Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[NH:13][CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]=[C:28]=[O:29])=[CH:23][CH:22]=1>C1C=CC=CC=1.O1CCCC1.CN(C)C1C=CN=CC=1>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28]([N:13]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:19]3[C:11]([C:5]3[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)=[CH:12]2)=[O:29])=[CH:23][CH:22]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: COc1ccc(-c2c[nH]c3ncccc23)cc1OC
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: c1ccccc1
Product: COc1ccc(-c2cn(C(=O)Nc3ccc(Cl)cc3)c3ncccc23)cc1OC
Temperature: 200 °C
Yield: 39.8 %

Procedure:
3-(3,4-Dimethoxy-phenyl)-1H-pyrrolo-[2,3-b]pyridine 1 (40 mg, 0.16 mmol) was dissolved in benzene and 4-chlorophenyl isocyanate (36 mg, 0.24 mol) dissolved in tetrahydrofuran (4 mL) was added. 4-Dimethylaminopyridine (20 mg, polymer bound) was added. The reaction was heated in a CEM Discover microwave at 200° C. for 10 minutes. The mixture was filtered and concentrated. The resulting solid was washed with a minimum of methanol, filtered, and then washed with dichloromethane to provide 26, (26 mg, 40%). MS(ESI) [M+H+]+=408.4.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:8]#[N:9])[CH:7]=1.[CH:10]1(B(O)O)[CH2:12][CH2:11]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCCC1>[CH:10]1([C:2]2[CH:3]=[N:4][CH:5]=[C:6]([CH:7]=2)[C:8]#[N:9])[CH2:12][CH2:11]1
Reactant: N#Cc1cncc(Br)c1
Reactant: OB(O)C1CC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: N#Cc1cncc(C2CC2)c1
Yield: 58.9 %

Procedure:
To a solution of 3-bromo-5-cyanopyridine (1 g, 5.3 mmol) in tetrahydrofuran was added cyclopropyl boronic acid (0.5 g, 5.6 mmol) and potassium phosphate (1.08 g, 15.9 mmol). The resulting solution was degassed with nitrogen for 10 minutes and then palladium (II) acetate and S-phos were added. The reaction mixture was refluxed for 16 h. The reaction mixture was diluted with water, extracted with ethyl acetate and concentrated under reduced pressure. The crude material was purified via column chromatography to afford 5-cyclopropylnicotinonitrile (0.45 g, 58%). MS (ES+) (M+H) 145.1774.
Reaction SMILES: [ClH:1].[CH3:2][N:3]([CH2:5][C:6]1[S:10][C:9]([NH:11]C(=O)C)=[N:8][CH:7]=1)[CH3:4].Cl>CCO.O1CCOCC1>[ClH:1].[ClH:1].[CH3:2][N:3]([CH2:5][C:6]1[S:10][C:9]([NH2:11])=[N:8][CH:7]=1)[CH3:4]
Reactant: CC(=O)Nc1ncc(CN(C)C)s1
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Product: CN(C)Cc1cnc(N)s1
Temperature: 50 °C

