)=CC=2)=O)=CC=1.C1(N)CC1>CS(C)=O.C(N(CC)C(C)C)(C)C.[Cl-].[Na+].O>[NH2:1][C:2]1[N:23]=[C:22]([NH:45][CH:42]2[CH2:44][CH2:43]2)[CH:21]=[CH:20][C:3]=1[C:4]([NH:6][CH2:7][C:8]1[S:9][C:10]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:11][CH:12]=1)=[O:5]
Reactant: Nc1nc(Cl)ccc1C(=O)NCc1ccc(Oc2ccccc2)s1
Reactant: O=C(Cc1ccccc1)NCN[C@@H](Cc1ccc([N+](=O)[O-])cc1)C(=O)O
Agent: NC1CC1
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nc(NC2CC2)ccc1C(=O)NCc1ccc(Oc2ccccc2)s1
Temperature: 130 °C
Yield: 47.5 %

Procedure:
2-Amino-6-chloro-N-(5-phenoxy-thiophen-2-ylmethyl)-nicotinamide described in Example A-101 (30 mg, 0.083 mmol) was dissolved in a mixture solution of dimethylsulfoxide (1 mL) and N,N-diisopropylethylamine (0.5 mL), cyclopropylamine (0.058 mL, 0.84 mmol) was added thereto, followed by heating in a sealed tube for 15 hours 30 minutes (oil bath temperature: 130° C.). The reaction mixture was allowed to room temperature, poured into brine, which was then extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, then concentrated, the obtained residue was purified by NH silica gel column chromatography (ethyl acetate:hexane=2:1), and the title compound (15 mg, 0.039 mmol, 47.5%) was obtained.
Reaction SMILES: C([Mg]Cl)(C)C.I[C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][CH:8]=1.[CH3:17][CH:18]([CH3:22])[C:19](=[O:21])[CH3:20].Cl>C1COCC1>[OH:21][C:19]([C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][CH:8]=1)([CH3:20])[CH:18]([CH3:22])[CH3:17]
Reactant: CC(=O)C(C)C
Reactant: COC(=O)c1ccc(I)cc1
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C(C)(O)C(C)C)cc1
Temperature: -40 °C
Reaction time: 1 h

Procedure:
Isopropyl magnesium chloride (12.0 mL of a 2 M solution in THF, 24.0 mmol) was added to a solution of methyl 4-iodobenzoate (5.24 g, 20.0 mmol) in THF (50 mL) at −40° C. After 1 h, a second portion of isopropyl magnesium chloride (5.00 ml, of a 2 M solution in THF, 10.0 mmol) was added and the resulting mixture allowed to stir at −40° C. for 4 h. 3-Methyl-2-butanone (2.10 mL, 19.6 mmol) was then added and the resulting mixture allowed to warm to room temperature overnight. The reaction mixture was poured into 1 N HCl and extracted three times with EtOAc. The combined organic extracts were washed water, brine, dried (MgSO4) and concentrated in vacuo. Purification of the crude residue by flash chromatography on silica gel (gradient elution; 0%-20% EtOAc/hexanes as eluent) afforded the title compound i-2a. 1HNMR (500 MHz, CDCl3): δ 8.02 (d, 2H, J=8.5 Hz), 7.52 (d, 2H, J=8.5 Hz), 3.95 (s, 3H), 2.05 (p, 1H, J=6.6 Hz), 1.57 (s, 3H), 0.95 (d, 3H, J=6.6 Hz), 0.80 (d, 3H, J=6.9 Hz).
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([C@@H:15]3[N:19]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C@H:18]([C:27]([O:29][CH3:30])=[O:28])[CH2:17][CH2:16]3)=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:32][C:33]#[N:34].C1CCCCC1>C(OCC)(=O)C>[C:33]([CH2:32][C@@:18]1([C:27]([O:29][CH3:30])=[O:28])[CH2:17][CH2:16][C@H:15]([C:12]2[CH:11]=[CH:10][C:9]([O:8][CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:14][CH:13]=2)[N:19]1[C:20]([O:22][C:23]([CH3:25])([CH3:26])[CH3:24])=[O:21])#[N:34]
Reactant: COC(=O)[C@@H]1CC[C@H](c2ccc(OCc3ccccc3)cc2)N1C(=O)OC(C)(C)C
Reactant: N#CCBr
Solvent: CCOC(C)=O
Solvent: C1CCCCC1
Product: COC(=O)[C@]1(CC#N)CC[C@H](c2ccc(OCc3ccccc3)cc2)N1C(=O)OC(C)(C)C

