Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.[C:22]1(=[O:33])[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][C:23]1=[O:32].C(N(CC)CC)C>ClCCl>[O:32]=[C:23]1[C:22](=[O:33])[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25]([N:1]2[CH2:2][CH2:3][C:4]3([O:11][C:10]4[C:12]5[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=4[S:8][CH2:7]3)=[CH:16][CH:15]=[CH:14][CH:13]=5)[CH2:5][CH2:6]2)=[CH:24]1
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Reactant: O=C1C=Cc2ccccc2C1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1C=C(N2CCC3(CC2)CSC2=C(O3)c3ccccc3C(=O)C2=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 14.3 %

Procedure:
To a solution of spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione (2.3 g, 7.64 mmol) in dichloromethane (200 mL) was added naphthalene-1,2-dione (1.2 g, 7.64 mmol) followed by triethylamine (1.05 mL, 8.4 mmol). The reaction mixture was stirred at room temperature for 2 hours. The mixture was then concentrated under reduced pressure. The residue was dissolved in minimal tetrahydrofuran and then precipitated with EtOAc. The precipitate was collected by vacuum filtration. The filtrate was then suspended in tetrahydrofuran:EtOAc (1:1, 100 mL). The suspension was stirred, sonicated, and the solid collected by vacuum filtration. The tituration was once more repeated and the resulting reddish brown powder was recrystallized from dichloromethane/methanol (1:1) to afford the product (0.5 g) as the pure reddish brown solid. M.p.=250-260° C.; 400 MHz 1H NMR (DMSO-d6) δ: 7.89-7.93 (m, 3H), 7.71-7.81 (m. 3H), 7.55-7.65 (m, 2H), 6.10 (s, 1H), 3.67-3.75 (m, 2H), 3.45-3.53 (m, 2H), 3.19 (s, 2H), 2.20 (m, 2H), 1.25 (m, 1H), 1.01 (m, 1H). LCMS: 458 [M+H].
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N+:3]=1[O-].[ClH:10]>>[Cl:10][C:6]1[CH:7]=[C:2]([CH3:1])[N:3]=[C:4]([CH3:8])[CH:5]=1
Reactant: Cc1cccc(C)[n+]1[O-]
Reactant: Cl
Product: Cc1cc(Cl)cc(C)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 33 %

Procedure:
To a solution of concentrated HCl (10 ml) at 10° C. was added 2,6-dimethylpyridine N-oxide (3.0 g, 24.3 mmol) and the resulting white slurry was stirred at room temperature for 3 hours. The product was filtered and washed with iPrOH (2×10 ml) and dried at reduced pressure. The resulting solid was dissolved in POCl3 (10 ml) and heated at reflux for 8 hours then cooled to 0° C. The reaction was quenched carefully with saturated K2CO3 (40 ml) and extracted with dichloromethane (2×50 ml), dried (Na2SO4), filtered and concentrated at reduced pressure. The residue was dissolved in ethanol (20 ml) and NEt3 (5 ml) and heated at reflux for 24 hours then cooled to room temperature and concentrated at reduced pressure. Water (5 ml) was added to the residue the aqueous mixture was extracted with chloroform (2×10 ml). The organics were combined and washed with brine (10 ml), dried (Na2SO4), filtered and concentrated at reduced pressure to give the title compound as brown solid (1.0 g, 33%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:14]([CH2:15][CH:16]4[CH2:21][CH2:20][O:19][CH2:18][CH2:17]4)[C:13]([CH2:22][O:23][CH2:24][CH3:25])=[N:12][C:7]=3[CH:8]=[N:9][C:10]=2[CH:11]=1.ClC1C=C(C=CC=1)C(OO)=O.[OH-].[NH4+:38].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>ClC1C=C(C=CC=1)C(OO)=O.C(#N)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:14]([CH2:15][CH:16]4[CH2:21][CH2:20][O:19][CH2:18][CH2:17]4)[C:13]([CH2:22][O:23][CH2:24][CH3:25])=[N:12][C:7]=3[C:8]([NH2:38])=[N:9][C:10]=2[CH:11]=1
Reactant: [NH4+]
Reactant: CCOCc1nc2cnc3cc(Br)ccc3c2n1CC1CCOCC1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: CC#N
Product: CCOCc1nc2c(N)nc3cc(Br)ccc3c2n1CC1CCOCC1
Reaction time: 8 h

