Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:4]([CH2:18][CH2:19][CH3:20])[CH:5]1[CH2:17][CH2:16][C:8]2[C:9]3[CH:10]=[CH:11][NH:12][C:13]=3[CH:14]=[CH:15][C:7]=2[CH2:6]1)[CH2:2][CH3:3].P(Cl)(Cl)(Cl)=O.[OH-].[Na+].CN(C)[C:30](=[O:32])[CH3:31]>>[CH2:18]([N:4]([CH2:1][CH2:2][CH3:3])[CH:5]1[CH2:17][CH2:16][C:8]2[C:9]3[C:10]([C:30](=[O:32])[CH3:31])=[CH:11][NH:12][C:13]=3[CH:14]=[CH:15][C:7]=2[CH2:6]1)[CH2:19][CH3:20]
Reactant: CC(=O)N(C)C
Reactant: CCCN(CCC)C1CCc2c(ccc3[nH]ccc23)C1
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: CCCN(CCC)C1CCc2c(ccc3[nH]cc(C(C)=O)c23)C1
Temperature: 80 °C
Yield: 89 %

Procedure:
A mixture of dipropyl-(6,7,8,9-tetrahydro-3H-benzo[e]indol-7-yl)amine (55 mg, 0.20 mmol) and phosphorous oxychloride (130 μL, 213 mg, 1.39 mmol) in N,N-dimethylacetamide (200 μL) was heated at 80° C. for 4 hours. After cooling 5M sodium hydroxide was added and the mixture was heated again for 0.5 hours. After cooling the mixture was extracted 3 times with ethyl acetate, dried (magnesium sulfate), filtered and evaporated to yield a residue to which 99% ethanol was added. This was then evaporated to dryness. A few repetitions of the last procedure yielded a residue of 56 mg (89%) of the product, which was further purified on silica using methanol as eluant to give the pure material as a solid.:
Reaction SMILES: [N:1]([C@H:4]1[CH2:9][CH2:8][CH2:7][CH2:6][C@H:5]1[N:10]1[CH2:14][CH2:13][C@@H:12]([NH:15]C(=O)OC(C)(C)C)[CH2:11]1)=[N+:2]=[N-:3]>Cl.O1CCOCC1>[N:1]([C@H:4]1[CH2:9][CH2:8][CH2:7][CH2:6][C@H:5]1[N:10]1[CH2:14][CH2:13][C@@H:12]([NH2:15])[CH2:11]1)=[N+:2]=[N-:3]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCN([C@@H]2CCCC[C@@H]2N=[N+]=[N-])C1
Agent: Cl
Solvent: C1COCCO1
Product: [N-]=[N+]=N[C@H]1CCCC[C@H]1N1CC[C@@H](N)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 124.5 %