Procedure:
Dissolved N-(5-dimethylaminomethyl-thiazol-2-yl)-acetamide hydrochloride (300 mg, 1.27 mmol) in 5 mL of EtOH. Added 2 mL of 4 M HCl in dioxane and heated at 50° C. for 16 h. LC-MS analysis indicated complete acetyl removal. Concentrated to give 5-dimethylaminomethyl-thiazol-2-ylamine dihydrochloride.
Reaction SMILES: C(OC([NH:8][C:9]1[NH:13][C:12]2[CH:14]=[CH:15][C:16]([O:18][S:19]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)(=[O:21])=[O:20])=[CH:17][C:11]=2[N:10]=1)=O)(C)(C)C.[F:29][C:30]([F:35])([F:34])[C:31]([OH:33])=[O:32]>ClCCl>[F:29][C:30]([F:35])([F:34])[C:31]([OH:33])=[O:32].[NH2:8][C:9]1[NH:13][C:12]2[CH:14]=[CH:15][C:16]([O:18][S:19]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)(=[O:20])=[O:21])=[CH:17][C:11]=2[N:10]=1
Reactant: CC(C)(C)OC(=O)Nc1nc2cc(OS(=O)(=O)c3ccc(F)cc3)ccc2[nH]1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1nc2cc(OS(=O)(=O)c3ccc(F)cc3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6.45 g of 4-fluoro-benzenesulfonic acid 2-tert-butoxycarbonylamino-1H-benzoimidazol-5-yl ester were combined with 15 ml trifluoroacetic acid in 60 ml dichloromethane. The reaction mixture was stirred overnight at room temperature. Solvents were evaporated under reduced pressure. The residue was washed with ethyl ether and dried on glass frit yielding 6.58 g of 4-fluoro-benzenesulfonic acid 2-amino-1H-benzoimidazol-5-yl ester trifluoroacetic acid salt.
Reaction SMILES: [CH3:1][O:2]/[N:3]=[C:4](/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)\[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][OH:14])=[CH:9][CH:8]=1.[C:21]([CH:23]([C:35]1[CH:40]=[CH:39][C:38](O)=[CH:37][CH:36]=1)[CH2:24][C:25]([O:27]CC1C=CC=CC=1)=[O:26])#[N:22]>>[C:21]([CH:23]([C:35]1[CH:40]=[CH:39][C:38]([O:14][CH2:13][C:10]2[CH:11]=[CH:12][C:7]([O:6][CH2:5]/[C:4](=[N:3]\[O:2][CH3:1])/[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:8][CH:9]=2)=[CH:37][CH:36]=1)[CH2:24][C:25]([OH:27])=[O:26])#[N:22]
Reactant: N#CC(CC(=O)OCc1ccccc1)c1ccc(O)cc1
Reactant: CO/N=C(\COc1ccc(CO)cc1)c1ccccc1
Product: CO/N=C(\COc1ccc(COc2ccc(C(C#N)CC(=O)O)cc2)cc1)c1ccccc1
Yield: 39.91 %

Procedure:
Compound 74 was synthesized from (4-{[(2Z)-2-(methoxyimino)-2-phenylethyl]oxy}phenyl)methanol (0.04 g, 2.2 mmol) and benzyl 3-cyano-3-(4-hydroxyphenyl)propanoate (0.66 g, 2.2 mmol) by following the procedure described in scheme 24 (0.2 g, yield: 39.91%); Purity: 98.51%.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[NH:12][C:11](=[O:13])[NH:10][C:9](=[O:14])[CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:15]Br>C(O)(=O)C>[Br:15][C:8]1[C:9](=[O:14])[NH:10][C:11](=[O:13])[NH:12][C:7]=1[CH2:6][N:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: BrBr
Reactant: O=c1cc(CN2CCCC2)[nH]c(=O)[nH]1
Solvent: CC(=O)O
Product: O=c1[nH]c(CN2CCCC2)c(Br)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 20 h
Yield: 39.9 %

Procedure:
To a solution of 1.0 g of the 6-(1-pyrrolidinyl-methyl)uracil, which had been obtained in Referential Example 7, in acetic acid (10 ml), 1.0 g of bromine was added dropwise, followed by stirring at room temperature for 20 hours. A crystallized matter was collected by filtration and then washed with methanol, whereby 560 mg of the title compound were obtained (yield: 40%). The melting point and NMR spectrum of the thus-obtained compound were in full conformity with those of Compound 2 synthesized by Process A in Example 2.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:20][C:21]1[O:25][N:24]=[C:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:22]=1[C:32]1[N:36]2[CH2:37][C:38]3[C:43]([C:35]2=[N:34][N:33]=1)=[CH:42][C:41]([OH:44])=[CH:40][CH:39]=3.O[CH2:46][C:47]1[CH:48]=[N:49][CH:50]=[CH:51][CH:52]=1.N(C(OCC)=O)=NC(OCC)=O>ClCCl>[CH3:20][C:21]1[O:25][N:24]=[C:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:22]=1[C:32]1[N:36]2[CH2:37][C:38]3[C:43]([C:35]2=[N:34][N:33]=1)=[CH:42][C:41]([O:44][CH2:46][C:47]1[CH:48]=[N:49][CH:50]=[CH:51][CH:52]=1)=[CH:40][CH:39]=3
Reactant: OCc1cccnc1
Reactant: Cc1onc(-c2ccccc2)c1-c1nnc2n1Cc1ccc(O)cc1-2
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1onc(-c2ccccc2)c1-c1nnc2n1Cc1ccc(OCc3cccnc3)cc1-2
Temperature: 25 °C
Reaction time: 8 h
Yield: 16.6 %