Procedure:
The method described in Part J of Example 365 was used to oxidize and aminate 7-bromo-2-ethoxymethyl-1-(tetrahydropyran-4-ylmethyl)-1H-imidazo[4,5-c]quinoline (9.3 g, 23.0 mmol). 3-Chloroperoxybenzoic acid (7.9 g of 50% pure material, 23 mmol) was added in five portions during the oxidation step, which was stirred overnight. Additional 3-chloroperoxybenzoic acid (200 mg) was added, and the reaction was stirred for 20 mintues before ammonium hydroxide (60 mL) and p-toluenesulfonyl chloride (6.58 g, 34.5 mmol) were added. The crude product was obtained as an oil, which was treated with acetonitrile to form a precipitate. The precipitate was isolated by filtration and purified by HPFC (eluting with chloroform:CMA in a gradient from 100:0 to 80:20) to provide 6.0 g of 7-bromo-2-ethoxymethyl-1-(tetrahydropyran-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-4-amine as a white solid, mp 186–188° C.
Reaction SMILES: [Cl-].[O:2]=[C:3]([CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1)[CH2:4][P+:5]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.O>[OH-].[Na+]>[O:2]=[C:3]([CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1)[CH2:4][PH:5]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C(CCc1ccc(F)cc1)C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(CCc1ccc(F)cc1)C[PH](c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
To a solution of 29.25 g. of (2-oxo-4-p-fluorophenylbutyl)-triphenylphosphonium chloride of part 3, in 250 ml. of warm water is added 80 ml. of IN sodium hydroxide solution. An oil separates which solidifies. The solid is collected by filtration and dissolved in methylene chloride. The solution is dried and then concentrated on a steam bath. Skellysolve B is added to the boiling solution. Cooling gives cream prisms of the title compound (25.85 g.); m.p. 123°-125°. The infrared spectrum shows absorptions at 3490, 3540, 3240, 1605, 1590, 1575, 1550, 1525, 1510, 1485, 1440, 1390, 1220, 1105, 875, 860, 755, 720, and 700 cm -1. NMR peaks are observed at 2.6-3.0, 6.9-7.4 and 7.4-7.8 δ.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([OH:10])=O)[C:5]([O:11][CH3:12])=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[F:19].S(Cl)(Cl)=O.[CH:24]1[CH:25]=[CH:26][N:27]2[CH2:33][C:32]3[CH:34]=[CH:35][CH:36]=[CH:37][C:31]=3[NH:30][CH2:29][C:28]=12.C(N(CC)CC)C>O1CCCC1.ClCCl.CN(C)C=O>[Cl:1][C:2]1[C:3]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[F:19])=[CH:4][C:5]([O:11][CH3:12])=[C:6]([C:8]([N:30]2[C:31]3[CH:37]=[CH:36][CH:35]=[CH:34][C:32]=3[CH2:33][N:27]3[CH:26]=[CH:25][CH:24]=[C:28]3[CH2:29]2)=[O:10])[CH:7]=1
Reactant: COc1cc(-c2ccccc2F)c(Cl)cc1C(=O)O
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc(-c2ccccc2F)c(Cl)cc1C(=O)N1Cc2cccn2Cc2ccccc21
Reaction time: 2 h