Procedure:
The mixture of tert-butyl [(3R)-1-(cis-2-azidocyclohexyl)pyrrolidin-3-yl]carbamate (0.57 g, 1.842 mmol) in 4 N HCl/dioxane (10 mL) was stirred at room temperature for 1 hour. The solution was concentrated to give 0.48 g of the title compound as HCl salt. MS (EI) calcd: (M+H)+=210.2; found: 210.2.
Reaction SMILES: CS(O[CH2:6][C:7]1[O:11][N:10]=[C:9]([CH3:12])[C:8]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19](=[O:27])[C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1)(=O)=O.CN(C=O)C.[N-:33]=[N+:34]=[N-:35].[Na+]>O>[N:33]([CH2:6][C:7]1[O:11][N:10]=[C:9]([CH3:12])[C:8]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]([C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1)=[O:27])=[N+:34]=[N-:35]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1noc(COS(C)(=O)=O)c1-c1ccccc1C(=O)c1ccc(Cl)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1noc(CN=[N+]=[N-])c1-c1ccccc1C(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a round bottomed flask was added crude (4-(2-(4-chlorobenzoyl)phenyl)-3-methylisoxazol-5-yl)methyl methanesulfonate (30.8 mg, 0.076 mmol), DMF (2 mL), and sodium azide (4.93 mg, 0.076 mmol). The reaction was stirred at room temperature for 2 h before diluting with water and extracting with EtOAc. The combined organics were washed with brine, dried over Na2SO4, filtered, and concentrated to afford crude (2-(5-(azidomethyl)-3-methylisoxazol-4-yl)phenyl) (4-chlorophenyl)methanone.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=2)[N:3]=1.[CH3:21][C:22]1[C:23](B(O)O)=[CH:24][S:25][CH:26]=1>>[CH3:20][C:18]1[NH:17][N:16]=[C:15]([NH:14][C:4]2[N:3]=[C:2]([C:23]3[C:22]([CH3:21])=[CH:26][S:25][CH:24]=3)[C:11]3[C:6]([CH:5]=2)=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=3)[CH:19]=1
Reactant: COc1ccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2c1
Reactant: Cc1cscc1B(O)O
Product: COc1ccc2c(-c3cscc3C)nc(Nc3cc(C)[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-6-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and 4-methyl-thiophene-3-boronic acid to give (5-methyl-1H-pyrazol-3-yl)-[1-(4-methyl-thiophen-3-yl)-6-methoxy-isoquinolin-3-yl]-amine. LC-MS m/e 351(MH+).
Reaction SMILES: [NH2:1][C@H:2]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=1)[C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[NH:17][S:18]([CH3:21])(=[O:20])=[O:19])[CH2:7][CH2:6]1)=[O:4].[C:31]([N:38]1[CH2:41][CH:40]([C:42](O)=[O:43])[CH2:39]1)([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32].CCN=C=NCCCN(C)C.CI.C1C=NC2N(O)N=NC=2C=1>CN(C=O)C>[Cl:30][C:25]1[CH:24]=[C:23]([CH2:22][C@@H:2]([NH:1][C:42]([CH:40]2[CH2:41][N:38]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:39]2)=[O:43])[C:3]([N:5]2[CH2:6][CH2:7][N:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[NH:17][S:18]([CH3:21])(=[O:19])=[O:20])[CH2:9][CH2:10]2)=[O:4])[CH:28]=[CH:27][C:26]=1[Cl:29]
Reactant: CS(=O)(=O)Nc1ccccc1N1CCN(C(=O)[C@H](N)Cc2ccc(Cl)c(Cl)c2)CC1
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)O)C1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CI
Product: CC(C)(C)OC(=O)N1CC(C(=O)N[C@H](Cc2ccc(Cl)c(Cl)c2)C(=O)N2CCN(c3ccccc3NS(C)(=O)=O)CC2)C1

Procedure:
tert-Butyl 3-{N-[(1R)-1-[(3,4-dichlorophenyl)methyl]-2-(4-{2-[(methylsulfonyl)amino]phenyl}piperazinyl)-2-oxoethyl]carbamoyl}azetidinecarboxylate was prepared from (2R)-2-amino-3-(3,4-dichlorophenyl)-1-(4-{2-[(methylsulfonyl)amino]phenyl}-piperazinyl) propan-1-one (Example 2, Step 2) (320 mg, 0.67 mmol), according to the procedure for Preparation XIX using Boc-azetidine-3-carboxylic acid (140 mg, 0.71 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide methiodide (400 mg, 1.3 mmol), HOAT (96 mg, 0.71 mmol), and DMF (5 mL) (448 mg crude). MS (ESI, pos. ion) m/z: 654 (M+H), (ESI, neg. ion) m/z: 652 (M−H). Calc'd for C29H37Cl2N5O6S: 653.18.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][CH:6](P(OCC)(OCC)=O)[C:7]([O:9][CH3:10])=[O:8])[CH3:4].[Cl:19][CH2:20][CH2:21][O:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=1>O1CCCC1>[Cl:19][CH2:20][CH2:21][O:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=[C:6]([O:5][CH2:3][CH3:4])[C:7]([O:9][CH3:10])=[O:8])=[CH:25][CH:24]=1
Reactant: O=Cc1ccc(OCCCl)cc1
Reactant: CCOC(C(=O)OC)P(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=Cc1ccc(OCCCl)cc1)C(=O)OC
Reaction time: 1 h