Procedure:
Under nitrogen atmosphere, triphenylphosphine bound resin (0.41 g, 0.45 mmol, 1.12 mmol/g) was swelled in dichloromethane for 30 minutes. 3-(5-Methyl-3-phenylisoxazol-4-yl)-5H-[1,2,4]triazolo[3,4-a]isoindol-8-ol (0.1 g, 0.30 mmol) (prepared by Example 3 step (a)), 3-hydroxymethylpyridine (44 μl, 0.45 mmol, 1.5 eq.) and diethyl azodicarboxylate (71 μl, 0.45 mmol, 1.5 eq.) were added and the reaction was stirred at room temperature overnight. The resin was filtered off and washed with dichloromethane, methanol and diethyl ether. The combined organics were concentrated in vacuo. The residue was purified firstly by alumina chromatography, eluting with 1% methanol/dichloromethane, and secondly by silica chromatography, using dichloromethane→5% methanol/dichloromethane as the eluant, to afford the title compound (21 mg, 16%). 1H NMR (400 MHz, CDCl3) δ 8.70–8.69 (1H, m), 8.61–8.59 (1H, m), 7.80 (1H, dt, J=7.8, 2.1 Hz), 7.59 (1H, d, J=2.4 Hz), 7.54–7.52 (2H, m), 7.46–7.33 (4H, m), 7.18 (1H, d, J=8.4 Hz), 7.02 (1H, dd, J=8.4, 2.4 Hz), 5.16 (2H, s), 3.96 (2H, s), 2.70 (3H, s). m/z (ES+) 422 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][N:9]1[C:13]([CH2:14]O)=[C:12]([CH3:16])[N:11]=[CH:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P([N:31]=[N+:32]=[N-:33])(C2C=CC=CC=2)=O)C=CC=CC=1.C1CCN2C(=NCCC2)CC1>CN(C=O)C.C(Cl)Cl.CCOCC.C(OCC)(=O)C>[C:1]([O:5][C:6]([CH2:8][N:9]1[C:13]([CH2:14][N:31]=[N+:32]=[N-:33])=[C:12]([CH3:16])[N:11]=[CH:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ncn(CC(=O)OC(C)(C)C)c1CO
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1ncn(CC(=O)OC(C)(C)C)c1CN=[N+]=[N-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1-t-butoxycarbonylmethyl-4-methyl-5-hydroxymethylimidazole (4.61 g, 20 mmol) in DMF (100 ml) was cooled to 0° C. and treated sequentially with diphenylphosphoryl azide (5.4 ml, 25 mmol) and DBU (3.7 ml, 25 ml). The resulting solution was allowed to warm gradually to room temperature and was then stirred there overnight. The DMF was rotavapped off, the residue dissolved in a minimum quantity of methylene chloride and the resulting solution diluted several fold with ether and ethyl acetate. This solution was washed sequentially with 1M citric acid, water, 10% sodium carbonate, brine and then dried over magnesium sulfate. Filtration and concentration gave an oil which was purified by flash chromatography (19:1 chloroform/methanol) to give the title compound as an oil: 1H NMR (CDCl3) d 1.48 (s, 9 H), 2.27 (s, 3 H), 4.28 (s, 2 H), 4.56 (s, 2 H), 7.43 (s, 1 H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][C:12]=2[CH3:18])[CH2:7][CH2:6]1.[Br:19][C:20]1[C:28]2[O:27][C:26](SC)=[N:25][C:24]=2[CH:23]=[CH:22][CH:21]=1>>[Br:19][C:20]1[C:28]2[O:27][C:26]([NH:17][C:14]3[CH:15]=[CH:16][C:11]([N:8]4[CH2:9][CH2:10][N:5]([CH2:4][CH2:3][O:2][CH3:1])[CH2:6][CH2:7]4)=[C:12]([CH3:18])[CH:13]=3)=[N:25][C:24]=2[CH:23]=[CH:22][CH:21]=1
Reactant: COCCN1CCN(c2ccc(N)cc2C)CC1
Reactant: CSc1nc2cccc(Br)c2o1
Product: COCCN1CCN(c2ccc(Nc3nc4cccc(Br)c4o3)cc2C)CC1