Procedure:
To a stirred solution of 2-chloro-2′-fluoro-5-methoxy[1,1′-biphenyl]-4-carboxylic acid of Step A (3.80 g, 13.5 mmol) in tetrahydrofuran (20 mL) containing a catalytic amount of N,N-dimethylformamide was added dropwise thionyl chloride (1.77 g, 14.9 mmol). The reaction mixture was stirred for 2 hours, and then added dropwise to a solution of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (2.49 g, 13.5 mmol) in tetrahydrofuran (20 mL) containing triethylamine (3.0 g, 29.8 mmol). The reaction mixture was stirred for 2 hours, diluted with dichloromethane and washed with saturated aqueous sodium bicarbonate and brine. The organic layer was dried over anhydrous magnesium sulfate, filtered, and evaporated to dryness. Recrystallization of the residue from ethyl acetate/heptane provided the title compound as a pale yellow solid, m.p. 192-194° C., found to be 99.99% pure by analytical HPLC [Primesphere C-18 column (2.0×150 mm); mobile phase: gradient from 10 to 100% of acetonitrile/water containing 0.1% phosphoric acid, 7 minute gradient].
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C@@H:7]1[CH2:24][C:23]2[CH:22]=[C:21]([OH:25])[CH:20]=[CH:19][C:18]=2[C@@H:17]2[C@@H:8]1[C@H:9]1[C@@:13]([CH2:15][C@@H:16]2[F:26])([CH3:14])[CH:12]([OH:27])[CH2:11][CH2:10]1.[CH3:28][NH:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36]([F:42])([F:41])[C:37]([F:40])([F:39])[F:38].[Cl-].[Na+]>CN1CCCC1=O>[F:26][C@H:16]1[CH2:15][C@@:13]2([CH3:14])[C@@H:9]([CH2:10][CH2:11][C@@H:12]2[OH:27])[C@H:8]2[C@H:17]1[C:18]1[CH:19]=[CH:20][C:21]([OH:25])=[CH:22][C:23]=1[CH2:24][C@H:7]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:29]([CH3:28])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36]([F:41])([F:42])[C:37]([F:38])([F:39])[F:40]
Reactant: CNCCCCCCC(F)(F)C(F)(F)F
Reactant: C[C@]12C[C@H](F)[C@@H]3c4ccc(O)cc4C[C@@H](CCCCCBr)[C@H]3[C@@H]1CCC2O
Agent: [Cl-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CN(CCCCCCC(F)(F)C(F)(F)F)CCCCC[C@@H]1Cc2cc(O)ccc2[C@@H]2[C@@H]1[C@@H]1CC[C@H](O)[C@@]1(C)C[C@@H]2F
Yield: 94.8 %

Procedure:
A solution of 466 mg of 7α-(5-bromopentyl)-11β-fluor-estra-1,3,5(10)-triene-3,17-diol in 10 ml of 1-methyl-2-pyrrolidinone is stirred with 702 mg of methyl-(7,7,8,8,8-pentafluor-octyl)-amine for 3 hours at a bath temperature of 80° C. For working-up, the batch is added to saturated sodium chloride solution, extracted with ethyl acetate, dried on sodium sulfate, concentrated by evaporation in a vacuum and chromatographed on silica gel with dichloromethane/methanol. 595 mg of 11β-fluoro-7α-{5-[methyl-(7,7,8,8,8-pentafluor-octyl)-amino]-pentyl}-estra-1,3,5(10)-triene-3,17β-diol is obtained as a foam, [α]D=+39° (c=0.5 in CHCl3).
Reaction SMILES: [CH:1]12[CH2:9][CH2:8][CH:5]([CH:6]=[CH:7]1)[C:4](=[O:10])[CH2:3][C:2]2=[O:11].C1(C)C=CC=CC=1.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Br:31][C:32]1[CH:33]=[CH:34][C:35]([CH2:39][CH3:40])=[C:36]([Pb+3])[CH:37]=1.Cl>C(Cl)(Cl)Cl.CN(C)C1C=CN=CC=1>[Br:31][C:32]1[CH:37]=[CH:36][C:35]([CH2:39][CH3:40])=[C:34]([CH:3]2[C:2](=[O:11])[CH:1]3[CH2:9][CH2:8][CH:5]([CH:6]=[CH:7]3)[C:4]2=[O:10])[CH:33]=1
Reactant: O=C1CC(=O)C2C=CC1CC2
Reactant: CCc1ccc(Br)cc1[Pb+3]
Agent: CC(=O)[O-]
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: CCc1ccc(Br)cc1C1C(=O)C2C=CC(CC2)C1=O
Temperature: 80 °C
Reaction time: 8 h
Yield: 21.5 %