Procedure:
To 150 ml of freshly distilled tetrahydrofuran, placed in a bath of ice-cold water at 0° C., under argon, add sodium hydride (0.0473 mol) and then methyl 2-ethoxy-2-diethylphosphonoacetate (0.0394 mol) while maintaining the temperature at 0° C. After stirring for 1 hour, add 4-(2-chloroethoxy)benzaldehyde (0.0394 mol) dissolved in a minimum of freshly distilled tetrahydrofuran, under argon at 0° C. Stir the solution for 1 hour at 0° C. Allow the solution to return to ambient temperature while stirring for 16 hours. Evaporate off the tetrahydrofuran. Add 100 ml of water and then extract with 100 ml of dichloromethane twice. The organic phase is washed with water, dried over MgSO4 and then evaporated. The oily product is purified over a column of silica gel using the eluant mixture: petroleum ether/dichloromethane (1/1). The title compound is obtained in the form of an oil.
Reaction SMILES: [N+:1]([C:4]1[CH:21]=[CH:20][C:7]([CH2:8][C:9]2O[C:13](=O)[C:12]3[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=3[N:10]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(=O)(O)O.[NH2:26][NH:27][C:28]([NH2:30])=[NH:29]>N1C=CC=CC=1.C(OCC)(=O)C>[N+:1]([C:4]1[CH:21]=[CH:20][C:7]([CH2:8][C:9]2[N:26]3[N:27]=[C:28]([NH2:30])[N:29]=[C:13]3[C:12]3[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=3[N:10]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=c1oc(Cc2ccc([N+](=O)[O-])cc2)nc2ccccc12
Reactant: N=C(N)NN
Agent: O=C(O)O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: Nc1nc2c3ccccc3nc(Cc3ccc([N+](=O)[O-])cc3)n2n1
Yield: 41.7 %

Procedure:
A solution of 2-(4-nitrobenzyl)-4H-3,1-benzoxazin-4-one (5.7 g, 20.2 mmol) and aminoguanidine hydrogencarbonate (2.7 g, 20.2 mmol) in pyridine (25 mL) was heated under microwave condition at 180° C. for 30 minutes. After cooling, the red solution was taken up in ethyl acetate, washed with brine and dried over Na2SO4. The solvent was removed in vacuum and the residue was chromatographed on silica gel eluting with DCM/CH3OH 95/5 to furnish the title compound (2.7 g, 42% yield)
Reaction SMILES: [F:1][C:2]1([F:20])[CH2:8][O:7][CH2:6][C:5]([NH2:9])=[N:4][C@@:3]21[C:18]1[C:13](=[CH:14][CH:15]=[C:16]([NH2:19])[CH:17]=1)[O:12][CH2:11][CH2:10]2.[C:21]([C:23]1[CH:24]=[CH:25][C:26]([C:29](O)=[O:30])=[N:27][CH:28]=1)#[N:22]>>[NH2:9][C:5]1[CH2:6][O:7][CH2:8][C:2]([F:1])([F:20])[C@@:3]2([C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH:19][C:29](=[O:30])[C:26]4[CH:25]=[CH:24][C:23]([C:21]#[N:22])=[CH:28][N:27]=4)[CH:17]=3)[O:12][CH2:11][CH2:10]2)[N:4]=1
Reactant: N#Cc1ccc(C(=O)O)nc1
Reactant: NC1=N[C@@]2(CCOc3ccc(N)cc32)C(F)(F)COC1
Product: N#Cc1ccc(C(=O)Nc2ccc3c(c2)[C@@]2(CCO3)N=C(N)COCC2(F)F)nc1
Yield: 51 %

Procedure:
The condensation of (R)-6′,6′-difluoro-6′,7′-dihydro-2′H-spiro[chroman-4,5′-[1,4]oxazepine]-3′,6-diamine (intermediate C4.2) and 5-cyanopicolinic acid yielded the title compound (51% yield) as a yellow solid. MS (ISP): m/z=414.3 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:9])=[N:4][C:5](Cl)=[CH:6][CH:7]=1.[CH3:10][N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:14]2[CH2:15][CH2:16][N:11]([CH3:10])[CH2:12][CH2:13]2)=[N:4][C:3]=1[CH3:9]
Reactant: CN1CCNCC1
Reactant: Cc1nc(Cl)ccc1Br
Solvent: CN(C)C=O
Product: Cc1nc(N2CCN(C)CC2)ccc1Br

