Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:9]1[CH:21]=[CH:20][C:12]([C:13]([O:15]C(C)(C)C)=[O:14])=[C:11]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[C:29]([F:32])([F:31])[F:30])[CH:10]=1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>FC(F)(F)C(O)=O>[CH2:1]([C:9]1[CH:21]=[CH:20][C:12]([C:13]([OH:15])=[O:14])=[C:11]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[C:29]([F:30])([F:31])[F:32])[CH:10]=1)[CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)c1ccc(CCc2ccccc2)cc1Nc1ccccc1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1ccc(CCc2ccccc2)cc1Nc1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Trifluoroacetic acid 10 mL was added to the obtained tert-butyl 4-phenethyl-2-(2-(trifluoromethyl)anilino)benzoate, and it was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure,diisopropyl ether was added to the obtained residue, and solid matter was filtrated to give 4-phenethyl-2-(2-(trifluoromethyl)anilino)benzoic acid 17 mg of white solid.
Reaction SMILES: [Cl:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([CH3:13])[CH:3]=1.[N+:14]([O-])([O:16]C(=O)C)=[O:15].[N+]([O-])(O)=O>C(OC(=O)C)(=O)C>[Cl:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([CH3:13])[C:3]=1[N+:14]([O-:16])=[O:15]
Reactant: Cc1cc(Cl)n(-c2ccccc2)n1
Reactant: CC(=O)O[N+](=O)[O-]
Solvent: O=[N+]([O-])O
Solvent: CC(=O)OC(C)=O
Product: Cc1nn(-c2ccccc2)c(Cl)c1[N+](=O)[O-]
Reaction time: 2 h

Procedure:
A solution of 9.6 g (0.05 mole) of 5-chloro-3-methyl-1-phenylpyrazole and 25 ml of acetic anhydride was added at 10° C. to a solution of acetyl nitrate prepared from 25 ml of 90% nitric acid and 10 ml of acetic anhydride. The solution was stirred 2 hours at 20°-30° C. and carefully poured onto ice water. The solid was filtered off and washed with cold water. One recrystallization from ethanol gave long white needles of product.
Reaction SMILES: [NH2:1][C:2]1[N:6]=[C:5]([NH:7][C:8]2[C:13]([Cl:14])=[CH:12][CH:11]=[CH:10][C:9]=2[Cl:15])[O:4][N:3]=1.[CH3:16][C:17](OC(C)=O)=[O:18]>N1C=CC=CC=1>[NH2:1][C:2]1[N:6]=[C:5]([N:7]([C:17](=[O:18])[CH3:16])[C:8]2[C:13]([Cl:14])=[CH:12][CH:11]=[CH:10][C:9]=2[Cl:15])[O:4][N:3]=1
Reactant: Nc1noc(Nc2c(Cl)cccc2Cl)n1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)N(c1nc(N)no1)c1c(Cl)cccc1Cl
Reaction time: 2 h

Procedure:
2.4 g (0.01 mole) 3-amino-5-(2,6-dichlorophenylamino)-1,2,4-oxadiazole in 10 ml pyridine are mixed with 5 moles acetanhydride at room temperature and stirred for 2 hours at 25°-30° C. After evaporation of the solvent, the residue is taken up at CHCl3 and shaken with sodium hydrogen carbonate solution. The CHCl3 phase contains 3 g of the N-acetyl compound, which is purified by column-chromatography on silica gel. The product has a melting point of 164°-165° C.
Reaction SMILES: O[CH2:2][C:3]1[C:8]([CH3:9])=[C:7]([S:10][CH2:11][CH2:12][N:13]2[CH2:22][CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14]2)[CH:6]=[CH:5][N:4]=1.[SH:23][C:24]1[NH:32][C:31]2[C:26](=[N:27][CH:28]=[CH:29][CH:30]=2)[N:25]=1>>[CH3:9][C:8]1[C:3]([CH2:2][S:23][C:24]2[NH:32][C:31]3[C:26](=[N:27][CH:28]=[CH:29][CH:30]=3)[N:25]=2)=[N:4][CH:5]=[CH:6][C:7]=1[S:10][CH2:11][CH2:12][N:13]1[CH2:22][CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14]1
Reactant: Sc1nc2ncccc2[nH]1
Reactant: Cc1c(SCCN2CCc3ccccc3C2)ccnc1CO
Product: Cc1c(SCCN2CCc3ccccc3C2)ccnc1CSc1nc2ncccc2[nH]1