Procedure:
A solution of bicyclo[3.2.2]non-6-ene-2,4-dione (0.835 g, 5.58 mmol), prepared by the method of R. Beaudegnies et al., WO2005/123667, in dry chloroform (30 ml) is stirred at room temperature then thoroughly flushed with nitrogen. To this mixture is added 4-dimethylaminopyridine (3.41 g, 28 mmol) and anhydrous toluene (5 ml), followed by heating to 80° C. 5-Bromo-2-ethylphenyllead triacetate (4.75 g, 8.36 mmol) is added portionwise over 20 minutes, and the mixture is further heated at this temperature for a further 4 hours then left to stand overnight. 2M hydrochloric acid (40 ml) is added, and the suspension is vigorously stirred for 30 minutes then filtered through diatomaceous earth (washing with additional dichloromethane, 40 ml). The organic phase is separated, and the aqueous phase is extracted with dichloromethane (40 ml×2). All organic fractions are combined, dried over magnesium sulfate, filtered and the filtrate concentrated under reduced pressure to give a brown oil. The crude product is purified by flash column chromatography on silica gel (100% to 40% hexane/ethyl acetate eluant ratio) to afford 3-(5-bromo-2-ethylphenyl)bicyclo[3.2.2]non-6-ene-2,4-dione (0.400 g, 22%) as a yellow gum.
Reaction SMILES: [N+](=[CH:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][CH2:15][CH:16]2[C:28]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:22]3[C:17]2=[CH:18][CH:19]=[CH:20][CH:21]=3)=[O:13])[CH2:8][CH2:7]1)=[O:5])=[N-].[BrH:29]>C1COCC1.O>[Br:29][CH2:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][CH2:15][CH:16]2[C:28]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:22]3[C:17]2=[CH:18][CH:19]=[CH:20][CH:21]=3)=[O:13])[CH2:8][CH2:7]1)=[O:5]
Reactant: [N-]=[N+]=CC(=O)C1CCN(C(=O)OCC2c3ccccc3-c3ccccc32)CC1
Reactant: Br
Solvent: C1CCOC1
Solvent: O
Product: O=C(CBr)C1CCN(C(=O)OCC2c3ccccc3-c3ccccc32)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 53 %

Procedure:
A solution of (9H-fluoren-9-yl)methyl 4-(diazoacetyl)piperidine-1-carboxylate (5 g, 13.3 mmol) in THF was cooled in an ice water bath and was treated with an aqueous HBr solution (10 mL). This reaction mixture was stirred at RT for 2 h. The reaction mixture was diluted with water and the organic content was extracted using EtOAc, dried over Na2SO4, filtered and concentrated at reduced pressure. The crude product was chromatographed over silica gel eluting with a gradient (0-15% EtOAc:hexanes) to afford (9H-fluoren-9-yl)methyl 4-(bromoacetyl)piperidine-1-carboxylate (3 g, 53%) as an off white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]([O:10][CH3:11])=[S:9])[S:5][C:6]=1[CH3:7].[CH3:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][C:18]=1[CH3:19]>>[CH3:12][C:13]1[CH:14]=[C:15]([NH:1][C:2]2[CH:3]=[C:4]([C:8]([O:10][CH3:11])=[S:9])[S:5][C:6]=2[CH3:7])[CH:16]=[CH:17][C:18]=1[CH3:19]
Reactant: Cc1ccc(B(O)O)cc1C
Reactant: COC(=S)c1cc(N)c(C)s1
Product: COC(=S)c1cc(Nc2ccc(C)c(C)c2)c(C)s1
Yield: 129.5 %

Procedure:
Using a procedure similar to Example 208, step (a), 74.4 mg (0.36 mmol) of methyl 4-amino-5-methylthiothiophene-2-carboxylate was allowed to react with 108 mg (2 equiv, 0.72 mmol) of 3,4-dimethylphenyl boronic acid to give 135.9 mg (32.4%) of methyl 4-[(3,4-dimethylphenyl)amino]-5-methylthiothiophene-2-carboxylate. 1H NMR (CDCl3, 400 MHz) δ2.24 (s, 3H), 2.26 (s, 3H), 2.38 (s, 3H), 3.88 (s, 3H), 6.11 (bs, 1H), 6.80-6.84 (m, 2H), 7.07 (d, 1H, J=7.9 Hz), 7.71 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[C:12]2[C:18]1[N:23]=[C:22]([O:24][C@@H:25]2[CH2:30][CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26]2)[CH:21]=[N:20][CH:19]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[C:12]2[C:18]1[CH:19]=[N:20][CH:21]=[C:22]([O:24][C@@H:25]2[CH2:30][CH2:29][CH2:28][NH:27][CH2:26]2)[N:23]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](Oc2cncc(-c3c[nH]c4ccc(-c5c(F)cccc5F)cc34)n2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Fc1cccc(F)c1-c1ccc2[nH]cc(-c3cncc(O[C@@H]4CCCNC4)n3)c2c1
Temperature: 80 °C