Procedure:
The title compound is prepared from 4-[4-(2-methoxy-ethyl)-piperazin-1-yl]-3-methyl-phenylamine and 7-bromo-2-methylsulfanyl-benzooxazole using methodology described in the preparation of example 64.
Reaction SMILES: [H-].[Na+].[C:3]1([CH2:9][OH:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[C:15]([C:22]3[NH:30][C:29]4[CH2:28][CH2:27][NH:26][C:25](=[O:31])[C:24]=4[CH:23]=3)[CH:16]=[CH:17][CH:18]=2)[N:13]=1>CN(C=O)C>[CH2:9]([O:10][C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[C:15]([C:22]3[NH:30][C:29]4[CH2:28][CH2:27][NH:26][C:25](=[O:31])[C:24]=4[CH:23]=3)[CH:16]=[CH:17][CH:18]=2)[N:13]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: OCc1ccccc1
Reactant: O=C1NCCc2[nH]c(-c3cccc4ccc(Cl)nc34)cc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1NCCc2[nH]c(-c3cccc4ccc(OCc5ccccc5)nc34)cc21
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 19.4 %

Procedure:
NaH (60% in mineral oil; 0.071 g, 1.763 mmol) was suspended in 1 mL DMF. Phenylmethanol (0.183 ml, 1.763 mmol) was added slowly dropwise. After 10 min, 2-(2-chloroquinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 1; 0.075 g, 0.252 mmol) was added, and the reaction was heated to 100° C. for 30 min. The mixture was cooled and partitioned between saturated aq. NH4Cl and DCM. The aq. layer was extracted with DCM (3×), and the combined organics were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The material was treated with DCM and purified by silica gel chromatography using 0-100% 90/10 DCM/MeOH in DCM The product-containing fractions were concentrated to afford 2-(2-(benzyloxy)quinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (0.018 g, 0.049 mmol, 19% yield) as an orange solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 11.76 (1H, br. s), 8.32 (1H, d, J=9.0 Hz), 8.00 (1H, dt, J=7.2, 1.0 Hz), 7.76 (1H, dt, J=7.9, 0.8 Hz), 7.26-7.59 (6H, m), 7.10-7.22 (2H, m), 6.87-6.99 (1H, m), 5.62 (2H, s), 3.36-3.51 (2H, m), 2.86 (2H, t, J=6.9 Hz). m/z (ESI, +ve) 370.0 (M+H)+.
Reaction SMILES: [C:1]1([C:7]2[CH2:8][CH2:9][N:10]([C:13]([C@@H:15]3[C@@H:20]([C:21]([O:23][CH3:24])=[O:22])[CH2:19][C@H:18]([O:25][C:26]4[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=4)[CH2:17][N:16]3[C:32](OC(C)(C)C)=O)=[O:14])[CH2:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O.O1CCCC1.C(#N)C.C(N(CC)C(C)C)(C)C.C=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O>[CH3:32][N:16]1[CH2:17][C@@H:18]([O:25][C:26]2[CH:27]=[CH:28][N:29]=[CH:30][CH:31]=2)[CH2:19][C@H:20]([C:21]([O:23][CH3:24])=[O:22])[C@H:15]1[C:13]([N:10]1[CH2:9][CH:8]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:12][CH2:11]1)=[O:14]
Reactant: COC(=O)[C@H]1C[C@H](Oc2ccncc2)CN(C(=O)OC(C)(C)C)[C@@H]1C(=O)N1CC=C(c2ccccc2)CC1
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H]1C[C@H](Oc2ccncc2)CN(C)[C@@H]1C(=O)N1CC=C(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-tert-butyl 3-methyl(2S,3S,5S)-2-[(4-phenyl-3,6-dihydropyridin-1(2H)-yl)carbonyl]-5-(pyridin-4-yloxy)piperidine-1,3-dicarboxylate (0.09 g, 0.0002 mol) was treated with trifluoroacetic acid (1.0 mL, 0.013 mol) at rt for 1 h. The mixture was then concentrated to dry. The crude secondary amine made above was dissolved in tetrahydrofuran (0.80 mL, 0.0099 mol) and acetonitrile (0.80 mL, 0.015 mol). The mixture was then treated with N,N-diisopropylethylamine (0.061 mL, 0.00035 mol) to adjust the pH to around 7. To the resultant mixture was then added 12.32 M of formaldehyde in water (0.071 mL) followed by sodium triacetoxyborohydride (180 mg, 0.00087 mol). After stirred at rt overnight, the mixture was concentrated to dry in vacuo, diluted with with aq. sodium bicarbonate, extracted with EtOAc. The combined organic layers were washed with brine, dried, and evaporated to dry in vacuo. The residue was exposured in high vacuum and then used directly in next step. MS (ESI): (M+H)+=436.1.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:22])[N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13].C(N(CC)CC)C.[CH3:30][C:31]1[N:32]=[CH:33][O:34][C:35]=1[C:36](Cl)=[O:37]>CC#N>[O:21]=[C:15]1[CH:14]([N:7]2[C:6](=[O:22])[C:5]3[C:9](=[CH:10][CH:11]=[CH:12][C:4]=3[CH2:3][NH:2][C:36]([C:35]3[O:34][CH:33]=[N:32][C:31]=3[CH3:30])=[O:37])[C:8]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: Cc1ncoc1C(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1ncoc1C(=O)NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.8 %