Procedure:
The title compound was prepared (2.71 g, 76%) using a similar procedure t as set out earlier in Description 7 using crude 1-(1,1-dimethylethyl) 2-methyl (2S,5R)-5-{4-[(phenylmethyl)oxy]phenyl}-1,2-pyrrolidinedicarboxylate (D6, 3.25 g, 7.89 mmol) and bromoacetonitrile (3.3 ml, 47.38 mmol in 40 ml THF); Rt (HPLC): 6.4 min; Rf (cyclohexane:ethyl acetate=7:3): 0.40; MS: (ES/+) m/z: 473 [M+Na+]; C26H30N2O5 requires 450; 1H NMR (500 MHz, DMSO-d6) δ(ppm): 7.46-7.24 (m, 7H); 6.94 (d, 2H); 5.11 (s, 2H); 4.94-4.78 (m, 1H); 3.78 (s, 3H); 3.33 (d, 1H); 3.22 (d, 1H); 2.66-2.52 (m, 1H); 2.42-2.29 (m, 1H); 2.29-2.16 (m, 1H); 1.92-1.77 (m, 1H); 1.38-0.97 (br. s, 9H); NOE between the aromatic protons and the methyl ester could be observed.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][CH2:9][CH2:10][NH2:11])[N:2]=1.[CH3:12][N:13]([CH3:19])[CH2:14][CH2:15][N:16]=[C:17]=[S:18]>>[CH3:12][N:13]([CH3:19])[CH2:14][CH2:15][NH:16][C:17]([NH:11][CH2:10][CH2:9][NH:8][CH2:7][C:3]1[N:2]=[N:1][CH:6]=[CH:5][CH:4]=1)=[S:18]
Reactant: CN(C)CCN=C=S
Reactant: NCCNCc1cccnn1
Product: CN(C)CCNC(=S)NCCNCc1cccnn1

Procedure:
Reacting N-(3-pyridazinylmethyl)ethylenediamine with 2-dimethylaminoethyl isothiocyanate by the procedure of Example 40 gives the title compound.
Reaction SMILES: [CH3:1][N:2]([CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1.Cl[C:18]([O:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][N:29]=2)=[CH:23][CH:22]=1)=[O:19].C(NC(C)C)(C)C>>[F:36][C:34]([F:35])([F:37])[C:31]1[CH:32]=[CH:33][C:28]([O:27][C:24]2[CH:25]=[CH:26][C:21]([O:20][C:18]([N:14]3[CH2:15][CH2:16][CH:11]([N:2]([CH3:1])[CH2:3][CH2:4][C:5]4[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=4)[CH2:12][CH2:13]3)=[O:19])=[CH:22][CH:23]=2)=[N:29][CH:30]=1
Reactant: O=C(Cl)Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Reactant: CN(CCc1ccccn1)C1CCNCC1
Solvent: CC(C)NC(C)C
Product: CN(CCc1ccccn1)C1CCN(C(=O)Oc2ccc(Oc3ccc(C(F)(F)F)cn3)cc2)CC1