Procedure:
A glass microwave reaction vessel was charged with (R)-tert-butyl 3-(6-(5-(2,6-difluorophenyl)-1H-indol-3-yl)pyrazin-2-yloxy)piperidine-1-carboxylate (1.91 g, 3.77 mmol) in DCM (10 mL)/TFA (4 mL). The reaction mixture was stirred and heated in a Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc., Uppsala, Sweden) at 80° C. for 15 min, and then the solvent was removed. The residue was purified with RP-HPLC to give (R)-5-(2,6-difluorophenyl)-3-(6-(piperidin-3-yloxy)pyrazin-2-yl)-1H-indole.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([C:10]([O-:12])=[O:11])=[C:8]([CH3:13])[S:7][C:6]=2[CH:14]=1.Cl[C:16]1[CH:21]=[CH:20][N:19]=[C:18]2[CH:22]=[C:23]([C:25]([N:27]3[CH2:31][CH2:30][C@@H:29]([OH:32])[CH2:28]3)=[O:26])[S:24][C:17]=12.C([O-])([O-])=O.[Cs+].[Cs+].O[Li].O>>[OH:32][C@@H:29]1[CH2:30][CH2:31][N:27]([C:25]([C:23]2[S:24][C:17]3[C:18](=[N:19][CH:20]=[CH:21][C:16]=3[O:1][C:2]3[CH:3]=[CH:4][C:5]4[C:9]([C:10]([OH:12])=[O:11])=[C:8]([CH3:13])[S:7][C:6]=4[CH:14]=3)[CH:22]=2)=[O:26])[CH2:28]1
Reactant: O=C(c1cc2nccc(Cl)c2s1)N1CC[C@@H](O)C1
Reactant: Cc1sc2cc(O)ccc2c1C(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [Li]O
Solvent: O
Product: Cc1sc2cc(Oc3ccnc4cc(C(=O)N5CC[C@@H](O)C5)sc34)ccc2c1C(=O)O
Yield: 45 %

Procedure:
This material was prepared from the reaction of methyl 6-hydroxy-2-methylbenzo[b]thiophene-3-carboxylate 11a (283 mg, 1.00 mmole) with 7-chloro-2-[(R)-3-hydroxypyrrolidine-1-carbonyl]thieno[3,2-b]pyridine 4a and Cs2CO3 (977 mg, 3.00 mmole) in a manner as previously described for example 1. The crude product was then reacted with LiOH.H2O (227 mg, 5.4 mmole) in a manner similar to that described for example 11c to give a yellow solid (202 mg, 45%). 1H NMR (DMSO-d6, 300 MHz) δ 8.58 (1H, d, J=5.31 Hz), 8.44 (1H, d, J=8.84Hz), 8.14, 8.07 (1H, s), 8.00 (1H, s), 7.39 (1H, dd, J=2.40, 8.97 Hz), 6.78 (1H, d, J=5.56 Hz), 4.38, 4.33 (1H, br s), 4.01–3.91 (1 H, m), 3.68–3.56 (2H, m), 3.49–3.22 (2H, m), 2.81 (3H, s), 2.07–1.79 (2H, m).
Reaction SMILES: [N+:1]([C:4]1[C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N+:6]([O-])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[Cl-:17].[P+]=O>ClCCCl>[Cl:17][C:7]1[N:6]=[C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=1
Reactant: O=[N+]([O-])c1ccc[n+]([O-])c1-c1ccccc1
Reactant: [Cl-]
Agent: O=[P+]
Solvent: ClCCCl
Product: O=[N+]([O-])c1ccc(Cl)nc1-c1ccccc1
Temperature: 25 °C

