Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]=[C:2]([CH:4]1[C:12]2[C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[O:9][C:8]=2[CH:7]=[CH:6][C:5]1(C(C)=C)[NH2:17])[CH3:3].[CH2:21](O)[CH3:22].[C:24](O)(=O)C>[Pd].[Pt]>[CH:2]([C:4]1[C:12]2[C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[O:9][C:8]=2[CH:7]=[C:6]([CH:21]([CH3:22])[CH3:24])[C:5]=1[NH2:17])([CH3:3])[CH3:1]
Reactant: CCO
Reactant: CC(=O)O
Reactant: C=C(C)C1c2c(oc3ccccc23)C=CC1(N)C(=C)C
Agent: [Pd]
Agent: [Pt]
Product: CC(C)c1cc2oc3ccccc3c2c(C(C)C)c1N
Yield: 34 %

Procedure:
To a 500 mL Parr Hydrogenator bottle was added 1,2-di(prop-1-en-2-yl)dibenzo[b,d]furan-2-amine (19.1 g, 72.5 mmol), 10% palladium on carbon (5.7 g, 5.36 mmol), 5% platinum on carbon (5.7 g, 1.46 mmol), ethanol (180 mL), and acetic acid (20 mL). The mixture was hydrogenated on a Parr hydrogenator overnight. The reaction mixture was filtered through Celite and washed with dichloromethane. The filtrate was evaporated to brown oil. The oil was dissolved in dichloromethane, washed with 10% sodium hydroxide, dried over magnesium sulfate, filtered, evaporated to a brown oil. The oil was purified using a 200 g Varian column eluting with 10% ethyl acetate/hexanes. 6.55 g (34% yield) of product was obtained.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[N:5]=[CH:6][C:7]2[CH:13]=[C:12]([C:14]3[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:21])[C:11](=[O:22])[NH:10][C:8]=2[N:9]=1.Cl[CH2:24][CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CN(C)C=O.C(OCC)(=O)C>[NH2:3][C:4]1[N:5]=[CH:6][C:7]2[CH:13]=[C:12]([C:14]3[C:15]([Cl:21])=[CH:16][CH:17]=[CH:18][C:19]=3[Cl:20])[C:11](=[O:22])[N:10]([CH2:24][CH2:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:8]=2[N:9]=1
Reactant: Nc1ncc2cc(-c3c(Cl)cccc3Cl)c(=O)[nH]c2n1
Reactant: ClCCCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Nc1ncc2cc(-c3c(Cl)cccc3Cl)c(=O)n(CCCc3ccccc3)c2n1
Temperature: 60 °C
Yield: 57.2 %

Procedure:
To a suspension of NaH (60% in mineral oil, 58 mg) in 10 mL of dimethylformamide was added 2-amino-6-(2,6-dichlorophenyl)-pyrido[2,3-d]pyrimidin-7(8H)-one (320 mg, 1.04 mmol). The mixture was heated to 60° C. resulting in a clear solution. 1-Chloro-3-phenylpropane (260 μL, 1.81 mmol) was added, and the reaction mixture was heated at 60° C. for 35 minutes, then poured onto ice water. The resulting gummy solid was dissolved in ethyl acetate, washed with water, and dried over magnesium sulfate. Filtration, followed by concentration in vacuo, gave an oil that was purified by flash chromatography, eluting with 1:3 hexane:ethyl acetate to provide 345 mg of crude product. Recrystallization from ethyl acetate and hexane followed by drying in vacuo provided 253 mg (57%) of 2-amino-6-(2,6-dichlorophenyl)-8-(3-phenylpropyl)-8H-pyrido[2,3-d]pyrimidin-7-one; mp 161°-163° C.
Reaction SMILES: Br[CH:2]([CH2:8][CH2:9]Br)[C:3]([O:5][CH2:6][CH3:7])=[O:4].C(N(CC)CC)C.[CH2:18]([NH2:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>O>[CH2:18]([N:25]1[CH2:9][CH2:8][CH:2]1[C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: NCc1ccccc1
Reactant: CCOC(=O)C(Br)CCBr
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)C1CCN1Cc1ccccc1
Yield: 52.4 %