Procedure:
The title product was prepared from methyl-piperidin-4-yl-(2-pyridin-2-yl-ethyl)-amine and 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate, 5 equivalent of diisopropylamine was added, preparative HPLC (method C) (48%, colourless oil). HPLC-MS m/z=501.1 (M+1), Rt: 2.77 min.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:33])[NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([S:29](=[O:32])(=[O:31])[NH2:30])=[CH:25][CH:24]=3)(=[O:20])=[O:19])=[CH:14][CH:13]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].[O:34]1[CH2:38][CH2:37][O:36][CH:35]1[CH2:39][N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1>>[O:34]1[CH2:38][CH2:37][O:36][CH:35]1[CH2:39][N:40]1[CH2:41][CH2:42][N:43]([C:1](=[NH:2])[C:3]2[CH:4]=[C:5]([NH:9][C:10](=[O:33])[NH:11][C:12]3[CH:17]=[CH:16][C:15]([S:18]([NH:21][CH2:22][C:23]4[CH:28]=[CH:27][C:26]([S:29](=[O:31])(=[O:32])[NH2:30])=[CH:25][CH:24]=4)(=[O:20])=[O:19])=[CH:14][CH:13]=3)[CH:6]=[CH:7][CH:8]=2)[CH2:44][CH2:45]1
Reactant: N#Cc1cccc(NC(=O)Nc2ccc(S(=O)(=O)NCc3ccc(S(N)(=O)=O)cc3)cc2)c1
Reactant: C1CN(CC2OCCO2)CCN1
Product: N=C(c1cccc(NC(=O)Nc2ccc(S(=O)(=O)NCc3ccc(S(N)(=O)=O)cc3)cc2)c1)N1CCN(CC2OCCO2)CC1
Yield: 43 %

Procedure:
The title compound was prepared from 4-(3-(3-cyanophenyl)ureido)-N-(4-sulfamoylbenzyl)benzenesulfonamide following procedure C and using 2.2 equivalent of 1-(1,3-dioxolan-2-ylmethyl)piperazine as secondary amine. The product was purified by preparative HPLC.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][O:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[CH:11]=1.[CH2:24](O)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1.CCCCCC>[CH2:24]([O:8][C:6]1[CH:7]=[C:2]([CH3:1])[C:3]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][O:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][O:19]3)[CH:11]=2)=[C:4]([CH3:9])[CH:5]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: Cc1cc(O)cc(C)c1-c1cccc(COC2CCCCO2)c1
Reactant: OCc1ccccc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: Cc1cc(OCc2ccccc2)cc(C)c1-c1cccc(COC2CCCCO2)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 74.5 %

Procedure:
A solution of 2,6-dimethyl-3′-[(tetrahydro-2H-pyran-2-yloxy)methyl]biphenyl-4-ol (1.78 g, 5.70 mmol), benzyl alcohol (0.885 mL, 8.55 mmol) and tributylphosphine (2.13 mL, 8.55 mmol) in toluene (80 mL) was stirred under ice-cooling, and 1,1′-(azodicarbonyl)dipiperidine (2.16 g, 8.55 mmol) was added by small portions. The mixture was warmed to room temperature and stirred for 24 hrs. Hexane (40 mL) was added to the reaction mixture and the precipitated insoluble material was filtered off. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane-10% ethyl acetate/hexane) to give the title compound as a colorless oil (1.71 g, yield 75%).
Reaction SMILES: [N:1]([CH:4]1[CH2:16][N:8]2[C:9]3[C:14]([CH:15]=[C:7]2[CH2:6][CH2:5]1)=[CH:13][CH:12]=[CH:11][CH:10]=3)=[N+]=[N-]>CO.[Pd]>[CH:13]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:14]=1[CH:15]=[C:7]1[CH2:6][CH2:5][CH:4]([NH2:1])[CH2:16][N:8]12
Reactant: [N-]=[N+]=NC1CCc2cc3ccccc3n2C1
Agent: [Pd]
Solvent: CO
Product: NC1CCc2cc3ccccc3n2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
To a solution of (+/−) 7-azido-6,7,8,9-tetrahydropyrido[1,2-α]indole from Step 8 in MeOH (0.1 M) was added 10% palladium on carbon (200 mg per g of substrate). The reaction mixture was flushed a few times with hydrogen and then stirred overnight at rt under a 1 atmosphere pressure of hydrogen. The reaction mixture was diluted with CH2Cl2 and was filtered through Celite, the cake was washed with EtOAc and the filtrate concentrated under vacuum. The residue was purified by column chromatography on silica gel eluting with CH2Cl2/MeOH/NH4OH (100:0:0 to 89:10:01) to give the title compound (81%) as a brown gum.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[CH2:5][NH2:6].C[Al](C)C.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[S:25][C:26]3[C:32](=[O:33])[O:31][CH2:30][CH2:29][C:27]=3[N:28]=2)=[CH:20][CH:19]=1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[CH2:5][NH:6][C:32]([C:26]1[S:25][C:24]([C:21]2[CH:22]=[CH:23][C:18]([Cl:17])=[CH:19][CH:20]=2)=[N:28][C:27]=1[CH2:29][CH2:30][OH:31])=[O:33]
Reactant: COc1ccc(CN)c(OC)c1
Reactant: O=C1OCCc2nc(-c3ccc(Cl)cc3)sc21
Agent: C[Al](C)C
Solvent: ClCCl
Product: COc1ccc(CNC(=O)c2sc(-c3ccc(Cl)cc3)nc2CCO)c(OC)c1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 61.7 %

