Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH2:5].[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[O:18][CH3:19])[N:14]=[CH:13][CH:12]=[C:11]2[O:20][C:21]1[CH:22]=[CH:23][C:24]([NH:27][C:28]([C:30]2[C:31](=[O:43])[N:32]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH:33]=[CH:34][C:35]=2I)=[O:29])=[N:25][CH:26]=1>C(O)(C)C.ClCCl>[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[O:18][CH3:19])[N:14]=[CH:13][CH:12]=[C:11]2[O:20][C:21]1[CH:22]=[CH:23][C:24]([NH:27][C:28]([C:30]2[C:31](=[O:43])[N:32]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH:33]=[CH:34][C:35]=2[NH:5][CH2:4][CH2:3][O:2][CH3:1])=[O:29])=[N:25][CH:26]=1
Reactant: COc1cc2nccc(Oc3ccc(NC(=O)c4c(I)ccn(-c5ccccc5)c4=O)nc3)c2cc1OC
Reactant: COCCN
Solvent: CC(C)O
Solvent: ClCCl
Product: COCCNc1ccn(-c2ccccc2)c(=O)c1C(=O)Nc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)cn1
Temperature: 100 °C
Yield: 75.1 %

Procedure:
2-methoxyethylamine (137 μl, 1573 μmol) was added to a suspension of N-(5-(6,7-dimethoxyquinolin-4-yloxy)pyridin-2-yl)-4-iodo-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamide (122 mg, 197 μmol) in iso-propanol (1 mL). The reaction mixture was heated at 100° C. for 80 min. An aliquot was taken and analyzed by LCMS: The reaction was done. The reaction mixture was diluted with dichloromethane. The crude was adsorbed on silica and purified by MPLC (CH2Cl2/MeOH: 100/0 to 95/5) to afford the title compound N-(5-(6,7-dimethoxyquinolin-4-yloxy)pyridin-2-yl)-4-(2-methoxyethylamino)-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamide (84 mg, 148 μmol, 75% yield). MS (ESI pos. ion) m/z: 568 (MH+). Calc'd exact mass for C31H29N5O6: 567. 1H NMR (400 MHz, DMSO-d6) 13.28 (s, 1H), 10.80-10.71 (m, 1H), 8.49 (d, J=5.2 Hz, 1H), 8.34 (d, J=9.1 Hz, 1H), 8.30 (d, J=2.8 Hz, 1H), 7.79 (dd, J=9.2, 3.1 Hz, 1H), 7.73 (d, J=7.8 Hz, 1H), 7.58-7.37 (m, 7H), 6.53 (d, J=5.2 Hz, 1H), 6.32 (d, J=8.1 Hz, 1H), 3.95 (s, 3H), 3.94 (s, 3H), 3.64-3.54 (m, 4H), 3.34 (s, 3H).
Reaction SMILES: CN1[CH:7]=[CH:6][C:5](=[O:8])N(C)C1=O.[C:11]([NH2:17])(=[O:16])[CH2:12][C:13]([NH2:15])=[O:14].[O-]CC.[Na+]>CCO>[OH:14][C:13]1[N:15]=[C:5]([OH:8])[CH:6]=[CH:7][C:12]=1[C:11]([NH2:17])=[O:16]
Reactant: Cn1ccc(=O)n(C)c1=O
Reactant: NC(=O)CC(N)=O
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: NC(=O)c1ccc(O)nc1O
Yield: 65 %