Procedure:
(Wasserman, H. H. et al. J Org. Chem. 1981, 46(15), 2991-2999). A mixture of (±)ethyl 2,4-dibromobutanoate (39) (15 g, 54.8 mmol), triethylamine (16.6 g, 164 mmol) and benzylamine (5.87 g, 54.8 mmol) was heated to reflux for 3 hours then concentrated under reduced pressure to give a solid suspension. Water (150 ml) was then added and the mixture extracted with ether (2×100 ml). The organic phase was dried and then concentrated under reduced pressure and the residue purified by dry flash chromatography on silica (hexanes then 1:3 ethyl acetate/hexanes) to give 40 as a pale yellow oil (6.3 g, 53%); 1H NMR (300 MHz, CDCl3) δ 7.37-7.27 (m, 5H), 4.16-4.03 (m, 2H), 3.82 (d, J=12.6 Hz, 1H), 3.73 (dd, J=8.4, 8.4 Hz, 1H), 3.61 (d, J=12.8 Hz, 1H), 3.34 (ddd, J=7.4, 7.4, 2.0 Hz, 1H), 2.95 (ddd, J=7.4, 7.4, 7.4 Hz, 1H), 2.44-2.31 (m, 1H), 2.27-2.16 (m, 1H), 1.20 (t, J=7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 172.5, 137.1, 129.0, 128.7, 128.2, 127.1, 64.5, 62.4, 60.5, 50.8, 21.5, 14.0.
Reaction SMILES: [CH2:1]([C:8]1[C:12]2[C:13](Cl)=[N:14][CH:15]=[CH:16][C:11]=2[NH:10][C:9]=1[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][CH2:21][NH:20]1>>[CH2:1]([C:8]1[C:12]2[C:13]([N:20]3[CH2:21][CH2:22][C:23]4[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH2:19]3)=[N:14][CH:15]=[CH:16][C:11]=2[NH:10][C:9]=1[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc2c(c1)CCNC2
Reactant: Cc1[nH]c2ccnc(Cl)c2c1Cc1ccccc1
Product: Cc1[nH]c2ccnc(N3CCc4ccccc4C3)c2c1Cc1ccccc1
Yield: 89.7 %

Procedure:
In accordance with the same procedures as Example 1, except for using 3-benzyl-4-chloro-2-methyl-1H-pyrrolo[3,2-c]pyridine prepared in Preparation 2 and 1,2,3,4-tetrahydroisoquinoline, the titled compound was obtained as a pale yellow solid. (Yield: 89.7%).
Reaction SMILES: S(=O)(=O)(O)O.[C:6]([CH2:9][C:10](=[O:12])[CH3:11])(=[O:8])[CH3:7].[N:13]([O-])=[O:14].[Na+]>>[CH3:11][C:10](=[O:12])[C:9](=[N:13][OH:14])[C:6](=[O:8])[CH3:7]
Reactant: O=N[O-]
Reactant: CC(=O)CC(C)=O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CC(=O)C(=NO)C(C)=O
Temperature: 17.5 °C
Reaction time: 0.33 h
Yield: 96 %

Procedure:
Variant a): In a stirred vessel, 21 l of 20% strength sulfuric acid and 6 kg (60 mol) of acetylacetone were initially charged. The mixture was cooled to about 17° C. and, at 15-20° C., 4.2 kg (60.84 mol) of 40.5% strength aqueous sodium nitrite solution were metered in. The mixture was subsequently stirred at about 17° C. for another 20 minutes and then extracted with 25 l of ethyl acetate. The organic phase was concentrated under reduced pressure, giving 7.42 kg (96% yield) of the title compound.
Reaction SMILES: Cl.[C:2]1([C:8]23[CH2:15][CH2:14][C:11]([CH2:16][C:17]([OH:19])=[O:18])([CH2:12][CH2:13]2)[CH2:10][CH2:9]3)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20]O>>[C:2]1([C:8]23[CH2:9][CH2:10][C:11]([CH2:16][C:17]([O:19][CH3:20])=[O:18])([CH2:14][CH2:15]2)[CH2:12][CH2:13]3)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CC12CCC(c3ccccc3)(CC1)CC2
Reactant: CO
Agent: Cl
Product: COC(=O)CC12CCC(c3ccccc3)(CC1)CC2
Reaction time: 4 h