Procedure:
In a 100 ml single-necked round-bottomed flask equipped with a condensor, 5.00 g of 3-nitro-2-phenyl-pyridine-1-oxide is dissolved in 25.0 ml dry 1,2-dichloroethane. Phosphorous oxide chloride (3.18 ml) is added carefully (yellow-orange solution). This mixture is then stirred under heating to reflux for 17 h. After cooling the mixture to ambient temperature. Ice/water is added then. The extraction is carried out with dichloromethane (2×50 ml). After washing with brine, the organic phase is dried over sodium sulfate, filtered and concentrated in vacuo. Purification by flash chromatography over a silica gel cartridge (25 g, 150 ml) of a solid deposition with hexane/ethyl acetate 4:1 (v:v) gives 2.61 g of the title compound as a yellow oil.
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12][C@@H:13]([NH:25][C:26](=[O:39])[C:27]1[CH:32]=[CH:31][C:30]([C:33]2[N:37]([CH3:38])[N:36]=[N:35][CH:34]=2)=[CH:29][CH:28]=1)[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=C[C:16]=1[C:21]([F:24])(F)F.C(O)(C(F)(F)F)=O>>[NH2:3][CH2:12][C@@H:13]([NH:25][C:26](=[O:39])[C:27]1[CH:28]=[CH:29][C:30]([C:33]2[N:37]([CH3:38])[N:36]=[N:35][CH:34]=2)=[CH:31][CH:32]=1)[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:21]([F:24])[CH:16]=1
Reactant: Cn1nncc1-c1ccc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)cc1
Solvent: O=C(O)C(F)(F)F
Product: Cn1nncc1-c1ccc(C(=O)N[C@H](CN)Cc2cccc(F)c2)cc1

Procedure:
The title compound was prepared as a white solid according to the procedure of Example 43, except substituting N-{(1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-[(3-fluorophenyl)methyl]ethyl}-4-(1-methyl-1H-1,2,3-triazol-5-yl)benzamide for N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(1-methyl-1H-1,2,3-triazol-5-yl)benzamide. The title compound was a TFA salt: LC-MS (ES) m/z 354.2 (M+H)+, 1H NMR (400 MHz, MeOD) δ ppm 7.94-7.90 (m, 3H), 7.69 (m, 2H), 7.33 (m, 1H) 7.15-7.07 (m, 2H), 6.98 (m, 1H), 4.62 (m, 1H), 4.15 (s, 3H), 3.30-2.96 (m, 4H).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([CH2:7][CH2:8][NH2:9])=[CH:4][CH:3]=1.[C:10](OC(=O)C)(=[O:12])[CH3:11]>>[CH3:1][C:2]1[O:6][C:5]([CH2:7][CH2:8][NH:9][C:10](=[O:12])[CH3:11])=[CH:4][CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccc(CCN)o1
Product: CC(=O)NCCc1ccc(C)o1
Yield: 55 %

Procedure:
In close analogy to the procedure described above, 2-(5-Methyl-furan-2-yl)-ethylamine is reacted with acetic anhydride to provide the title compound.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].Cl[C:14]1[C:15]2[C:28]([CH3:29])=[CH:27][S:26][C:16]=2[N:17]=[C:18]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[N:19]=1>>[N:22]1[CH:23]=[CH:24][CH:25]=[C:20]([C:18]2[N:19]=[C:14]([NH:7][CH2:6][C:5]3[CH:8]=[CH:9][CH:2]=[C:3]([N+:10]([O-:12])=[O:11])[CH:4]=3)[C:15]3[C:28]([CH3:29])=[CH:27][S:26][C:16]=3[N:17]=2)[CH:21]=1
Reactant: NCc1ccc(F)c([N+](=O)[O-])c1
Reactant: Cc1csc2nc(-c3cccnc3)nc(Cl)c12
Product: Cc1csc2nc(-c3cccnc3)nc(NCc3cccc([N+](=O)[O-])c3)c12