Procedure:
A mixture of compound 1,3-dimethylpyrimidine-2,4(1H,3H)-dione (14 g, 0.1 mol), malonamide (45 g, 0.44 mol) and sodium ethoxide (34 g, 0.4 mol) in EtOH (500 mL) was refluxed for 20 mins. The mixture was cooled to r.t, quenched by water and acidified with 1 M HCl to pH=1-2. The solid was filtered and the filter cake was concentrated in vacuo to afford compound 2,6-dihydroxynicotinamide. (10 g, yield: 65%). 1H-NMR (400 MHz, DMSO-d6) δ (ppm) 7.90-7.88 (d, 1H), 5.66-5.64 (d, 1H).
Reaction SMILES: [BH4-].[Na+].[CH:3]1([C:6]([C:8]2[N:12]([CH3:13])[C:11]3[CH:14]=[C:15]([N:18]4[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]5[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=5)=[CH:20][C:19]4=[O:33])[CH:16]=[CH:17][C:10]=3[N:9]=2)=[O:7])[CH2:5][CH2:4]1.CO>C1COCC1>[CH:3]1([CH:6]([OH:7])[C:8]2[N:12]([CH3:13])[C:11]3[CH:14]=[C:15]([N:18]4[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]5[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=5)=[CH:20][C:19]4=[O:33])[CH:16]=[CH:17][C:10]=3[N:9]=2)[CH2:5][CH2:4]1
Reactant: Cn1c(C(=O)C2CC2)nc2ccc(-n3ccc(OCc4ccc(F)cc4)cc3=O)cc21
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: Cn1c(C(O)C2CC2)nc2ccc(-n3ccc(OCc4ccc(F)cc4)cc3=O)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.4 %

Procedure:
Sodium borohydride (10.9 mg) was added to a solution of 1-(2-(cyclopropylcarbonyl)-1-methyl-1H-benzimidazol-6-yl)-4-((4-fluorobenzyl)oxy)pyridin-2(1H)-one (60.0 mg) in THF (2 ml)-MeOH (0.2 ml) at room temperature. The mixture was stirred at room temperature for 30 min. The mixture was quenched with water and extracted with EtOAc/THF twice. The organic layer was separated, washed with brine, dried over MgSO4 and concentrated in vacuo. The solid was washed with Et2O to give the title compound (47.9 mg) as a white solid.
Reaction SMILES: [F:1][C:2]1([F:29])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:28][C:13]3=[N:14][CH:15]=[C:16]([O:18][CH:19]4[CH2:24][CH2:23][N:22]([CH:25]([CH3:27])[CH3:26])[CH2:21][CH2:20]4)[CH:17]=[C:12]3[CH:11]=2)=[O:9])[CH2:4][CH2:3]1.[H-].[Na+].[CH3:32][S:33](Cl)(=[O:35])=[O:34]>CN(C=O)C>[F:29][C:2]1([F:1])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:28]([S:33]([CH3:32])(=[O:35])=[O:34])[C:13]3=[N:14][CH:15]=[C:16]([O:18][CH:19]4[CH2:20][CH2:21][N:22]([CH:25]([CH3:27])[CH3:26])[CH2:23][CH2:24]4)[CH:17]=[C:12]3[CH:11]=2)=[O:9])[CH2:4][CH2:3]1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)N1CCC(Oc2cnc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)N1CCC(Oc2cnc3c(c2)cc(C(=O)N2CCC(F)(F)CC2)n3S(C)(=O)=O)CC1
Temperature: 70 °C
Yield: 44 %

Procedure:
The suspension of 0.25 g (0.6 mmol) (4,4-difluoro-piperidin-1-yl)-[5-(1-isopropyl-piperidin-4-yloxy)-1H-pyrrolo[2,3-b]pyridin-2-yl]-methanone (example 13) and 30 mg (0.68 mmol; 55% dispersion in mineral oil) sodium hydride in 3 ml DMF was heated to 70° C. To the resulting solution 53 μl (77 mg, 0.67 mmol) methanesulfonyl chloride were added. After 1.5 h the heating bath was removed and the solution was poured on water and was extracted three times with ethyl acetate. The combined organic layers were washed with water and brine, dried over magnesium sulfate, filtered and evaporated. The crude product was purified by flash-chromatography on silica gel with dichloromethane:methanol:ammonia (9:1:0.1 v/v) to give 13 mg (44%) of the product as a light brown foam.
Reaction SMILES: [Cl-].[NH4+].[CH3:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]>>[CH3:3][CH:4]=[CH:5][CH2:6][CH2:7][CH2:8][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCC
Agent: [Cl-]
Agent: [NH4+]
Product: CC=CCCCCCCCC