Procedure:
Dissolve 2,4-dimethoxybenzylamine (22.4 g, 134.0 mmol) in CH2Cl2 (300 mL) and cool to 0° C. To the above solution, slowly add a solution of trimethylaluminum (110 mL, 220 mmol; 2 M in toluene) over 35 min while keeping the temperature below 10° C. Stir the resulting solution at room temperature for 45 min and then re-cool to 0° C. Add 2-(4-chloro-phenyl)-6,7-dihydro-pyrano[4,3-d]thiazol-4-one (52.2 g, 120.6 mmol), then allow the resulting slurry to warm to room temperature and stir overnight. Cool the reaction and carefully quench with saturated Rochelle's salt solution (300 mL) over 30 min. Add CH2Cl2 (750 mL), water (400 mL) and diatomaceous earth (100 g) and stir the mixture at room temperature for 30 min, then filter. Collect the solids and triturate with CH2Cl2 (1 L) at 35° C. for 3 h, then filter. Concentrate the filtrate to obtain the title compound (32.2 g). Repeat the trituration step with the second solid cake and obtain an additional 20 g of title compound (90% total yield). 1H NMR (400 MHz, DMSO-d6) δ9.01 (br s, 1H), 7.96 (d, 2H, J=8.5), 7.57 (d, 2H, J=8.5), 7.15 (d, 1H, J=7.9), 6.57 (d, 1H, J=2.6), 6.48 (dd, 1H, J=2.6, 8.5), 5.34 (t, 1H, J=4.3), 4.34 (d, 2H, J=6.6), 3.81 (s, 3H), 3.79 (m, 2H), 3.75 (s, 3H), 3.11 (t, 3H, J=6.6).
Reaction SMILES: [CH2:1]([C:3]1[C:4]([CH3:20])=[C:5]([C:12]2[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=2)[C:15]#[N:16])[C:6]([CH3:11])=[N:7][C:8]=1[O:9]C)[CH3:2].[I-].[Na+].Cl[Si](C)(C)C.C(#N)C>O>[CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:11])=[C:5]([C:12]2[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=2)[C:15]#[N:16])[C:4]=1[CH3:20])[CH3:2]
Reactant: CCc1c(OC)nc(C)c(-c2cccc(C#N)c2)c1C
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CCc1c(C)c(-c2cccc(C#N)c2)c(C)[nH]c1=O
Yield: 31.2 %