Procedure:
To a suspension of 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (1.90 g, 5.9 mmol) in CH3CN (25 ml), were added triethyl amine (2.05 mL, 14.7 mmol) and 4-methyl-oxazole-5-carbonyl-chloride (0.85 g, 5.9 mmol). The mixture was stirred at room temperature overnight and a suspension was obtained. The reaction mixture was filtered, and the solid was rinsed with CH3CN (20 mL), water (2×20 mL) and EtOAc (20 mL) to afford 4-methyl-oxazole-5-carboxylic acid [2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-amide as a white solid (1.82 g, 78%): mp, 308-310° C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, gradient from 10/90 (CH3CN/H2O) to 95/5(CH3CN/H2O) in 10 minutes: tR=5.49 (98%); 1H NMR (DMSO-d6): δ 2.06-2.10 (m, 1H), 2.38 (s, 3H), 2.59-2.64 (m, 2H), 2.85-2.97 (m, 1H), 4.88 (d, J=5.9 Hz, 2H), 5.17 (dd, J=6, 12 Hz, 1H), 7.70-8.47 (m, 4H), 9.05 (t, J=5.9 Hz, 1H), 11.16 (s, 1H). 13C NMR (DMSO-d6) δ: 12.52, 21.96, 30.92, 37.57, 48.86, 121.91, 127.09, 131.51, 133.01, 134.81, 138.86, 138.89, 140.67, 151.42, 157.96, 166.94, 167.51, 169.82, 172.74. Anal Calcd for C19H16N4O6: C, 57.58; H, 4.07; N, 14.14. Found: C, 57.48; H, 4.04; N, 14.33.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:11])[C:5]([O:9][CH3:10])=[C:6]([CH3:8])[CH:7]=1.[Br:12][C:13]1[CH:18]=[C:17](/[C:19](/[C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[C:28]=2[C:34]#[N:35])=[N:20]\S(C(C)(C)C)=O)[CH:16]=[CH:15][N:14]=1>>[Br:12][C:13]1[CH:18]=[C:17]([C:19]2([C:2]3[CH:3]=[C:4]([CH3:11])[C:5]([O:9][CH3:10])=[C:6]([CH3:8])[CH:7]=3)[C:27]3[C:28](=[C:29]([F:33])[CH:30]=[CH:31][CH:32]=3)[C:34]([NH2:35])=[N:20]2)[CH:16]=[CH:15][N:14]=1
Reactant: COc1c(C)cc(Br)cc1C
Reactant: CC(C)(C)S(=O)/N=C(\c1ccnc(Br)c1)c1cccc(F)c1C#N
Product: COc1c(C)cc(C2(c3ccnc(Br)c3)N=C(N)c3c(F)cccc32)cc1C