Procedure:
At the end of reaction, 50 ml of a saturated ammonium chloride aqueous solution and 100 ml of n-hexane were added to the reaction solution. The organic layer was extracted, dried over magnesium sulfate, and filtered. By distilling off the solvent, there was obtained 12 grams of 2-undecene in a substantially quantitative yield.
Reaction SMILES: C([O:8][C:9]1[CH:36]=[CH:35][C:34]([N:37]2[CH2:42][CH2:41][O:40][CH2:39][CH2:38]2)=[CH:33][C:10]=1[C:11]([NH:13][C:14]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:24]=[CH:23][C:15]=1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:12])C1C=CC=CC=1>C(OCC)(=O)C.CO.[C].[Pd]>[OH:8][C:9]1[CH:36]=[CH:35][C:34]([N:37]2[CH2:38][CH2:39][O:40][CH2:41][CH2:42]2)=[CH:33][C:10]=1[C:11]([NH:13][C:14]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:24]=[CH:23][C:15]=1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:12]
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(N2CCOCC2)ccc1OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(N2CCOCC2)ccc1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.4 %

Procedure:
To a solution mixture of the obtained tert-butyl 2-(2-(benzyloxy)-5-(morpholin-4-yl)benzamido)-4-phenylbenzoate (0.060 g) in ethyl acetate (1.5 mL) and methanol (1.5 mL), 10% palladium-carbon (0.030 g) was added, followed by stirring under a hydrogen atmosphere at room temperature for 3 hours and 30 minutes. Ethyl acetate was added to the reaction mixture. The insoluble substance was removed by filtration, and the solvent was evaporated under reduced pressure. Diisopropyl ether was added to the obtained residue. The solid substance was collected by filtration to obtain 0.036 g of tert-butyl 2-(2-hydroxy-5-(morpholin-4-yl)benzamido)-4-phenylbenzoate as a yellow solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[ClH:9].[CH3:10][O:11][NH2:12].CO.C(=O)([O-])[O-].[K+].[K+]>O>[ClH:9].[CH3:10][O:11][N:12]=[C:5]1[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]1
Reactant: CON
Reactant: CN1CCC(=O)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CON=C1CCN(C)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 32.3 %

Procedure:
1-Methyl-4-piperidone (5 g, 44.2 mmol) and methoxyamine hydrochloride (3.69 g, 44.2 mmol) were taken into 25 mL of methanol and stirred at room temperature for 2 days. The reaction mixture was evaporated in vacuo to afford a solid residue. The residue was dissolved in water, made basic with solid potassium carbonate, and extracted with dichloromethane (3×100 mL). The combined extracts were dried over anhydrous sodium sulfate and evaporated to give a clear, yellow liquid that was purified on silica gel, eluting with dichloromethane-methanol (95:5)to afford 2.55 g of the desired product. Treatment with ethereal hydrogen chloride gave the hydrochloride salt, 2.99 g, mp 145°-147° C.
Reaction SMILES: Br[CH2:2][CH:3]=[C:4]([CH3:12])[CH2:5][CH2:6][CH:7]=[C:8]([CH3:11])[CH2:9][CH3:10].[OH:13][C:14]1[CH:22]=[CH:21][C:17]2[CH2:18][CH2:19][O:20][C:16]=2[CH:15]=1>>[CH3:12][C:4]([CH2:5][CH2:6][CH:7]=[C:8]([CH3:11])[CH2:9][CH3:10])=[CH:3][CH2:2][O:13][C:14]1[CH:22]=[CH:21][C:17]2[CH2:18][CH2:19][O:20][C:16]=2[CH:15]=1
Reactant: Oc1ccc2c(c1)OCC2
Reactant: CCC(C)=CCCC(C)=CCBr
Product: CCC(C)=CCCC(C)=CCOc1ccc2c(c1)OCC2