Procedure:
The same reaction as in Example 1 was carried out using 2-hydroxymethyl-3-methyl-4-(2-(1,2,3,4-tetrahydroisoquinolin-2-yl)ethylthio)pyridine in place of 2-hydroxymethyl-3-methyl-4-(2-morpholinoethylthio)pyridine and 2-mercaptoimidazo[5,4-b]pyridine in place of 2-mercaptobenzimidazole to give 2-((3-methyl-4-(2-(1,2,3,4-tetrahydroisoquinolin-2-yl)ethylthio)-2-pyridyl)methylthio)imidazo[5,4-b]pyridine as crystals, melting point 180° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([O-:13])=O)[S:10][C:3]=12.[Li+].C(Cl)(=O)C(Cl)=O.O/[N:22]=[C:23](\[NH2:25])/[CH3:24]>CN(C=O)C.C(Cl)Cl.C1(C)C(C)=CC=CC=1.N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[O:13][N:25]=[C:23]([CH3:24])[N:22]=3)[S:10][C:3]=12
Reactant: C/C(N)=N/O
Reactant: O=C([O-])c1cc2nccc(Cl)c2s1
Agent: O=C(Cl)C(=O)Cl
Agent: [Li+]
Solvent: Cc1ccccc1C
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1noc(-c2cc3nccc(Cl)c3s2)n1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a mixture of lithium 7-chlorothieno[3,2-b]pyridine-2-carboxylate (2.125 g, 9.7 mmol) and DMF (20 drops) in CH2Cl2(35 mL), oxalyl dichloride (1.3 ml, 15 mmol) was added dropwise. The mixture was stirred at RT for 2.5 h and then was concentrated to give a yellow solid. The resultant crude acid chloride and (Z)-N′-hydroxyacetamidine (1.4 g, 19 mmol) were heated at 140° C. in xylene/pyridine (6/1, 35 mL) for 1 h. The mixture was diluted with CH2Cl2, and then washed with water, then sat. NaHCO3 and brine. The crude product was purified via column chromatography on silica gel (RediSep 120 g column, gradient elution with 0-50% EtOAc in Hexane) to afford 7-chloro-2-(3-methyl-1,2,4-oxadiazol-5-yl)thieno[3,2-b]pyridine as a white solid.
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:8](=[O:16])[C:7]2=[C:17]([CH3:20])[CH:18]=[CH:19][N:6]2[N:5]=1)[CH3:3].[Br:21][C:22]1[C:30]2[C:29](Cl)=[N:28][CH:27]=[N:26][C:25]=2[N:24]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[CH:23]=1.[F-].[Cs+].C(N(CC)C(C)C)(C)C>C(O)CCC>[Br:21][C:22]1[C:30]2[C:29]([NH:1][C@H:2]([C:4]3[N:9]([C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=4)[C:8](=[O:16])[C:7]4=[C:17]([CH3:20])[CH:18]=[CH:19][N:6]4[N:5]=3)[CH3:3])=[N:28][CH:27]=[N:26][C:25]=2[N:24]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[CH:23]=1
Reactant: C[Si](C)(C)CCOCn1cc(Br)c2c(Cl)ncnc21
Reactant: Cc1ccn2nc([C@H](C)N)n(-c3ccccc3)c(=O)c12
Agent: [Cs+]
Agent: [F-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(Br)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Yield: 37.4 %

Procedure:
(S)-2-(1-Aminoethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (330 mg, 1.08 mmol) was treated with 5-bromo-4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (430 mg, 1.19 mmol), cesium fluoride (33 mg, 0.22 mmol), N,N-diisopropylethylamine (1.1 mL, 6.49 mol) and 1-butanol according to Preparation 13. The residue was purified using SP1® Purification System (0% to 30%, hexane-ethyl acetate) to give 0.24 g (38% yield) of the title compound. Purity 100%.
Reaction SMILES: [C:1]1([N:7]2[C:11](=[O:12])[CH:10](C(OCC)=O)[CH:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+].Cl>C(O)C.O>[C:1]1([N:7]2[C:11](=[O:12])[CH2:10][C:9]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)C1C=NN(c2ccccc2)C1=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C1CC(c2ccccc2)=NN1c1ccccc1
Yield: 50.8 %