Procedure:
A solution of 3-bromo-6-chloro-2-methylpyridine (700 mg, 3.39 mmol) and 1-methylpiperazine (0.753 mL, 6.78 mmol) in DMF (4 mL) was heated in microwave reactor at 150° C. for 50 minutes. The mixture was subsequently purified via preparative HPLC, eluting with a gradient of 10-70% ACN (containing 0.035% TFA) in H2O (containing 0.05% TFA) to give the title compound.
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][CH:8]([O:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4[N:19]([CH3:30])[C:20](=[O:29])[C:21]5[CH:27]=[CH:26][NH:25][C:24](=[O:28])[C:22]=5[N:23]=4)=[CH:14][CH:13]=3)[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.Cl[C:32]([F:37])([F:36])C([O-])=O.[Na+].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.C(OCC)(=O)C>[CH:1]1([N:5]2[CH2:6][CH2:7][CH:8]([O:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4[N:19]([CH3:30])[C:20](=[O:29])[C:21]5[CH:27]=[CH:26][N:25]=[C:24]([O:28][CH:32]([F:37])[F:36])[C:22]=5[N:23]=4)=[CH:14][CH:13]=3)[CH2:9][CH2:10]2)[CH2:2][CH2:3][CH2:4]1
Reactant: Cn1c(-c2ccc(OC3CCN(C4CCC4)CC3)cc2)nc2c(=O)[nH]ccc2c1=O
Reactant: O=C([O-])C(F)(F)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Cn1c(-c2ccc(OC3CCN(C4CCC4)CC3)cc2)nc2c(OC(F)F)nccc2c1=O
Yield: 8.5 %

Procedure:
2-{4-[(1-Cyclobutylpiperidin-4-yl)oxy]phenyl}-3-methyl-3,7-dihydropyrido[3,4-d]pyrimidine-4,8-dione (50 mg, 0.123 mmol), sodium chlorodifluoroacetate (19 mg, 0.13 mmol) and potassium carbonate (34 mg, 0.25 mmol) were heated under reflux in acetonitrile (1 mL) for 6 hours. Sodium chlorodifluoroacetate (19 mg, 0.13 mmol) and acetonitrile (1 mL) were further added to the reaction solution and heated under reflux for 18 hours. After restored to room temperature, the reaction solution was diluted with ethyl acetate, washed with water and saturated saline water in that order, and the organic layer was dried with magnesium sulfate. The solvent was evaporated off, and the residue was purified through silica gel thin-layer chromatography (chloroform/methanol=9/1) to obtain a low-polar compound, 2-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}-8-(difluoromethoxy)-3-methylpyrido[3,4-d]pyrimidin-4(3H)-one (4.8 mg, 9%), and a high-polar compound, 2-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}-7-(difluoromethyl)-3-methyl-3,7-dihydropyrido[3,4-d]pyrimidine-4,8-dione (11.4 mg, 21%) as a pale yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](/[CH:8]=[CH:9]/[C:10]([OH:12])=O)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.C1(P([N:34]=[N+:35]=[N-:36])(C2C=CC=CC=2)=O)C=CC=CC=1>C1(C)C=CC=CC=1>[N:34]([C:10](=[O:12])/[CH:9]=[CH:8]/[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1)=[N+:35]=[N-:36]
Reactant: O=C(O)/C=C/c1cccc(Br)c1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: [N-]=[N+]=NC(=O)/C=C/c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of (E)-3-(3-bromophenyl)acrylic acid (100 g, 0.44 mol) and triethylamine (0.48 mol) in toluene (1000 mL) was added diphenylphosphoryl azide (127.4 g, 0.45 mol) dropwise at 0-10° C. The mixture was stirred at room temperature overnight. Thin layer chromatography (petroleum ether/ethyl acetate=8:1) indicated completion of reaction. The resulting mixture was washed with 1 N sodium hydroxide (500 mL) and extracted with ethyl acetate (2000 mL×3). The organic layer was concentrated to give crude (E)-1-azido-3-(3-bromophenyl)prop-2-en-1-one, which was used in the next step directly.
Reaction SMILES: P(=O)([O-])O[C:3](CC)(CC)[S:4][C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=1.[Li]CCCC.[Si:23]([O:30][C@H:31]([CH3:34])[CH:32]=O)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]>O1CCCC1>[Si:23]([O:30][C@H:31]([CH3:34])/[CH:32]=[CH:3]/[S:4][C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=1)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]
Reactant: CCC(CC)(O[PH](=O)[O-])Sc1ccc(C)cc1
Reactant: C[C@H](C=O)O[Si](C)(C)C(C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ccc(S/C=C/[C@@H](C)O[Si](C)(C)C(C)(C)C)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
Under the nitrogen atmosphere, 3.02 g (11 mmole) of diethyl-p-methylphenylthiomethyl phosphonate was dissolved in 50 ml of anhydrous tetrahydrofuran and after lowering the reaction temperature to -78° C., 6.25 ml (10 mmole) of 1.6M n-BuLi was added to the reaction mixture for ten minutes, and the resultant mixture was agitated at the temperature of -78° C. for 30 minutes. At the same temperature, 1.87 g (10 mmole) of (2R)-2-(t-butyldimethylsilyloxy)propanal diluted with 10 ml of anhydrous tetrahydrofuran was added to the said mixture and the reaction temperature was slowly raised from -78° C. to 0° C., and then the the mixture agitated at 0° C. for another one hour. Once the reaction was completed, the reaction was quenched by adding saturated ammonium chloride solution. After the work-up treatment in the same manner as did in method A of EXAMPLE 32, 2.8 g of crude product was obtained. The crude product was purified by a column chromatography (using n-hexane containing 1% diethyl ether as an eluent), thereby obtaining 2.5 g of desired compound having E/Z ratio of over 100/1 (yield: 81%) stereoselectively.
Reaction SMILES: Cl[C:2]1[C:7]([NH2:8])=[C:6]([Cl:9])[N:5]=[C:4]([NH2:10])[N:3]=1.Cl.[N+:12]([C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH2:18][NH2:19])([O-:14])=[O:13].C(N(CC)CC)C>CCCCO>[Cl:9][C:6]1[N:5]=[C:4]([NH2:10])[N:3]=[C:2]([NH:19][CH2:18][C:17]2[CH:20]=[CH:21][CH:22]=[C:15]([N+:12]([O-:14])=[O:13])[CH:16]=2)[C:7]=1[NH2:8]
Reactant: NCc1cccc([N+](=O)[O-])c1
Reactant: Nc1nc(Cl)c(N)c(Cl)n1
Agent: Cl
Solvent: CCCCO
Solvent: CCN(CC)CC
Product: Nc1nc(Cl)c(N)c(NCc2cccc([N+](=O)[O-])c2)n1
Yield: 78.6 %