Procedure:
A freshly prepared solution of hydrogen chloride in methanol (˜3 M; ˜2 mL, ˜6 mmol) was added to a solution of (4-Phenylbicyclo[2.2.2]oct-1-yl)acetic acid (0.3 g) in methanol (3 mL) under a calcium chloride guard tube and the mixture stirred for 4 h. The solvent was evaporated to leave the title compound as an off white solid (0.25 g; 78%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH2:6].Cl[C:12]1[C:13]2[C:26]([CH3:27])=[CH:25][S:24][C:14]=2[N:15]=[C:16]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)[N:17]=1>>[N:21]1[CH:20]=[CH:19][C:18]([C:16]2[N:17]=[C:12]([NH:6][CH2:5][C:4]3[CH:7]=[CH:8][C:9]([Cl:10])=[C:2]([Cl:1])[CH:3]=3)[C:13]3[C:26]([CH3:27])=[CH:25][S:24][C:14]=3[N:15]=2)=[CH:23][CH:22]=1
Reactant: Cc1csc2nc(-c3ccncc3)nc(Cl)c12
Reactant: NCc1ccc(Cl)c(Cl)c1
Product: Cc1csc2nc(-c3ccncc3)nc(NCc3ccc(Cl)c(Cl)c3)c12

Procedure:
With the procedure of Example 1, the reaction of 3,4-dichlorobenzylamine with 4-chloro-2-(pyridin-4-yl)-5-methyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-4-yl)-4-(3,4-dichlorobenzylamino)-5-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1.[CH3:10][Si:11]([CH3:18])([CH3:17])[CH2:12][CH2:13][O:14][CH2:15]Cl.O>CCCCCC.C(COC)OC>[CH3:10][Si:11]([CH3:18])([CH3:17])[CH2:12][CH2:13][O:14][CH2:15][O:3][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: Oc1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: O
Solvent: COCCOC
Product: C[Si](C)(C)CCOCOc1cccnc1
Reaction time: 0.17 h
Yield: 91.6 %

Procedure:
Sodium hydride (3.85 g, 96.3 mmol) was washed with hexane and dimethoxyethane (90 mL) was added thereto. 3-Hydroxypyridine (4.97 g, 52.3 mmol) was added to the obtained mixture under cooling with ice over 10 minutes and the reaction mixture was stirred for 10 minutes, and then 2-(trimethylsilyl)ethoxymethyl chloride (10.0 mL, 56.5 mmol) was added thereto under cooling with ice over 25 minutes. The reaction mixture was stirred at room temperature for 14.5 hours. Under cooling with ice, to the reaction mixture was added water and the mixture was extracted with ether and the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel flash column chromatography [developing solution=n-hexane:ethyl acetate (3:1)] to obtain the title product (10.8 g, 92%).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:12]1([O:18][CH2:19][CH:20]=[CH2:21])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[O:18]([CH2:19][CH:20]=[CH:21][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COC(=O)c1ccccc1Br
Reactant: C=CCOc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)c1ccccc1C=CCOc1ccccc1
Temperature: 100 °C
Reaction time: 4 h
Yield: 14.6 %

Procedure:
To a solution of methyl 2-bromobenzoate (0.206 g, 0.96 mmol) in acetonitrile (3 ml) were added allyl phenyl ether (0.65 ml, 1.09 mmol), tri-o-tolylphosphine (0.014 g, 0.045 mmol), palladium acetate (0.006 g, 0.027 mmol) and triethylamine (0.16 ml, 1.15 mmol), and the mixture was stirred at 100° C. for 4 hr. The reaction mixture was filtered through celite, and ethyl acetate was added to the filtrate. The mixture was washed with water, and the organic layer was dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate) to give methyl 2-(3-phenoxypropenyl)benzoate (0.037 g, 0.14 mmol, yield 15%).
Reaction SMILES: C[C:2]1[CH:8]=[C:7]([OH:9])[CH:6]=[CH:5][C:3]=1[OH:4].[C:10](=O)([O-])[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1Cl.Cl[C:22]1[CH:27]=CC=C[C:23]=1O>C1([B-](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([N+](CCCC)(CCCC)CCCC)CCC.OC1C=CC(C(C2C=CC(O)=CC=2)(C)C)=CC=1>[CH3:23][C:22]([C:7]1[CH:6]=[CH:5][C:3]([OH:4])=[CH:2][CH:8]=1)([C:15]1[CH:14]=[CH:13][C:12]([OH:11])=[CH:17][CH:16]=1)[CH3:27].[CH3:10][O:9][C:7]1[CH:8]=[CH:2][C:3]([OH:4])=[CH:5][CH:6]=1
Reactant: O=C([O-])Oc1ccccc1Cl
Reactant: Cc1cc(O)ccc1O
Reactant: Oc1ccccc1Cl
Agent: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: c1ccc([B-](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: COc1ccc(O)cc1