Procedure:
To a mixture of 2,4-dihydro-2-phenyl-4-ethoxycarbonyl-3H-pyrazol-3-one (5.8 g; 25 mmol) in 16 ml of ethanol/water (1:1) 4 g of KOH was added and the resulting mixture was heated at reflux for 4 hours. The mixture was cooled in an ice/bath, conc. HCl solution was added (until pH=1-2), and the resulting mixture was refluxed overnight. The reaction mixture was cooled, concentrated in vacuo, and the residue was dissolved in water. The aqueous layer was extracted with ethyl acetate (2×), the combined organic layer was dried over magnesium sulfate and concentrated in vacuo. The residual yellow oil was purified by silica gel column chromatography (25-30% ethyl acetate/hexane) to afford 1.5 g (38%) of 2,4-dihydro-2-phenyl-3H-pyrazol-3-one (Formula III: R1 =Ph; R2 =H; R3 =H) as a solid, m.p. 113°-114° C.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([NH2:7])[CH:4]=[N:3]1.[C:8]1([CH2:14][O:15][C:16]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=3)=[CH:21][C:17]=2[C:18](O)=[O:19])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C)C=O.O>[CH3:1][N:2]1[CH:6]=[C:5]([NH:7][C:18](=[O:19])[C:17]2[CH:21]=[C:22]([C:25]3[CH:26]=[CH:27][N:28]=[CH:29][CH:30]=3)[CH:23]=[CH:24][C:16]=2[O:15][CH2:14][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:4]=[N:3]1
Reactant: Cn1cc(N)cn1
Reactant: O=C(O)c1cc(-c2ccncc2)ccc1OCc1ccccc1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: Cn1cc(NC(=O)c2cc(-c3ccncc3)ccc2OCc2ccccc2)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Neat 1-methyl-1H-pyrazol-4-amine (38.2 mg, 0.39 mmol) was added in one charge to a stirred solution of 2-[(phenylmethyl)oxy]-5-(4-pyridinyl)benzoic acid (may be prepared as described in Description 79; 100 mg, 0.33 mmol), EDC (188 mg, 0.98 mmol) and HOBT (150 mg, 0.983 mmol) in dimethylformamide (3 ml) in air at room temperature. The reaction mixture was stirred at room temperature overnight. Water (20 ml) was added, and the mixture was extracted with ethyl acetate (20 ml×2). The organic phase was dried over Na2SO4, and concentrated in vacuo to give crude product, which was purified by prep-HPLC (Gilson GX-281; waters X-Bridge 5 μm 30*100 mm; A: 0.1M NH3.H2O/Water; B: CH3CN) twice to yield the title compound as a white solid. 58 mg.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:7][C:6]([F:9])([F:8])[CH2:5][CH:4]1[NH:10][C:11](=[O:23])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N:18]1[N:22]=[CH:21][CH:20]=[N:19]1.Cl[C:25]1[CH:30]=[N:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=1.CCN(C(C)C)C(C)C>CS(C)=O>[F:8][C:6]1([F:9])[CH2:5][CH:4]([NH:10][C:11](=[O:23])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:18]2[N:19]=[CH:20][CH:21]=[N:22]2)[CH:3]([NH:2][C:25]2[CH:30]=[N:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=2)[CH2:7]1
Reactant: FC(F)(F)c1cnc(Cl)cn1
Reactant: NC1CC(F)(F)CC1NC(=O)c1ccccc1-n1nccn1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: O=C(NC1CC(F)(F)CC1Nc1cnc(C(F)(F)F)cn1)c1ccccc1-n1nccn1