Procedure:
A mixture of 4,6-dichloropyrimidine-2,5-diamine (700 mg, 3.91 mmol), 3-nitrobenzylamine hydrochloride (885 mg, 4.69 mmol) and triethylamine (1.6 mL, 11.7 mmol) in n-BuOH (20 mL) was refluxed for 17 h, concentrated in vacuo and the residue partitioned between EtOAc (10 mL) and H2O (5 mL). The organic phase was dried (MgSO4) and concentrated in vacuo to give the title compound as an orange solid (906 mg, 76%) which was used in the next reaction without further purification; NMR δH (400 MHz, CDCl3) 8.16 (1H, s), 8.10 (1H, d, J 8.0 Hz), 7.80 (1H, d, J 7.5 Hz), 7.62 (1H, t, J 7.5 Hz), 7.25 (1H, t, J 6.0 Hz), 5.69 (2H, s), 4.67 (2H, d, J 6.0 Hz) and 3.93 (2H, br s).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[N:16]([CH2:17][CH:18]3[O:20][CH2:19]3)[C:15](=[O:21])[N:14]([CH3:22])[C:13](=[O:23])[CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[C:24]([NH2:28])([CH3:27])([CH3:26])[CH3:25]>>[C:24]([NH:28][CH2:19][CH:18]([OH:20])[CH2:17][N:16]1[C:11]([C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)=[CH:12][C:13](=[O:23])[N:14]([CH3:22])[C:15]1=[O:21])([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)N
Reactant: COc1ccc(-c2cc(=O)n(C)c(=O)n2CC2CO2)cc1OC
Product: COc1ccc(-c2cc(=O)n(C)c(=O)n2CC(O)CNC(C)(C)C)cc1OC