Procedure:
A stirred mixture of 3-(5-ethyl-6-methoxy-2,4-dimethylpyridin-3-yl)benzonitrile (44 mg, 0.165 mmol), sodium iodide (50 mg, 0.33 mmol), chlorotrimethylsilane (58.4 μL, 0.33 mL) and acetonitrile (2 mL) is heated at reflux temperature for 3 hr. The cooled reaction mixture is diluted with water (10 mL) and extracted with dichloromethane. The extract is dried, filtered, concentrated and the residue is purified by chromatography eluting with cyclohexane-ethyl acetate then with dichloromethane-5% methanol. Product containing fractions are combined and concentrated to afford 3-(5-ethyl-2,4-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)benzonitrile (13 mg, 32%) as a beige solid. LC/MS: MS m/e=253 (M+H); RT 2.92 min.; 1H NMR (CDCl3, δ ppm) 7.69 (1H, d), 7.59 (1H, t), 7.45 (1H, s), 7.41 (1H, d), 2.63 (2H, q), 2.02 (3H, s), 1.84 (3H, s), 1.11 (3H, t).
Reaction SMILES: COCCN(S(F)(F)F)CCOC.F[C:15]1[CH:16]=[C:17]([Br:24])[CH:18]=[C:19]([CH:21]([F:23])[F:22])[CH:20]=1.[CH3:25][O:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31][OH:32])=[CH:29][CH:28]=1.CC(C)([O-])C.[K+]>C1COCC1.C(Cl)Cl>[Br:24][C:17]1[CH:16]=[C:15]([O:32][CH2:31][C:30]2[CH:33]=[CH:34][C:27]([O:26][CH3:25])=[CH:28][CH:29]=2)[CH:20]=[C:19]([CH:21]([F:23])[F:22])[CH:18]=1
Reactant: Fc1cc(Br)cc(C(F)F)c1
Reactant: COc1ccc(CO)cc1
Agent: CC(C)(C)[O-]
Agent: COCCN(CCOC)S(F)(F)F
Agent: [K+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1ccc(COc2cc(Br)cc(C(F)F)c2)cc1

Procedure:
In a fourteenth embodiment of the present invention there is provided a process for the preparation of a compound according to formula 2 which process comprises the steps of: (a) contacting 3,5-dibromo-fluoro-benzene (25) with iso-propyl magnesium chloride to afford a 3-bromo-5-fluoro-phenylmagnesium halide (26); (b) contacting 26 with DMF followed by aqueous acid and MTBE to afford 3-bromo-5-fluoro-benzaldehyde (28); (c) contacting 28 with DEOXO-FLUOR and DCM to a afford 3-fluoro-5-difluoromethyl-1-bromo-benzene (30); (d) contacting 30 with p-methoxy-benzyl alcohol and potassium tert-butoxide in THF to afford 1-bromo-3-difluoromethyl-5-(4-methoxy-benzyloxy)-benzene (32); (e) contacting a solution of 32 and NMP with potassium ferrocyanide, Na2CO3, Pd(OAc)2 and DPPF at about 130° C. to afford 34; (f) treating a solution of 34 and anisole with TFA at temperatures sufficient to cleave the O-benzyl linkage and afford 36; (g) treating a solution of 36 and THF with 1,2,3-trifluoro-4-nitrobenzene (37) and K2CO3 to afford 3-difluoromethyl-5-(2,3-difluoro-6-nitro-phenoxy)-benzonitrile (38); (h) contacting 4 with a strong base in an inert solvent said strong base capable of forming the conjugate base of 4 and contacting said conjugate base with 6 to afford 8; (i) exposing 8 to reaction conditions which are capable of hydrolyzing the ester and decarboxylating the resulting carboxylic acid 8a, (j) contacting 2 with a reducing agent capable of selective reduction of the nitro group to afford 12; (k) contacting 12 with a diazotizing reagent and either Cu(I)Br/LiBr or Cu(I)Cl/LiCl to afford 14, (l) exposing 14 to an oxidizing agent capable of oxidation of the sulfide to a sulfone 18; and (m) contacting 18 with acetic acid/acetic anhydride under conditions which result in cleavage of the S-heteroaryl bond and hydrolysis of the resulting acetate to afford 20 wherein R2 is bromo and chloro respectively, Ar is phenyl substituted with 2 or 3 groups independently selected from halogen, cyano and C1-6 haloalkyl, and R1 and R3 are C1-10 alkyl.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][NH2:8])([O-:3])=[O:2].Cl[C:13]1[C:14]2[CH:26]=[C:25]([Cl:27])[S:24][C:15]=2[N:16]=[C:17]([C:19]2[O:23][N:22]=[CH:21][CH:20]=2)[N:18]=1>>[O:23]1[C:19]([C:17]2[N:18]=[C:13]([NH:8][CH2:7][C:6]3[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)[C:14]3[CH:26]=[C:25]([Cl:27])[S:24][C:15]=3[N:16]=2)=[CH:20][CH:21]=[N:22]1
Reactant: NCc1cccc([N+](=O)[O-])c1
Reactant: Clc1cc2c(Cl)nc(-c3ccno3)nc2s1
Product: O=[N+]([O-])c1cccc(CNc2nc(-c3ccno3)nc3sc(Cl)cc23)c1