Procedure:
1-bromo-3,7-dimethyl-2,6-nonadiene and 6-hydroxy-2,3-dihydrobenzofuran are reacted to form 6-[(3,7-dimethyl-2,6-nonadienyl)-oxy]-2,3-dihydrobenzofuran of boiling point 138° C./0.002 mmHg; nD20 = 1.5382;
Reaction SMILES: [CH:1]1([N:4]([CH2:15][CH3:16])[CH2:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]#[CH:13])=[CH:8][C:7]=2[CH3:14])[CH2:3][CH2:2]1.C(O)(=O)C1C=CC=CC=1.[CH2:26]([O:28][C:29](=[O:37])[C:30]1[CH:35]=[CH:34][C:33](I)=[CH:32][CH:31]=1)[CH3:27]>C(N(CC)CC)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:1]1([N:4]([CH2:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]#[C:13][C:33]3[CH:34]=[CH:35][C:30]([C:29]([O:28][CH2:26][CH3:27])=[O:37])=[CH:31][CH:32]=3)=[CH:8][C:7]=2[CH3:14])[CH2:15][CH3:16])[CH2:3][CH2:2]1
Reactant: CCOC(=O)c1ccc(I)cc1
Reactant: C#Cc1ccc(CN(CC)C2CC2)c(C)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: O=C(O)c1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(C#Cc2ccc(CN(CC)C3CC3)c(C)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Using General Procedure F; cyclopropyl-ethyl-(4-ethynyl-2-methyl-benzyl)-amine (Intermediate 161, 190.0 mg, 0.89 mmol) and ethyl-4-iodo benzoate (Reagent A, 245.0 mg, 0.89 mmol) in triethylamine (5 mL) was treated with copper(I)iodide (56.0 mg, 0.30 mmol) and sparged with argon for 15 minutes. Dichlorobis(triphenylphosphine)-palladium(II) (208 mg, 0.30 mmol) was added and the reaction mixture was stirred overnight at room temperature. Column chromatography (3-5% EtOAc-hexanes) afforded the title compound.
Reaction SMILES: [OH:1][CH2:2][C@@:3]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([C:5]([OH:7])=O)[NH2:4].[Cl:14][C:15]1[CH:16]=[C:17]([N:22]=[C:23]=[O:24])[CH:18]=[CH:19][C:20]=1[Cl:21].Cl>[OH-].[Na+].O1CCOCC1>[Cl:14][C:15]1[CH:16]=[C:17]([N:22]2[C:5](=[O:7])[C@@:3]([CH2:2][OH:1])([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[NH:4][C:23]2=[O:24])[CH:18]=[CH:19][C:20]=1[Cl:21]
Reactant: O=C=Nc1ccc(Cl)c(Cl)c1
Reactant: N[C@@](CO)(C(=O)O)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C1N[C@](CO)(c2ccccc2)C(=O)N1c1ccc(Cl)c(Cl)c1
Reaction time: 1 h

Procedure:
217 mg of (S)-2-hydroxymethyl-2-phenylglycine (prepared according to A.Olma, Polish J. Chem., 70, (1996), 1442-1447) are dissolved in 5 mL of 0.5 N aqueous sodium hydroxide. 300 mg of 3,4-dichlorophenyl isocyanate dissolved in 5 mL dioxan are slowly added over 10 min then the mixture is stirred for 1 h, the pH is around 7 to 7.5. 3 mL of 0.5 N aqueous sodium hydroxide are added to make the pH alkaline then 300 mg of 3,4-dichlorophenyl isocyanate dissolved in 5 mL dioxan are slowly added again. The mixture is stirred for 1 further hour at room temperature then 12N hydrochloric acid is added to acidic pH and the mixture is heated for 1 h at reflux temperature. The dioxan is removed by evaporation under vacuum, the aqueous phase is extracted with ethyl acetate. The extracts are washed with brine, dried over magnesium sulfate and evaporated to dryness. The residue is purified over silica gel while eluting with a gradient mixture from heptane to pure ethyl acetate to provide expected product.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6][C:5]2([CH3:14])[CH3:13].C([Sn](CCCC)(CCCC)[C:20]([O:22]CC)=[CH2:21])CCC.Cl>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:20]([C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6][C:5]2([CH3:14])[CH3:13])(=[O:22])[CH3:21]
Reactant: CC1(C)CC(=O)Nc2ccc(Br)cc21
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: C1CCOC1
Product: CC(=O)c1ccc2c(c1)C(C)(C)CC(=O)N2
Temperature: 80 °C
Reaction time: 18 h
Yield: 66.9 %