Procedure:
Methylhydroquinone (1.9 moles, 235.87 g), bisphenol-A (0.1 moles, 22.83 g), chlorophenyl carbonate (2.04 moles, 577.12 g) and tetrabutylammonium tetraphenylborate (1.6 mmol, 0.899 g) were added to a 1 L 3-neck flask and melted at 165° C. with overhead stirring. 85 wt % chlorophenol (3.38 mole, 350 mL,) was collected by distillation at about 220° C. followed by a slight vacuum at 230° C. The molten prepolymer was quickly poured onto a foil-lined pyrex dish to obtain a solid (369 g). Subsequent polymerization took place in a 2CV Helicone reactor (500 mL capacity). The prepolymer (200 g) was added at 300° C. and stirred slowly until molten. Once molten, vacuum was applied and the system heated to about 325° C. (stirrer setting=6.5). After about 10 minutes, the vacuum reached about 2.5 mm Hg. The polymer was extruded after 25 minutes to obtain about 122 g of light pink strands (flexible in clear areas and brittle in cloudy areas).
Reaction SMILES: [C:1]1([S:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:15]1([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.[F:41][C:42]([F:48])([F:47])[S:43]([OH:46])(=[O:45])=[O:44]>CCCCCC.O>[F:41][C:42]([F:48])([F:47])[S:43]([O-:46])(=[O:45])=[O:44].[C:9]1([S+:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:18]2[CH:19]=[CH:20][C:15]([CH2:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[CH:16][CH:17]=2)[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: O=S(c1ccccc1)c1ccccc1
Reactant: c1ccc(Cc2ccccc2)cc1
Reactant: O=S(=O)(O)C(F)(F)F
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CCCCCC
Solvent: O
Product: O=S(=O)([O-])C(F)(F)F
Product: c1ccc(Cc2ccc([S+](c3ccccc3)c3ccccc3)cc2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 74.9 %

Procedure:
In 35 ml of n-hexane were suspended 6.07 g (0.03 mol) of diphenylsulfoxide and 6.06 g (0.036 mol) of diphenylmethane, and 7.56 g (0.036 mol) of trifluoroacetic anhydride was added thereto at 0° C. Then 4.5 g (0.03 mol) of trifluoromethanesulfonic acid was added dropwise thereto at 0 to 5° C., followed by gradually warming to room temperature and reacting for 4 hours with stirring. After completion of the reaction, 50 ml of water was poured into the reaction solution and the n-hexane layer was removed by fractionation. The aqueous layer was further washed with 50 ml of hexane three times and extracted with 60 ml of dichloromethane. The resulting dichloromethane layer was washed with 50 ml of water five times, followed by concentration under reduced pressure. 70 ml of ethyl acetate was poured into the resulting crude crystal, followed by dissolving by warming to 60° C., cooling to room temperature, the resulting crude crystal was filtered and dried under vacuum to obtain 11.3 g (Yield: 75%) of diphenyl-4-phenylmethylphenylsulfonium trifluoromethanesulfonate as a pale brown crystal.
Reaction SMILES: CO[C:3]([C:5]1([C:9]#[N:10])[CH2:8][CH2:7][CH2:6]1)=[O:4].CO.[CH2:13]([NH2:16])[CH2:14][NH2:15].Cl>O>[NH2:15][CH2:14][CH2:13][NH:16][C:3]([C:5]1([C:9]#[N:10])[CH2:8][CH2:7][CH2:6]1)=[O:4]
Reactant: NCCN
Reactant: COC(=O)C1(C#N)CCC1
Agent: Cl
Solvent: O
Solvent: CO
Product: N#CC1(C(=O)NCCN)CCC1
Yield: 60.6 %