Procedure:
To a solution of 6-(3,4-dimethoxyphenyl)-1-(2,3-epoxypropyl)-3-methyl-2,4(1H,3H)-pyrimidinedione (0.6 g) in ehtanol (20 ml) was added tert-butylamine (2 ml). The mixture was refluxed for 2.5 hours and evaporated in vacuo. The resulting syrup was triturated in a mixture of diethyl ether and diisopropyl ether to give 1-(3-tert-butylamino-2-hydroxy-1-propyl)-6-(3,4-dimethoxyphenyl)-3-methyl-2,4(1H,3H)pyrimidinedione (0.66 g).
Reaction SMILES: Br[C:2]1[CH:11]=[N:10][C:9]2[NH:8][C:7]3[CH:12]=[CH:13][C:14]([C:16]#[N:17])=[CH:15][C:6]=3[C:5]([C:23]([F:26])([F:25])[F:24])([CH2:18][O:19][CH:20]([CH3:22])[CH3:21])[C:4]=2[CH:3]=1.CCOC(C)=O.CCCCCC.[CH3:39][N:40](C=O)C>[C-]#N.[C-]#N.[Zn+2].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:39]([C:2]1[CH:11]=[N:10][C:9]2[NH:8][C:7]3[CH:12]=[CH:13][C:14]([C:16]#[N:17])=[CH:15][C:6]=3[C:5]([C:23]([F:26])([F:24])[F:25])([CH2:18][O:19][CH:20]([CH3:21])[CH3:22])[C:4]=2[CH:3]=1)#[N:40]
Reactant: CN(C)C=O
Reactant: CC(C)OCC1(C(F)(F)F)c2cc(C#N)ccc2Nc2ncc(Br)cc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(C)OCC1(C(F)(F)F)c2cc(C#N)ccc2Nc2ncc(C#N)cc21
Temperature: 100 °C
Yield: 60 %

Procedure:
A degassed mix of 3-bromo-7-cyano-5-trifluoromethyl-5-isopropoxymethyl-5,10-dihydrobenzo[b][1,8]naphthyridine (15) (73 mg, 0.171 mmol), Zn(CN)2 (20 mg, 0.171 mmol) and Pd(PPh3)4 (10 mg, 0.00855 mmol) in anhydrous DMF (2 mL) was heated at 100° C. for 16 h 30 min. The reaction mixture was cooled to room temperature, quenched 2 N NH4OH (20 mL), and extracted with EtOAc (2×). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. Flash chromatography (20%-30% EtOAc-Hexane) provided 17 (38 mg, 60% yield) as a white solid: m.p. 226-227° C.; low resolution mass spectrum (ESI) m/z 371.2 [(M−H)— calcd for C19H14F3N4O: 371.11].
Reaction SMILES: [CH:1]1([CH2:4][S:5]([N:8]2[CH2:13][CH2:12][CH2:11][CH:10]([NH:14][C:15]3[C:20]([C:21]4[N:22]=[C:23]5[CH:29]=[CH:28][N:27](COCC[Si](C)(C)C)[C:24]5=[N:25][CH:26]=4)=[CH:19][CH:18]=[C:17]([CH3:38])[N:16]=3)[CH2:9]2)(=[O:7])=[O:6])[CH2:3][CH2:2]1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(N)CN>C1COCC1>[CH:1]1([CH2:4][S:5]([N:8]2[CH2:13][CH2:12][CH2:11][CH:10]([NH:14][C:15]3[C:20]([C:21]4[N:22]=[C:23]5[CH:29]=[CH:28][NH:27][C:24]5=[N:25][CH:26]=4)=[CH:19][CH:18]=[C:17]([CH3:38])[N:16]=3)[CH2:9]2)(=[O:6])=[O:7])[CH2:3][CH2:2]1
Reactant: Cc1ccc(-c2cnc3c(ccn3COCC[Si](C)(C)C)n2)c(NC2CCCN(S(=O)(=O)CC3CC3)C2)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: NCCN
Product: Cc1ccc(-c2cnc3[nH]ccc3n2)c(NC2CCCN(S(=O)(=O)CC3CC3)C2)n1

Procedure:
(1-Cyclopropylmethanesulfonyl-piperidin-3-yl)-[6-methyl-3-(5H-pyrrolo[2,3-b]pyrazin-2-yl)-pyridin-2-yl]-amine was prepared from (1-cyclopropylmethanesulfonyl-piperidin-3-yl)-{6-methyl-3-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-pyridin-2-yl}-amine using 20 equivalents of tetrabutyl ammonium fluoride 1 M solution in THF, and 20 equivalents of ethylenediamine, and warming the mixture at 70° C. for 5 h.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[Br:11][C:12]1[N:13]([CH2:25][C:26]#[C:27][CH3:28])[C:14]([C:21]([O:23][CH3:24])=[O:22])=[C:15]([C:17](OC)=[O:18])[N:16]=1.Cl.O>O1CCCC1>[Br:11][C:12]1[N:13]([CH2:25][C:26]#[C:27][CH3:28])[C:14]([C:21]([O:23][CH3:24])=[O:22])=[C:15]([CH:17]=[O:18])[N:16]=1
Reactant: CC#CCn1c(Br)nc(C(=O)OC)c1C(=O)OC
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: CC#CCn1c(Br)nc(C=O)c1C(=O)OC
Temperature: -70 °C
Reaction time: 4 h
Yield: 52 %