Procedure:
The title compound was synthesized as described in Example 24i starting from 5-bromo-2-methoxy-1,3-dimethylbenzene (190 mg, 0.88 mmol) and (E)-N-((2-bromopyridin-4-yl)(2-cyano-3-fluorophenyl)methylene)-2-methylpropane-2-sulfinamide (300 mg, 0.73 mmol) to give the title compound which was used without further purification (400 mg, quant.).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:17][C:18]([NH:20][C:21]2[CH:22]=[N:23][C:24]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)=[CH:25][CH:26]=2)=[O:19])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[F:33][C:34]1[CH:42]=[CH:41][CH:40]=[C:39]([F:43])[C:35]=1[C:36](O)=[O:37].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(Cl)Cl>C(#N)C.O>[C:1]([C:5]1[CH:6]=[C:7]([NH:17][C:18]([NH:20][C:21]2[CH:22]=[N:23][C:24]([N:27]3[CH2:28][CH2:29][N:30]([C:36](=[O:37])[C:35]4[C:34]([F:33])=[CH:42][CH:41]=[CH:40][C:39]=4[F:43])[CH2:31][CH2:32]3)=[CH:25][CH:26]=2)=[O:19])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(N3CCNCC3)nc2)cc1
Reactant: O=C(O)c1c(F)cccc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(N3CCN(C(=O)c4c(F)cccc4F)CC3)nc2)cc1
Temperature: 25 °C

Procedure:
Place 1-(5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-3-(6-piperazin-1-yl-pyridin-3-yl)-urea (48 mg, 0.111 mmol), 2,6-difluorobenzoic acid (21 mg, 0.133 mmol), and 4-N,N-dimethylaminopyridine (3 mg, 0.022 mmol) in acetonitrile (5 mL). Add O-(7-azabenzotriazole-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) (50 mg, 0.133 mmol) and heat to 70° C. for 19 hours. Cool to room temperature and add CH2Cl2 and water. Separate organic layer and extract aqueous with CH2Cl2 (2×25 mL). Combine organics, dry over Mg2SO4, filter, and concentrate under reduced pressure. Subject residue to silica gel chromatography eluting with 0-60% EtOAc:hexane to yield the title compound. LCMS(ES): m/z=574.2 [M+H].
Reaction SMILES: [CH3:1][C:2]([CH3:13])([CH3:12])[C:3](=[N:10][OH:11])[CH:4]([S:7]([CH3:9])=[O:8])[S:5][CH3:6].[CH3:14][N:15]=[C:16]=[O:17]>C(Cl)Cl>[CH3:14][NH:15][C:16]([O:11][N:10]=[C:3]([C:2]([CH3:13])([CH3:12])[CH3:1])[CH:4]([S:7]([CH3:9])=[O:8])[S:5][CH3:6])=[O:17]
Reactant: CN=C=O
Reactant: CSC(C(=NO)C(C)(C)C)S(C)=O
Solvent: ClCCl
Product: CNC(=O)ON=C(C(SC)S(C)=O)C(C)(C)C
Reaction time: 18 h

Procedure:
To 50 mg of 3,3-dimethyl-1-(methylsulfinyl)-1-methylthio-2-butanone oxime in 5 ml of methylene chloride is added 0.5 ml of methyl isocyanate. After standing at room temperature 18 hrs., the solvent was removed to give 53 mg of impure 3,3-dimethyl-1-(methylsulfinyl)-1-methylthio-2-butanone O-[methylaminocarbonyl]oxime. The ir and pmr were identical to that of an authentic sample synthesized independently.
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23]([N:25]3[CH2:30][CH2:29][C:28]([F:32])([F:31])[CH2:27][CH2:26]3)=[O:24])=[CH:17]4)=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Br[CH2:36][C:37]#[N:38]>CN(C)C=O>[CH:1]1([N:6]2[CH2:7][CH2:8][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[N:19]([CH2:36][C:37]#[N:38])[C:18]([C:23]([N:25]3[CH2:26][CH2:27][C:28]([F:31])([F:32])[CH2:29][CH2:30]3)=[O:24])=[CH:17]4)=[O:13])[CH2:10][CH2:11]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCC(F)(F)CC3)cc2c1)N1CCN(C2CCCC2)CC1
Reactant: N#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CCn1c(C(=O)N2CCC(F)(F)CC2)cc2cc(C(=O)N3CCN(C4CCCC4)CC3)ccc21
Yield: 42 %