Procedure:
With the procedure of Example 1, the reaction of 4-fluoro-3-nitrobenzylamine with 4-chloro-2-(pyridin-3-yl)-5-methyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-3-yl)-4-(3-nitrobenzylamino)-5-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: C[O:2][C:3](=[O:33])[CH2:4][C:5]1[C:6]([Cl:32])=[N:7][C:8]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]([C:23](=[O:31])[C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)[CH3:22])=[CH:17][CH:16]=2)=[N:9][C:10]=1[N:11]([CH3:13])[CH3:12].[OH-].[Na+].CCOCC.Cl>C1COCC1>[Cl:32][C:6]1[C:5]([CH2:4][C:3]([OH:33])=[O:2])=[C:10]([N:11]([CH3:12])[CH3:13])[N:9]=[C:8]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]([C:23](=[O:31])[C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)[CH3:22])=[CH:17][CH:16]=2)[N:7]=1
Reactant: COC(=O)Cc1c(Cl)nc(Cc2ccc(N(C)C(=O)c3ccc(Cl)cc3)cc2)nc1N(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CN(C)c1nc(Cc2ccc(N(C)C(=O)c3ccc(Cl)cc3)cc2)nc(Cl)c1CC(=O)O
Temperature: 25 °C
Reaction time: 24 h
Yield: 27 %

Procedure:
This crude methyl[4-chloro-2-{4-[(4-chlorobenzoyl)(methyl)amino]benzyl}-6-(dimethyl-amino)pyrimidin-5-yl]acetate was dissolved in THF (3 mL) and treated with 1N NaOH (2 mL) and stirred at room temperature for 24 hour. Et2O was added and the organic phase was siphoned off. The remaining aqueous layer was acidified with 6N HCl to pH˜5 and the separated solids were collected by suction and rinsed with water and diisopropyl ether. Drying under high vacuum at room temperature for 4 hours then gave [4-chloro-2-{4-[(4-chlorobenzoyl)(methyl)amino]-benzyl}-6-(dimethylamino)pyrimidin-5-yl]acetic acid (0.029 g, 27% yield) as a pale yellow powder.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:14]([OH:16])=O)[N:6]2[CH2:12][CH3:13].C(Cl)(=O)C(Cl)=O.[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][N:33]([C:36]2[CH:41]=[CH:40][C:39]([NH2:42])=[CH:38][CH:37]=2)[CH2:32][CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24].C(N(CC)CC)C>C(Cl)Cl.CN(C=O)C>[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][N:33]([C:36]2[CH:37]=[CH:38][C:39]([NH:42][C:14]([C:5]3[N:6]([CH2:12][CH3:13])[C:7]4[C:3]([CH:4]=3)=[C:2]([Cl:1])[C:10]([Cl:11])=[CH:9][CH:8]=4)=[O:16])=[CH:40][CH:41]=2)[CH2:32][CH2:31]1)=[O:29])([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)cc2)CC1
Reactant: CCn1c(C(=O)O)cc2c(Cl)c(Cl)ccc21
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCn1c(C(=O)Nc2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2)cc2c(Cl)c(Cl)ccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 4,5-dichloro-1-ethyl-1H-indole-2-carboxylic acid (440 mg, 1.71 mmol), CH2Cl2 (10 mL), and a catalytic amount of DMF was stirred under Ar, and oxalyl chloride (2M in methylene chloride, 2.0 mL, 4.0 mmol) was added into the mixture over 5 min. The mixture was stirred at room temperature for 1.0 hr and the reaction was concentrated to dryness. Benzene was added and the solution was evaporated to dryness again. The white-yellow solid was re-dissolved in 5 mL of methylene chloride and dripped, under Ar, into a solution of 4-(4-amino-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (475 mg, 1.71 mmol), and triethylamine (204 mg, 2.0 mmol) in 5 mL of methylene chloride. The mixture was first stirred at room temperature for 0.5 hr then concentrated and the residue was taken up in 50 mL of ethyl acetate and washed with 50 mL of saturated ammonium chloride, brine and dried with anhydrous sodium sulfate. The solvent was removed and the crude product was purified by flash chromatography (hexanes/EtOAc), to afford the desired 4-{4-[(4,5-dichloro-1-ethyl-1H-indole-2-carbonyl)-amino]-phenyl}-piperazine-1-carboxylic acid tert-butyl ester, as an off white solid (750 mg, 85% yield). LCMS for C26H30Cl2N4O3 calcd. (m/e) 516, observed 517 (M+H).