Procedure:
A solution of 6-bromo-4,4-dimethyl-3,4-dihydro-1H-quinolin-2-one (Intermediate 4, 270 mg, 1.06 mmol) in 5 ml of THF was first degassed by bubbling with argon for 30 min. Tributyl(1-ethoxyvinyl)tin (766 mg, 2.12 mmol) and PdCl2(PPh3)2 (37mg, 0.05 mmol) were added. After stirring at 80° C. for 18 h, the mixture was cooled to room temperature and 3 mL of 10% HCl was added. The mixture was then stirred for another 30 min before extracted with ethyl acetate (3×10 mL). The combined organic layer was washed with brine (1×10 mL), dried (MgSO4) and concentrated at reduced pressure. Purification by flash chormatography (50:50 hexane/ethyl acetate) yielded the title compound as a white solid (154 mg, 67% yield).
Reaction SMILES: [F-:1].[K+].I([C:6]1[CH:7]=[C:8]([CH:23]=[CH:24][C:25]=1[N+:26]([O-:28])=[O:27])[C:9]([NH:11][CH2:12][C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])=[O:10])(=O)=O.C1OCCOCCOCCOCCOCCOC1.C(#N)C>CCOC(C)=O>[F:1][C:6]1[CH:7]=[C:8]([CH:23]=[CH:24][C:25]=1[N+:26]([O-:28])=[O:27])[C:9]([NH:11][CH2:12][C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])=[O:10]
Reactant: [F-]
Reactant: O=C(CNC(=O)c1ccc([N+](=O)[O-])c(I(=O)=O)c1)OCc1ccccc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=C(CNC(=O)c1ccc([N+](=O)[O-])c(F)c1)OCc1ccccc1
Yield: 61 %

Procedure:
A mixture of spray-dried KF (614 mg, 10.59 mmol), intermediate 7 (1 g, 2.12 mmol), 18-crown-6 (40 mg) and dry acetonitrile (20 mL) was refluxed for 40 min. After completion of reaction (TLC), the mixture was diluted with EtOAc (75 mL). The solution was successively washed with water (50 mL) and brine (50 mL) and dried over anhyd Na2SO4. The solution was filtered and evaporated the solvent. The residue was chromatographed over silica gel column using chloroform:hexane (75:25) as eluents to give the product as a colorless solid (430 mg, 61%), mp 118-120° C. 1H NMR (400 MHz, CDCl3): δ 8.13 (1H, t, J=7.8 Hz), 7.75 (1H, d, J=10.8 Hz), 7.68 (1H, d, J=8.0 Hz), 7.38 (5H, br s), 6.68 (1H, br s), 5.25 (2H, s), 4.29 (2H, d, J=4.8 Hz); LC-MS negative ion mode): m/z 331 (M−H)−.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]2[O:13][CH:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:14]1([O:21][CH3:22])[C:15](=[CH:17][CH:18]=[CH:19][CH:20]=1)[OH:16]>>[CH3:22][O:21][C:14]1[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=1[O:16][C@@H:11]1[CH2:12][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9][C@H:10]1[OH:13]
Reactant: c1ccc(CN2CC3OC3C2)cc1
Reactant: COc1ccccc1O
Product: COc1ccccc1O[C@@H]1CN(Cc2ccccc2)C[C@H]1O
Yield: 27 %