Procedure:
8.74 g (0.063 mol) of 4 and 50 mL of methanol were mixed, after which the mixture was added dropwisely into 3.77 g (4.25 mL) of ethylene diamine to form a reaction solution. The reaction solution was subjected to reaction at room temperature for 15 hours, followed by evaporation to obtain yellow oil. The yellow oil was stirred with water and was mixed with HCl to adjust pH to 2 to obtain a crude product. The crude product was purified by placing in a column (3×20 cm) filled with 100 mL of AG 50 W×8 cationic exchange resin and elutriating with water and HCl solution having gradient concentrations, collecting an eluent fraction of a gradient concentration from 0.5 N to 1.0 N, and followed by evaporating the eluent fraction to obtain 6.37 g (0.038 mol, 60.49%) of 5.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][C:12]3([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[C:11]2=[O:20])=[CH:6][CH:5]=1.O=C(Cl)[O:25][C:26](Cl)(Cl)Cl.[CH3:31][NH:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][CH:34]=1>>[CH3:31][N:32]([C:33]1[CH:34]=[CH:35][C:36]([C:39]([F:40])([F:41])[F:42])=[CH:37][CH:38]=1)[C:26]([N:17]1[CH2:16][CH2:15][C:12]2([C:11](=[O:20])[N:10]([C:7]3[CH:8]=[CH:9][C:4]([O:3][C:2]([F:1])([F:21])[F:22])=[CH:5][CH:6]=3)[CH2:14][CH2:13]2)[CH2:19][CH2:18]1)=[O:25]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: CNc1ccc(C(F)(F)F)cc1
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCNCC2
Product: CN(C(=O)N1CCC2(CC1)CCN(c1ccc(OC(F)(F)F)cc1)C2=O)c1ccc(C(F)(F)F)cc1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
This material was prepared in analogy to example 251 step B) from 2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one, diphosgene and methyl-(4-trifluoromethyl-phenyl)-amine. The reaction mixture was stirred for 1 h at room temperature, 2 h at 50° C. and 1 h at 80° C. before subjecting to work-up and purification. MS (ESI): 516.5 (MH+).
Reaction SMILES: Br[C:2]1[CH:18]=[CH:17][C:5]([O:6][CH:7]([CH3:16])[CH2:8][NH:9][S:10]([CH:13]([CH3:15])[CH3:14])(=[O:12])=[O:11])=[CH:4][CH:3]=1.[S:19]1[CH:23]=[CH:22][CH:21]=[C:20]1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>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.COCCOC>[CH3:14][CH:13]([S:10]([NH:9][CH2:8][CH:7]([O:6][C:5]1[CH:17]=[CH:18][C:2]([C:2]2[CH:18]=[CH:17][C:5]([C:20]3[S:19][CH:23]=[CH:22][CH:21]=3)=[CH:4][CH:3]=2)=[CH:3][CH:4]=1)[CH3:16])(=[O:12])=[O:11])[CH3:15]
Reactant: CC(CNS(=O)(=O)C(C)C)Oc1ccc(Br)cc1
Reactant: OB(O)c1cccs1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(CNS(=O)(=O)C(C)C)Oc1ccc(-c2ccc(-c3cccs3)cc2)cc1
Yield: 88.6 %

Procedure:
The title compound (145 mg, 54%, yellow foam) was prepared from [2-(4-bromophenoxy)propyl][(methylethyl)sulfonyl]amine (265 mg, 0.788 mmol, prepared in example 1), 2-thienylboronic acid (125 mg, 0.946 mmol), dichlorobis(triphenylphosphine)palladium(II) (22 mg, 0.031 mmol), 2 M sodium carbonate (285 mg in 1.35 mL water), and 1,2-dimethoxyethane (5.25 mL) in a manner analogous to the procedure described in Example 8.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH3:12])[CH:3]=1.[NH2:13][CH2:14][C:15]([CH3:18])([OH:17])[CH3:16].CN1CCCC1=O.CCN(C(C)C)C(C)C>O>[CH3:12][O:11][C:4]1[CH:3]=[C:2]([NH:13][CH2:14][C:15]([CH3:18])([OH:17])[CH3:16])[CH:7]=[CH:6][C:5]=1[N+:8]([O-:10])=[O:9]
Reactant: CC(C)(O)CN
Reactant: COc1cc(F)ccc1[N+](=O)[O-]
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COc1cc(NCC(C)(C)O)ccc1[N+](=O)[O-]
Temperature: 80 °C