Procedure:
The title compound was synthesized in analogy to example 51, from [5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone (example 8), sodium hydride and bromoacetonitrile in N,N-dimethylformamide, to give the desired product as a light brown foam (42%).
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[CH2:11][CH:10]=[C:9]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[C:8]2[CH:7]=[C:6]([C:18]#[C:19][C:20]3[CH:30]=[CH:29][C:23]([C:24]([O:26]CC)=[O:25])=[CH:22][CH:21]=3)[CH:5]=[CH:4][C:3]1=2.[OH-].[Na+].Cl>CCO.C1COCC1>[CH3:1][C:2]1([CH3:31])[CH2:11][CH:10]=[C:9]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[C:8]2[CH:7]=[C:6]([C:18]#[C:19][C:20]3[CH:21]=[CH:22][C:23]([C:24]([OH:26])=[O:25])=[CH:29][CH:30]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2cccnc2)=CCC3(C)C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC1(C)CC=C(c2cccnc2)c2cc(C#Cc3ccc(C(=O)O)cc3)ccc21
Temperature: 50 °C

Procedure:
To a solution of ethyl 4-[(5,6-dihydro-5,5-dimethyl-8-(3-pyridyl)-2-naphthalenyl)ethynyl]benzoate (Compound 11) 45.0 mg (0.110 mmol) in 3 ml of EtOH and 2 ml of THF was added 48.0 mg (1.20 mmol, 1.20 ml) of NaOH (1.0 M aqueous solution). The solution was heated to 50° C. for 2 hours, cooled to room temperature, and acidified with 10% HCl. Extraction with EtOAc, followed by drying over Na2SO4, and removal of the solvents under reduced pressure afforded the title compound as a colorless solid. 1H NMR (DMSO): δ 8.60 (1H, d, J=4.6 Hz), 8.55 (1H, s), 7.90 (2H, d, J=8.3 Hz), 7.76 (1H, d, J=7.5 Hz), 7.60 (2H, d, J=8.3 Hz), 7.51-7.46 (3H, m), 6.94 (1H, s), 6.14 (1H, t, J=4.5 Hz), 2.37 (2H, d, J=4.5 Hz), 1.31 (6H, s).
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][N:7]2[C:11](=[O:12])[N:10]([C:13]3[CH:14]=[C:15]([CH:20]=[CH:21][N:22]=3)[C:16](OC)=[O:17])[CH:9]=[N:8]2)=[CH:4][CH:3]=1.[C-:25]#[N:26].[Na+]>C(N)C1C=CC=CC=1>[CH2:25]([NH:26][C:16](=[O:17])[C:15]1[CH:20]=[CH:21][N:22]=[C:13]([N:10]2[C:11](=[O:12])[N:7]([CH2:6][C:5]3[CH:23]=[CH:24][C:2]([F:1])=[CH:3][CH:4]=3)[N:8]=[CH:9]2)[CH:14]=1)[C:2]1[CH:24]=[CH:23][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccnc(-n2cnn(Cc3ccc(F)cc3)c2=O)c1
Reactant: [C-]#N
Agent: [Na+]
Solvent: NCc1ccccc1
Product: O=C(NCc1ccccc1)c1ccnc(-n2cnn(Cc3ccc(F)cc3)c2=O)c1
Yield: 6 %

Procedure:
A solution of methyl 2-(1-(4-fluorobenzyl)-5-oxo-1H-1,2,4-triazol-4(5H)-yl)isonicotinate and sodium cyanide (0.80 g, 1.43 mmol) in benzylamine (50 mL) was stirred at 100° C. for 23 hours and at 110° C. for 3 hours and concentrated in vacuo. The residue was dissolved in ethyl acetate (30 mL), washed with water (20 mL) and brine (20 mL). The organic solution was dried over anhydrous sodium sulphate, filtered and concentrated in vacuo to dryness. The residue was purified by column chromatography eluting with ethyl acetate in dichloromethane (0% to 50%) to give N-benzyl-2-(1-(4-fluorobenzyl)-5-oxo-1H-1,2,4-triazol-4(5H)-yl)isonicotinamide as a colorless solid (0.29 g, 6%): mp 173-175° C.; 1H NMR (300 MHz, CDCl3) δ 8.56-8.55 (m, 1H), 8.49 (dd, J=5.1, 0.6 Hz, 1H), 8.41 (s, 1H), 7.73-7.70 (m, 1H), 7.32-7.22 (m, 7H), 7.00-6.95 (m, 3H), 4.90 (s, 2H), 4.60 (d, J=5.7 Hz, 2H); MS (ES+) m/z 403.9.