Procedure:
A mixture of 40 g. of crude 1-benzyl-3,4-epoxypyrrolidine and 70 g. of guaiacol was heated at 120° C. for 20 hr. Aspirator vacuum was then used to distill off the excess guaiacol. The residue was dissolved in methylene chloride and extracted with dilute sodium hydroxide. The methylene chloride solution was dried over anhydrous sodium sulfate and the solvent was evaporated. The residue weighed 54 g., was chromatographed on 1 kg. of silica gel. The product was eluted with 50% ethyl acetate in benzene and crystallized from cyclohexane. The m.p. was 115°-117° C. and the yield was 27%.
Reaction SMILES: Br[C:2]1[S:6][C:5]([NH:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:12]=2[C:18]([CH:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)=[O:19])=[O:9])=[N:4][CH:3]=1.[CH3:25][O:26][C:27]([C:29]1[C:34]([SH:35])=[CH:33][CH:32]=[CH:31][N:30]=1)=[O:28]>>[CH3:25][O:26][C:27]([C:29]1[C:34]([S:35][C:2]2[S:6][C:5]([NH:7][C:8]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:12]=3[C:18]([CH:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[O:19])=[O:9])=[N:4][CH:3]=2)=[CH:33][CH:32]=[CH:31][N:30]=1)=[O:28]
Reactant: COC(=O)c1ncccc1S
Reactant: Cc1ccc(NC(=O)Nc2ncc(Br)s2)c(C(=O)C2CCCC2)c1
Product: COC(=O)c1ncccc1Sc1cnc(NC(=O)Nc2ccc(C)cc2C(=O)C2CCCC2)s1
Yield: 30 %

Procedure:
3-{2-[3-(2-Cyclopentanecarbonyl-4-methyl-phenyl)-ureido]-thiazol-5-ylsulfanyl}-pyridine-2-carboxylic acid methyl ester (149 mg, 30%) was prepared from 1-(5-bromo-thiazol-2-yl)-3-(2-cyclopentanecarbonyl-4-methyl-phenyl)-urea (408 mg, 1 mmol) and 3-mercapto-pyridine-2-carboxylic acid methyl ester (340 mg, 2 mmol) following the general procedure Q.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[C:24]2[C:19](=[CH:20][C:21]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[CH:22][CH:23]=2)[CH2:18][CH2:17][NH:16]1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH2:17][CH2:18][C:19]4[C:24](=[CH:23][CH:22]=[C:21]([N:25]5[CH2:30][CH2:29][O:28][CH2:27][CH2:26]5)[CH:20]=4)[CH:15]3[CH3:14])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: CC1NCCc2cc(N3CCOCC3)ccc21
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Product: CC1c2ccc(N3CCOCC3)cc2CCN1C(=O)c1cc2ncc(Cl)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Methyl-6-morpholin-4-yl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC.[CH3:59][C:60]1[CH:61]=[CH:62][C:63]([CH2:66]O)=[N:64][CH:65]=1>C(OCC)(=O)C.O1CCCC1>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[N:8]([CH2:66][C:63]2[CH:62]=[CH:61][C:60]([CH3:59])=[CH:65][N:64]=2)[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: Cc1ccc(CO)nc1
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCc1nc(C)n(Cc2ccc(C)cn2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 45.6 %

Procedure:
A mixture of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1 g), 1,1′-(azodicarbonyl)dipiperidine (1.41 g), tributylphosphine (1.56 mL), (5-methylpyridin-2-yl)methanol (0.5 g) and tetrahydrofuran (50 mL) was stirred at room temperature for 4 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.59 g, 47%).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[NH:6][C:7]([CH:9]3[O:14][CH2:13][CH2:12][NH:11][CH2:10]3)=[N:8][C:4]=2[CH:3]=1.CCN(C(C)C)C(C)C.[Cl:26][C:27]1[CH:32]=[C:31](Cl)[N:30]=[C:29]([NH2:34])[N:28]=1>C(O)C>[Cl:26][C:27]1[CH:32]=[C:31]([N:11]2[CH2:12][CH2:13][O:14][CH:9]([C:7]3[NH:6][C:5]4[CH:15]=[CH:16][C:2]([F:1])=[CH:3][C:4]=4[N:8]=3)[CH2:10]2)[N:30]=[C:29]([NH2:34])[N:28]=1
Reactant: Fc1ccc2[nH]c(C3CNCCO3)nc2c1
Reactant: Nc1nc(Cl)cc(Cl)n1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nc(Cl)cc(N2CCOC(c3nc4cc(F)ccc4[nH]3)C2)n1
Temperature: 25 °C
Yield: 79.3 %