Procedure:
With the procedure of Example 1, the reaction of 3-nitrobenzylamine with 4-chloro-2-(isoxazol-5-yl)-6-chloro-thieno-[2,3-d]-pyrimidine yields 2-(isoxazol-5-yl)-4-(3-nitrobenzylamino)-6-chloro-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([OH:29])=O)=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.Cl.[CH3:60][N:61]1[CH:66]2[CH2:67][CH2:68][CH:62]1[CH2:63][CH:64]([NH2:69])[CH2:65]2>>[CH:1]1([N:7]2[CH2:13][C:12]([F:14])([F:15])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([NH:69][CH:64]5[CH2:65][CH:66]6[N:61]([CH3:60])[CH:62]([CH2:68][CH2:67]6)[CH2:63]5)=[O:29])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C
Reactant: CN1C2CCC1CC(N)C2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Product: COc1cc(C(=O)NC2CC3CCC(C2)N3C)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C

Procedure:
The title compound was synthesized from 4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid as described in the General procedure for amide bond synthesis using HATU and 8-methyl-8-azabicyclo[3.2.1]octan-3-amine dihydrochloride. The final compound was purified by reverse phase HPLC and basified to give the free base. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.13-1.45 (m, 4H) 1.37-1.85 (m, 12H) 1.99 (s, 2H) 2.29 (br. s., 2H) 3.31 (s, 3H) 3.93 (s, 3H) 3.97-4.22 (m, 3H) 4.45 (m, 1H) 7.47 (d, J=8.0 Hz, 1H) 7.49 (s, 1H) 7.90 (s, 1H) 8.15 (d, 1H) 8.20 (s, 1H) 8.25 (d, J=8.34 Hz, 1H). [M+H] calculated for C30H39F2N7O3, 584. found 584.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[N:4]([CH2:12][C:13]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:14]=1[C:23]1[CH:28]=[C:27]([CH:29]([CH3:31])[CH3:30])[CH:26]=[CH:25][C:24]=1[O:32][CH3:33])[CH2:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1.C1C=C(Cl)C=C(C(OO)=[O:43])C=1.OS([O-])=O.[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:34])[N:4]([CH2:12][C:13]1[CH:18]=[C:17]([C:19]([F:21])([F:22])[F:20])[CH:16]=[CH:15][C:14]=1[C:23]1[CH:28]=[C:27]([CH:29]([CH3:30])[CH3:31])[CH:26]=[CH:25][C:24]=1[O:32][CH3:33])[CH2:5][C:6]1[CH:7]=[N+:8]([O-:43])[CH:9]=[CH:10][CH:11]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC(=O)N(Cc1cccnc1)Cc1cc(C(F)(F)F)ccc1-c1cc(C(C)C)ccc1OC
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)N(Cc1ccc[n+]([O-])c1)Cc1cc(C(F)(F)F)ccc1-c1cc(C(C)C)ccc1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of methyl{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}(pyridin-3-ylmethyl)carbamate (12 mg, 0.025 mmol) (Example 123) in CH2Cl2 (400 μL) was added m-CPBA (28 mg, 0.13 mmol). The reaction was stirred at room temperature for two hours and then was poured into NaHSO3 (10 mL). The mixture was extracted with EtOAc (50 mL), and the organic extracts were washed with water (10 mL), brine (10 mL), dried over Na2SO4, filtered, and concentrated. Purification by flash chromatography with 10 to 20% MeOH/EtOAc afforded methyl{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}[(1-oxidopyridin-3-yl)methyl]carbamate. Rf=0.36 (20% MeOH/EtOAc). LCMS=489.2 (M+1)+. 1H NMR (C6D6, 500 MHz, 70° C.) δ 6.21-8.22 (m, aromatics, 10H), 4.32 (s, 2H), 3.77 (s, 2H), 3.37 (s, 3H), 3.17 (s, 3H), 2.89 (m, 1H), 1.19 (d, J=7.0 Hz, 6H).
Reaction SMILES: [C:1]([O:4][C:5](=O)[CH3:6])(=[O:3])[CH3:2].[N:8]1[C:17]2[C:12](=[N:13][CH:14]=[CH:15][N:16]=2)[C:11]([NH:18][CH2:19][CH2:20][C:21]2C=C[C:24]([O:28][C:29]3[CH:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[CH:31][N:30]=3)=[C:25](O)[CH:26]=2)=[N:10][CH:9]=1.N1C=CC=CC=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[N:8]1[C:17]2[C:12](=[N:13][CH:14]=[CH:15][N:16]=2)[C:11]([NH:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:28][C:29]3[CH:34]=[C:33]([C:35]([F:36])([F:37])[F:38])[CH:32]=[CH:31][N:30]=3)=[C:5]([O:4][C:1](=[O:3])[CH3:2])[CH:6]=2)=[N:10][CH:9]=1
Reactant: CC(=O)OC(C)=O
Reactant: Oc1cc(CCNc2ncnc3nccnc23)ccc1Oc1cc(C(F)(F)F)ccn1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Oc1cc(CCNc2ncnc3nccnc23)ccc1Oc1cc(C(F)(F)F)ccn1
Temperature: 25 °C
Reaction time: 15 h
Yield: 56 %