Procedure:
A microwave vial was charged with N-(2-amino-4,4-difluorocyclopentyl)-2-(2H-1,2,3-triazol-2-yl)benzamide hydrochloride (Intermediate 42; 65 mg, 0.19 mmol), 2-chloro-5-(trifluoromethyl)pyrazine (CAS number 799557-87-2; 38 mg, 0.21 mmol) and DIPEA (99 μl, 0.57 mmol) in dry DMSO (630 μl). The reaction was subjected to microwave irradiation at 140° C. for 30 minutes. The reaction was partitioned between ethyl acetate and water. The organics were washed with water and brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The crude material was purified by column chromatography (basic silica, 0-100% ethyl acetate/petrol) to afford the title compound.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.[O:13]([C:20]1[CH:29]=[CH:28][C:23]([C:24]([NH:26][NH2:27])=[O:25])=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(O)(=O)C>[I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N:27][NH:26][C:24](=[O:25])[C:23]1[CH:22]=[CH:21][C:20]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:29][CH:28]=1
Reactant: NNC(=O)c1ccc(Oc2ccccc2)cc1
Reactant: O=C1Nc2ccc(I)cc2C1=O
Solvent: CC(=O)O
Product: O=C1Nc2ccc(I)cc2C1=NNC(=O)c1ccc(Oc2ccccc2)cc1
Temperature: 100 °C
Yield: 93 %

Procedure:
Following the general method as outlined in Example 1, into a suspension of 5-iodo-1H-indole-2,3dione in acetic acid was added 4-phenoxybenzohydrazide. After stirring at 100 ° C., the reaction mixture was cooled to rt and a yellow solid precipitated out. Filtration on a fritté, washing with AcOH, water and drying under vacuo at 60° C. overnight gave 4940 mg of the title compound (93%) as a yellow solid in 99.9% purity by HPLC (Rt: 5.13, gradient of 8 min, MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [CH3:1][O:2][CH2:3][N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:7][CH:6]([NH:21][OH:22])[C:5]1=[O:23].[CH2:24]([N:27]=[C:28]=[O:29])[CH2:25][CH3:26].C(N(CC)CC)C>O1CCCC1>[CH3:1][O:2][CH2:3][N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:7][C:6](=[N:21][O:22][C:28]([NH:27][CH2:24][CH2:25][CH3:26])=[O:29])[C:5]1=[O:23]
Reactant: CCCN=C=O
Reactant: COCN1C(=O)C(NO)CN(c2ccccc2)c2ccccc21
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCNC(=O)ON=C1CN(c2ccccc2)c2ccccc2N(COC)C1=O
Yield: 63.8 %

Procedure:
To 1-methoxymethyl-2-oxo-3-hydroxyamino-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (41.4 g) in absolute tetrahydrofuran (500 ml) were added n-propyl isocyanate (28.3 g) and triethylamine (33.7 g). The resultant mixture was refluxed for three hours with heat. The reaction mixture was concentrated under reduced pressure, and the residue was crushed in isopropyl ether and collected by filtration, to thereby obtain 33.4 g of the title compound (yield: 63.3%).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[Cl:10][C:11]1[CH:36]=[CH:35][C:14]([CH2:15][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[C:13]([O:37]C)[CH:12]=1.C1CCN2C(=NCCC2)CC1.Cl>C(#N)C.C(O)C.C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Rh]>[Cl:10][C:11]1[CH:36]=[CH:35][C:14]([CH2:15][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:13]([OH:37])[CH:12]=1
Reactant: O=Cc1ccccc1
Reactant: COc1cc(Cl)ccc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Rh]
Agent: Cl
Agent: [Cl-]
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCO
Product: Oc1cc(Cl)ccc1CCc1ccccc1
Temperature: 50 °C
Reaction time: 14 h