Procedure:
A 20 mL reaction vial equipped with a stir bar was charged with 4-fluoro-2-methoxy-1-nitrobenzene (0.5 g, 2.92 mmol), 1-amino-2-methylpropan-2-ol (0.313 g, 3.51 mmol), N-methyl-2-pyrrolidinone (7.3 mL) and Hunig's base (N,N-diisopropylethylamine) (0.76 g, 5.84 mmol). The vessel was sealed and the reaction was heated on a thermal block at 80° C. for 24 hours. The reaction was cooled to ambient temperature, treated with water (40 mL) and extracted with ethyl acetate (3×60 mL). The combined organic layers were washed with brine (2×25 mL), dried over Na2SO4, filtered, and concentrated. The concentrate was purified by flash chromatography on a 10 g silica gel column eluting with 1% methanol/CH2Cl2 to provide the title compound. 1H NMR (500 MHz, dimethylsulfoxide-d6) δ ppm 1.16 (s, 6H) 3.10 (d, 2H) 3.84 (s, 3H) 4.58 (s, 1H) 6.35 (m, 2H) 6.96 (m, 1H) 7.83 (d, 1H).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([NH2:6])=[O:5].C(Cl)(=O)[C:8](Cl)=[O:9].[CH3:13][N:14]1[CH:18]=[C:17]([C:19]2[CH:24]=[C:23]([O:25][C:26]3[CH:27]=[CH:28][C:29]([NH2:32])=[N:30][CH:31]=3)[CH:22]=[CH:21][N:20]=2)[CH:16]=[N:15]1.N1C=CC=CC=1>ClCCCl.C1COCC1>[CH3:1][O:2][CH2:3][C:4]([NH:6][C:8](=[O:9])[NH:32][C:29]1[CH:28]=[CH:27][C:26]([O:25][C:23]2[CH:22]=[CH:21][N:20]=[C:19]([C:17]3[CH:16]=[N:15][N:14]([CH3:13])[CH:18]=3)[CH:24]=2)=[CH:31][N:30]=1)=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COCC(N)=O
Reactant: Cn1cc(-c2cc(Oc3ccc(N)nc3)ccn2)cn1
Solvent: C1CCOC1
Solvent: ClCCCl
Solvent: c1ccncc1
Product: COCC(=O)NC(=O)Nc1ccc(Oc2ccnc(-c3cnn(C)c3)c2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.7 %

Procedure:
A suspension of Example B6 (0.060 g, 0.673 mmol) in DCE (4 mL) was treated with oxalyl chloride (0.059 mL, 0.673 mmol), stirred at RT for 1 h, then heated to 80° C. for 1.5 h. The mixture was cooled to RT, added drop-wise to a solution of Example A2 (0.15 g, 0.561 mmol) and pyridine (0.226 mL, 2.81 mmol) in THF (4 mL) and stirred at RT overnight. The mixture was treated with satd. Na2CO3, extracted with EtOAc (4×) and the combined organics were dried over Na2SO4 and concentrated to dryness. The material was treated with MeCN, sonicated and the resulting solid collected via filtration to afford 2-methoxy-N-((5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)carbamoyl)acetamide (186 mg, 87%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6): δ 10.78 (s, 1H), 10.71 (s, 1H), 8.37 (d, J=5.7 Hz, 1H), 8.27 (d, J=2.9 Hz, 1H), 8.26 (s, 1H), 8.03 (m, 1H), 7.96 (d, J=0.7 Hz, 1H), 7.74 (dd, J=9.0, 2.9 Hz, 1H), 7.23 (d, J=2.4 Hz, 1H), 6.71 (dd, J=5.7, 2.4 Hz, 1H), 4.11 (s, 2H), 3.84 (s, 3H), 3.34 (s, 3H); MS (ESI) m/z: 383.1 (M+H+).
Reaction SMILES: [CH3:1][C@@H:2]([NH2:10])[C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.O.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1.[C:37]([N:45]1[C@H:49]([C:50](O)=[O:51])[CH2:48][S@@:47](=[O:53])[CH2:46]1)(=[O:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>CN(C)C=O>[C:37]([N:45]1[C@H:49]([C:50](=[O:51])[NH:10][C@H:2]([CH3:1])[C:3]2[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=2)[CH2:48][S@@:47](=[O:53])[CH2:46]1)(=[O:44])[C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: C[C@@H](N)c1ccc(O)cc1
Reactant: O=C(O)[C@@H]1C[S@@](=O)CN1C(=O)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: C[C@@H](NC(=O)[C@@H]1C[S@@](=O)CN1C(=O)c1ccccc1)c1ccc(O)cc1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 74.6 %