Procedure:
To 4 mL of acetic anhydride was added 5-[2-(Pteridin-4-ylamino)-ethyl]-2-(4-trifluoromethylpyridin-2-yloxy)-phenol (330 mg, 0.7 mmol), pyridine (0.5 mL), and 5 mg DMAP. The solution was stirred at ambient temperature for 15 h, then diluted with CH2Cl2 and washed sequentially with H2O and saturated aqueous NaHCO3 solution. The organic fraction was dried with Na2SO4, suction filtered, and concentrated in vacuo. The residue was diluted with 1:1 Et2O/pentane. The product precipitated, was collected by filtration, and the cake washed with cool 1:1 Et2O/pentane. This afforded 184 mg (56% yield) of acetic acid 5-[2-(pteridin-4-ylamino)-ethyl]-2-(4-trifluoromethylpyridin-2-yloxy)-phenyl ester, an off-white solid: ESIMS m/z: 471 ([M]).
Reaction SMILES: [CH3:1][C:2]([CH3:11])([O:4][C:5]([NH:7][CH2:8][CH2:9][NH2:10])=[O:6])[CH3:3].[CH3:12][O:13][C:14](=[O:28])[CH:15](Br)[C:16]1[C:17]([CH:22](Br)[C:23]([OH:25])=[O:24])=[CH:18][CH:19]=[CH:20][CH:21]=1.[CH2:29](N(CC)CC)C.O>C1C=CC=CC=1>[CH3:12][O:13][C:14]([CH:15]1[C:16]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:22]([C:23]([O:25][CH3:29])=[O:24])[N:10]1[CH2:9][CH2:8][NH:7][C:5]([O:4][C:2]([CH3:11])([CH3:1])[CH3:3])=[O:6])=[O:28]
Reactant: COC(=O)C(Br)c1ccccc1C(Br)C(=O)O
Reactant: CCN(CC)CC
Reactant: CC(C)(C)OC(=O)NCCN
Solvent: c1ccccc1
Solvent: O
Product: COC(=O)C1c2ccccc2C(C(=O)OC)N1CCNC(=O)OC(C)(C)C
Yield: 43.5 %

Procedure:
A solution of N-(1,1-dimethylethoxycarbonyl)-ethylene diamine (3 g) in benzene (25 ml) is added dropwise to a solution of α,α'-dibromo-1,2-benzenediacetic acid methyl ester (3.78 g) and triethylamine (3.5 g) in benzene (75 ml). The mixture is refluxed for 18 hr using a water separator condenser and filtered. The filtrate is evaporated and the residue is chromatographed on silica gel using diethyl ether-hexane-pyridine (500:500:1). The eluate is evaporated to give the title compound (1.7 g), nmr (CDCl3) δ1.4(s), 3.03(m), 3.63(s), 5.0(s) and 7.17(m).