Procedure:
1.10 g of benzaldehyde, 6.02g of 4-chloro-2-methoxybenzyltriphenyl-phosphonium chloride and 1.85 ml of DBU were allowed to react together in 20 ml of acetonitrile and were subsequently treated and purified by silica gel column chromatography, using a 10: 1 by volume mixture of hexane and ethyl acetate as the eluent, in the same manner as described in Preparation 2, to give 2.85 g of an oily substance. This oily substance was dissolved in 50 ml of ethanol, and 0.40 g of tris(triphenylphosphine)rhodium(I) chloride was added to the resulting solution. The resulting mixture was then stirred under a hydrogen atmosphere at atmospheric pressure and at 50° C. for 14 hours. At the end of this time, the reaction solution was filtered using a Celite (trade mark) filter aid. The filtrate was concentrated by evaporation under reduced pressure, and purified by silica gel column chromatography, using a 5:1 by volume mixture of hexane and ethyl acetate as the eluent, to give an intermediate compound. This intermediate compound was dissolved in 10 ml of ethyl acetate, and 10 ml of a 4N solution of hydrogen chloride in ethyl acetate were added to the resulting solution, whilst ice-cooling. The reaction mixture was then allowed to stand at room temperature for 1 hour. At the end of this time, the solvent was removed by evaporation under reduced pressure. The residue was purified by silica gel column chromatography, using a 5:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 2.40 g (a quantitative yield) of the title compound as a colorless oily substance.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:10]2[C:18]3[C:13](=[N:14][CH:15]=[N:16][C:17]=3[NH2:19])[N:12]([CH:20]([CH3:22])[CH3:21])[N:11]=2)[CH:5]=[C:6]([O:8]C)[CH:7]=1.B(Br)(Br)Br>C(Cl)Cl>[NH2:19][C:17]1[N:16]=[CH:15][N:14]=[C:13]2[N:12]([CH:20]([CH3:22])[CH3:21])[N:11]=[C:10]([C:4]3[CH:5]=[C:6]([OH:8])[CH:7]=[C:2]([Br:1])[CH:3]=3)[C:18]=12
Reactant: COc1cc(Br)cc(-c2nn(C(C)C)c3ncnc(N)c23)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(C)n1nc(-c2cc(O)cc(Br)c2)c2c(N)ncnc21
Yield: 30.7 %

Procedure:
3-(3-bromo-5-methoxyphenyl)-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (BA85, 0.1 mmol) was dissolved in CH2Cl2 (1 ml) and BBr3 (1 mL, 1 mol) was added slowly with a syringe, while stirring. The reaction was stirred at room temperature for 35 minutes then concentrated in vacuo and purified using by RP-HPLC (MeCN:H2O:0.1% TFA) to yield BA87 (10.7 mg, 31% yield). ESI-MS (M+H)+ m/z calcd 348.0, found 348.0.
Reaction SMILES: COC1C=CC(N2C=CN=C2C=[N:15][S@@:16]([C:18]([CH3:21])([CH3:20])[CH3:19])=[O:17])=CC=1.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[O:33][CH:32]=[N:31][C:30]=2[CH:34]=O)=[CH:25][CH:24]=1.CC([S@@](N)=O)(C)C>>[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[O:33][CH:32]=[N:31][C:30]=2/[CH:34]=[N:15]/[S:16]([C:18]([CH3:21])([CH3:20])[CH3:19])=[O:17])=[CH:25][CH:24]=1
Reactant: O=Cc1ncoc1-c1ccc(Cl)cc1
Reactant: COc1ccc(-n2ccnc2C=N[S@](=O)C(C)(C)C)cc1
Agent: CC(C)(C)[S@@](N)=O
Product: CC(C)(C)S(=O)/N=C/c1ncoc1-c1ccc(Cl)cc1

Procedure:
The title compound was prepared according to the method presented for the synthesis of compound 5B of Example 5 utilizing 33D and (S)-2-methylpropane-2-sulfinamide. MS (m/z) 311.2 [M+H]+.
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[K+].FC(F)(F)C(O)=O.[C:13]([N:16]1[CH2:20][CH2:19][CH2:18][CH:17]1[C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=2)=[O:29])=[CH:23][C:22]=1[F:36])(=[O:15])[CH3:14]>>[C:13]([N:16]1[CH2:20][CH2:19][CH2:18][CH:17]1[C:21]1[C:22]([F:36])=[CH:23][C:24]([NH:27][C:28]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=2)=[O:29])=[C:25]([N+:1]([O-:4])=[O:2])[CH:26]=1)(=[O:15])[CH3:14]
Reactant: CC(=O)N1CCCC1c1ccc(NC(=O)c2ccccn2)cc1F
Reactant: O=[N+]([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)N1CCCC1c1cc([N+](=O)[O-])c(NC(=O)c2ccccn2)cc1F
Temperature: 25 °C
Reaction time: 48 h