Procedure:
To a suspension of 5-fluoro-2-(2-morpholinyl)-1H-benzimidazole (200 mg, 0.904 mmol) and Hunig's base (409 mg, 3.16 mmol) in ethanol (10 mL) stirred at room temperature was added 4,6-dichloro-2-pyrimidinamine (148 mg, 0.904 mmol), and the reaction mixture was stirred overnight at 85° C. The reaction mixture was cooled to room temperature and partitioned between EtOAc (25 mL) and water (25 mL). The organic solvent was evaporated in vacuo to give the crude product. The residue was triturated with EtOAc (1×5 mL). The resulting solid was filtered and collected to afford the title compound (250 mg). LC-MS (ES) m/z=349 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([CH3:22])=[N:10][C:11]2[C:16]([N:17]=1)=[C:15]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:13][CH:12]=2.[Br:23]N1C(C)(C)C(=O)N(Br)C1=O.C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>>[Br:23][CH2:22][C:9]1[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])=[N:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][C:15]=2[C:18]([F:21])([F:19])[F:20])[N:10]=1
Reactant: Cc1nc2cccc(C(F)(F)F)c2nc1-c1ccccc1Cl
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: FC(F)(F)c1cccc2nc(CBr)c(-c3ccccc3Cl)nc12
Temperature: 25 °C
Reaction time: 20 h

Procedure:
3-(2-Chlorophenyl)-2-methyl-5-(trifluoromethyl)quinoxaline (0.9969 g, 3.089 mmol) and 1,3-dibromo-5,5-dimethylhydantoin (0.5299 g, 1.853 mmol) were suspended in carbon tetrachloride (30.89 mL, 3.089 mmol). To the mixture was added benzoyl peroxide (0.09977 g, 0.3089 mmol) and the mixture was heated at reflux. After 20 h, the mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography on a 80 g of Redi-Sep™ column using 0 to 5% gradient of EtOAc in hexane over 10 min, then 5% isocratic of EtOAc for 30 min, then 5 to 20% gradient of EtOAc in hexane over 20 min, then 20% isocratic of EtOAc for 4 min as eluent to give 2-(bromomethyl)-3-(2-chlorophenyl)-5-(trifluoromethyl)-quinoxaline as an off-white syrupy solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 8.48 (1H, dd, J=8.6, 0.8 Hz), 8.37 (1H, d, J=6.7 Hz), 8.09 (1H, t, J=7.8 Hz), 7.55-7.77 (4H, m), 4.73 (2H, d, J=61.8 Hz); LC-MS (ESI) m/z 403.0 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C:6]1[NH:7][C:8]2[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=2[N:10]=1)=[O:4].[C:15]1([O:21][C:22]#[N:23])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(Cl)(Cl)Cl>[C:15]1([O:21][C:22]([N:10]2[C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]=[C:6]2[NH:5][C:3]([O:2][CH3:1])=[O:4])=[NH:23])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: N#COc1ccccc1
Reactant: COC(=O)Nc1nc2ccccc2[nH]1
Solvent: ClC(Cl)Cl
Product: COC(=O)Nc1nc2ccccc2n1C(=N)Oc1ccccc1
Temperature: 20 °C
Reaction time: 8 h

Procedure:
To a suspension of 420.6 g (2.2 mole) 2-(methoxycarbonylamino)-benzimidazole in 10 ltr chloroform a solution of 274 g (2.3 moles) phenyl cyanate in 2 ltr chloroform is added in drops while stirring at 20°C. The reaction mixture is stirred for 6 hours at room temperature and then left standing overnight. The product is then filtered and the solvent removed under vacuum. The colorless, crystalline residue is treated with ether.