Procedure:
43 ml (43 mmol) of a 1 molar solution of diisobutyl-aluminium hydride in tetrahydrofuran within 20 minutes were added dropwise to a solution of 13.5 g (42.84 mmol) of dimethyl 2-bromo-1-(but-2-ynyl)-1H-imidazol-4,5-dicarboxylate in 220 ml of tetrahydrofuran under an argon atmosphere at −70° C. The mixture was stirred for a further 4 hours at −70° C., then 20 ml of a mixture of 1M hydrochloric acid and tetrahydrofuran were added dropwise. After heating to ambient temperature approx. 200 ml of water were added and the mixture was extracted three times with 70 ml of ethyl acetate. The extracts were dried and evaporated down, and the crude product thus obtained was purified by column chromatography (silica gel; eluant:petroleum ether with 20–50% ethyl acetate).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:20](=[O:39])[CH2:21][C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]2[CH:31]=[N:32][C:33]([CH:36]([CH3:38])[CH3:37])=[CH:34][CH:35]=2)[CH:25]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:36]([C:33]1[N:32]=[CH:31][C:30]([C:26]2[CH:25]=[C:24]([C:22]3[CH2:21][C:20](=[O:39])[NH:19][C:9]4[CH:10]=[C:11]([C:15]([F:18])([F:17])[F:16])[C:12]([CH3:14])=[CH:13][C:8]=4[N:7]=3)[CH:29]=[CH:28][CH:27]=2)=[CH:35][CH:34]=1)([CH3:38])[CH3:37]
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccc(C(C)C)nc3)c2)cc1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3ccc(C(C)C)nc3)c1)=N2

Procedure:
The title compound was prepared from (2-{3-[3-(6-isopropyl-pyridin-3-yl)-phenyl]-3-oxo-propionylamino}-5-methyl-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M162) (167 mg, 0.30 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (91 mg, 69%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][C:8]=2[CH:16]=1)([O-])=O.[C:17](OC(=O)C)(=[O:19])[CH3:18].CN(C1C=CC=CN=1)C.O>C(OCC)(=O)C.[Pd]>[NH:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][C:8]=2[CH:16]=1)[C:17]([CH3:18])=[O:19]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)c1cc2cc([N+](=O)[O-])ccc2o1
Agent: [Pd]
Agent: CN(C)c1ccccn1
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc2cc(NC(C)=O)ccc2o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61 %

Procedure:
Methyl 5-nitrobenzofuran-2-carboxylate (13, 0.5 g, 2.26 mmol, made from 5-nitrobenzofuran-2-carboxylic acid, Trans World Chemicals, Inc.) was dissolved in ethyl acetate (40 mL) and 5% Pd/C (30 mg) was added. The reaction mixture was hydrogenated for 1 h at room temperature at a pressure of 60 lb/inch2. The reaction mixture was filtered and the solvent was removed in vacuo. The residue was dissolved in acetone (10 mL) and was used without further purification. Acetic anhydride (0.86 mL, 9.1 mmol) and dimethylaminopyridine (20 mg) was added. The solution was stirred for 1 h at room temperature. Water (20 mL) was added and the mixture was extracted with ethyl acetate (40 mL×5). The solution was dried using sodium sulfate and solvent was removed in vacuo. A grey powder 9 was obtained (321 mg, 61% yield). An analytical sample was recrystallized in ethyl acetate. mp: 158°-159° C. 1H NMR (DMSO-d6, ppm): 10.03 (s, 1 H, NH), 8.19-8.18 (d, 1 H, J=1.6 Hz, Ar--H), 7.76-7.75 (d, 1 H, J=1.1 Hz, Ar--H), 7.65-7.63 (d, 1 H, J=9.0 Hz, Ar--H), 7.55-7.52 (dd, 2 H, J=2.3, 8.9 Hz, Ar--H), 3.89 (s, 1 H, OCH3), 2.07 (s, 3 H, CH3CO), Anal. (C12H11 NO4), C, H, N.