Procedure:
94 mg of potassium nitrate was added to a trifluoroacetic acid (3 ml) solution of pyridine-2-carboxylic acid-(4-(1-acetyl-pyrrolidin-2-yl)-3-fluoro-phenyl)-amide, and the reaction liquid was stirred at room temperature for 2 days. The reaction liquid was distilled under reduced pressure, diluted with chloroform, and made basic with aqueous saturated sodium bicarbonate solution, and then extracted with chloroform. The organic layers were combined, washed with saturated saline, and dried with anhydrous magnesium sulfate. The solvent was evaporated away under reduced pressure, and the resulting residue was purified through silica gel column chromatography (developing solvent: chloroform/methanol=50/1) to obtain the entitled compound as a pale yellow solid.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[S:29][CH:30]=[CH:31][N:32]=3)=[CH:24][CH:23]=2)=[CH:17][CH:16]=1)=O)(C)(C)C.[ClH:33].O1CCOCC1>>[ClH:33].[NH:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[S:29][CH:30]=[CH:31][N:32]=3)=[CH:24][CH:23]=2)=[CH:17][CH:16]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1COc1ccc(Cc2ccc(-c3nccs3)cc2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: c1csc(-c2ccc(Cc3ccc(OC[C@@H]4CCCN4)cc3)cc2)n1
Yield: 83 %

Procedure:
The title compound (60 mg, 83%) was prepared from the product of step 1 (0.09 g, 0.21 mmol) and 4M HCl in dioxane (0.5 ml, 2.1 mmol) using the procedure of Example 146, step 4; 1HNMR (400 MHz, CD3OD) δ 8.17 (d, J=4 Hz, 1H), 7.98 (d, J=3.6 Hz, 1H), 7.90 (d, J=8.4 Hz, 2H), 7.45 (d, J=8.4 Hz, 2H), 7.20 (d, J=8.8 Hz, 2H), 6.95 (d, J=8.8 Hz, 2H), 4.32 (dd, J=10.4, 3.6 Hz, 1H), 4.10 (m, 1H), 4.04 (s, 2H), 4.03 (m, 1H), 3.36 (m, 2H), 2.25 (m, 1H), 2.10 (m, 2H), 1.90 (m, 1H); LC/MS (APCI+) 93%, 351 (M+1, 100); HPLC 94%.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[C:10]1(=[O:16])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.CC(C)([O-])C.[Na+].Cl>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([CH:11]2[CH2:12][CH2:13][CH2:14][CH2:15][C:10]2=[O:16])=[CH:3][CH:4]=1
Reactant: O=C1CCCCC1
Reactant: COc1ccc(Br)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: COc1ccc(C2CCCCC2=O)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 38.4 %