Procedure:
9.47 g (69.11 mmole) of (R)-α-methyl-p-hydroxybenzylamine (prepared as described in Preparation 13), 10.58 g (69.11 mmole) of N-hydroxybenzotriazole monohydrate and 14.26 g (69.11 mmole) of dicyclohexylcarbodiimide were added in that order to a solution of 17.50 g (69.11 mmole) of (1R,4R)-3-benzoyl-1-oxo-thiazolidine-4-carboxylic acid (prepared as described in Preparation 10) in 100 ml of dimethylformamide cooled at 5° C., and the mixture was stirred at a temperature between 3° and 6° C. for 30 minutes and then at room temperature for a further 4 hours. At the end of this time, the reaction mixture was filtered and the insolubles were washed with 100 ml of hot dimethylformamide. The filtrate and the washings were combined and concentrated by evaporation under reduced pressure to leave crystals. These crystals were recrystallized from methanol to give 19.21 g (74.6%) of the title compound in the form of colorless needles melting at 233°-234° C.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](Cl)=[N:7][OH:8])=[CH:4][CH:3]=1.[CH3:12][CH2:13][O:14][C:15](/[CH:17]=[C:18](/N1CCCC1)\[CH3:19])=[O:16].C(N(CC)CC)C>C(O)C>[CH2:13]([O:14][C:15]([C:17]1[C:6]([C:5]2[CH:10]=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=2)=[N:7][O:8][C:18]=1[CH3:19])=[O:16])[CH3:12]
Reactant: CCOC(=O)/C=C(\C)N1CCCC1
Reactant: ON=C(Cl)c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)c1c(-c2ccc(Cl)cc2)noc1C
Yield: 69.8 %

Procedure:
To a suspension of 4-chloro-N-hydroxy-benzimidoyl chloride (1.11 g, 5.88 mmol) in dry ethanol (9 ml) was added a solution of ethyl (E)-3-(1-pyrrolidino)crotonate (1.08 g, 5.88 mmol) and triethylamine (492 μl, 3.53 mmol) in dry ethanol (9 ml) over a period of twenty minutes at room temperature. The suspension was stirred for eighteen hours before the mixture was concentrated and the residue partitioned between ethyl acetate and water. The organic layer was washed with 0.5 N HCl and brine, before it was dried and concentrated in vacuo. The residue was purified by flash column chromatography with a gradient of ethyl acetate and hexanes on silica gel (40 g) to give the title compound as a white solid (1.09 g): 1H NMR (CDCl3, 200 MHz): δ=7.57 (m, 2H), 7.42 (m, 2H), 4.25 (q, J=7.0 Hz, 2H), 2.74 (s, 3H), 1.27 (t, J=7.0 Hz, 3H); MS: (+) m/z 266.31 (M+1).
Reaction SMILES: [C:1]1([N:7]2[C:11]3[N:12]=[CH:13][C:14]4[C:19](=[O:20])[N:18]5[N:21]=[CH:22][CH:23]=[C:17]5[NH:16][C:15]=4[C:10]=3[CH:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:24][O:25][CH2:26][CH2:27]Br>>[C:1]1([N:7]2[C:11]3[N:12]=[CH:13][C:14]4[C:19](=[O:20])[N:18]5[N:21]=[CH:22][CH:23]=[C:17]5[N:16]([CH2:27][CH2:26][O:25][CH3:24])[C:15]=4[C:10]=3[CH:9]=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=c1c2cnc3c(cnn3-c3ccccc3)c2[nH]c2ccnn12
Reactant: COCCBr
Product: COCCn1c2c(cnc3c2cnn3-c2ccccc2)c(=O)n2nccc12

Procedure:
By treating the product of Example 23 with methoxyethyl bromide instead of 1-bromo-3-methylbutane according to the procedure of Example 2, 3-phenyl-3,11-dihydro-11-methoxyethyl-6H-pyrazolo[1,5-a]pyrazolo[4',3':5,6]pyrido[4,3-d]pyrimidin-6-one is obtained.