Procedure:
Combine 4-bromoanisole (19.6 g, 104 mmol), cyclohexanone (13.2 g, 136 mmol), sodium tert-butoxide (11.8 g, 120 mmol), palladium acetate (0.47 g, 2.1 mmol), (oxy-di-2,1-phenylene)bis-diphenylphosphine (2.28 g, 4.1 mmol) and toluene (240 mL) and heated at 90° C. under nitrogen. After 18 hours, cool to room temperature and add 1N HCl (120 mL). Extract with methylene chloride and wash the combined extracts with brine. Dry the organic layer over sodium sulfate and concentrate in vacuo. Purify by flash chromatography using silica gel and 10% ethyl acetate-hexanes to yield the titled compound (8.15 g, 38%) as a white solid. 1H NMR (CDCl3) δ 7.12 (d, 2H, J=7.5 Hz), 6.92 (d, 2H, J=7.5 Hz), 3.84 (s, 3 H), 3.59 (dd, 1H, J=8.0 and 3.5 Hz), 2.60-2.45 (m, 2H), 2.29 (m, 1H), 2.18 (m, 1H), 2.04 (m, 2H), 1.85 (m, 2H). MS m/z 205 (M+1).
Reaction SMILES: [C:1]([Si:5]([CH3:33])([CH3:32])[O:6][C@H:7]1[CH2:11][CH2:10][C@H:9]([N:12]2[C:17]3=[N:18][C:19](Cl)=[N:20][CH:21]=[C:16]3[CH2:15][N:14]([C:23]3[CH:28]=[CH:27][C:26]([CH2:29][CH3:30])=[CH:25][CH:24]=3)[C:13]2=[O:31])[CH2:8]1)([CH3:4])([CH3:3])[CH3:2].[F:34][C:35]1[CH:41]=[CH:40][C:38]([NH2:39])=[CH:37][CH:36]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(O)C.ClCCl>[C:1]([Si:5]([CH3:33])([CH3:32])[O:6][C@H:7]1[CH2:11][CH2:10][C@H:9]([N:12]2[C:17]3=[N:18][C:19]([NH:39][C:38]4[CH:40]=[CH:41][C:35]([F:34])=[CH:36][CH:37]=4)=[N:20][CH:21]=[C:16]3[CH2:15][N:14]([C:23]3[CH:28]=[CH:27][C:26]([CH2:29][CH3:30])=[CH:25][CH:24]=3)[C:13]2=[O:31])[CH2:8]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1ccc(F)cc1
Reactant: CCc1ccc(N2Cc3cnc(Cl)nc3N([C@H]3CC[C@H](O[Si](C)(C)C(C)(C)C)C3)C2=O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)O
Solvent: ClCCl
Product: CCc1ccc(N2Cc3cnc(Nc4ccc(F)cc4)nc3N([C@H]3CC[C@H](O[Si](C)(C)C(C)(C)C)C3)C2=O)cc1
Temperature: 160 °C

Procedure:
(±)-1-[trans-3-(tert-Butyl-dimethyl-silanyloxy)-cyclopentyl]-7-chloro-3-(4-ethyl-phenyl)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one (125 mg, 0.25 mmol) (from Example 39b supra) was suspended in 2-propanol (3 mL) (Fisher). 4-Fluoroaniline (0.036 mL, 0.38 mmol) (Aldrich) and p-toluenesulfonic acid mono-hydrate (12.5 mg, 0.05 mmol) (Aldrich) were added and the mixture was heated to 160° C. in a microwave synthesizer (SmithSynthesizer®) for 30 minutes. After cooling to room temperature, the heterogeneous reaction mixture was diluted with dichloromethane. The resulting solution was washed with 1 N aqueous hydrochloric acid. The layers were separated and the organic phase was dried over anhydrous sodium sulfate, filtered and then concentrated under reduce pressure to give (±)-1-[trans-3-(tert-butyl-dimethyl-silanyloxy)-cyclopentyl]-3-(4-ethyl-phenyl)-7-(4-fluoro-phenylamino)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one as a pale green solid. (Yield 123 mg, 85%).
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:40][C:41]3[CH:46]=[C:45]([CH3:47])[CH:44]=[C:43]([CH3:48])[CH:42]=3)[C:19]([N:21]3[CH2:26][CH2:25][N:24]([CH:27]4[CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29][CH2:28]4)[CH2:23][CH2:22]3)=[O:20])=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:49]=[CH:50][CH:51]=[CH:52][C:4]=2[NH:3]1.C([O-])([O-])=O.[K+].[K+]>Cl.CN(C=O)C>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:40][C:41]3[CH:46]=[C:45]([CH3:47])[CH:44]=[C:43]([CH3:48])[CH:42]=3)[C:19](=[O:20])[N:21]3[CH2:22][CH2:23][N:24]([CH:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)[CH2:25][CH2:26]3)=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:49]=[CH:50][CH:51]=[CH:52][C:4]=2[NH:3]1
Reactant: Cc1cc(C)cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCN(C3CCN(C(=O)OC(C)(C)C)CC3)CC2)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(C)cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCN(C3CCNCC3)CC2)c1

Procedure:
A solution of 45 mg (0.06 mmol) of (R)-1-(3,5-dimethyl-benzyl)-2-[4-(1-tert-butoxycarbonyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate (Example 42) in 10 mL 2 M HCl was stirred overnight at RT. The reaction mixture was lyophilised. The crude product was taken up in 1 mL DMF, made alkaline with 0.6 mL saturated K2CO3 solution and purified chromatographically by HPLC.