Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1N=C(C2C=CC=CC=2C(N2CC3CN(C(OC(C)(C)C)=O)CC3C2)=O)NC=1.[CH3:29][C:30]1[CH:35]=[C:34]([CH3:36])[N:33]=[C:32]([N:37]2[CH2:44][CH:43]3[CH:39]([CH2:40][NH:41][CH2:42]3)[CH2:38]2)[N:31]=1.C(OC(N1CC2C(CNC2)C1)=O)(C)(C)C.[CH3:60][C:61]1[N:65]=[C:64]([C:66]2[CH:74]=[CH:73][CH:72]=[CH:71][C:67]=2[C:68](O)=[O:69])[O:63][N:62]=1.N1N=C(C2C=CC=CC=2C(O)=O)NC=1>>[CH3:29][C:30]1[CH:35]=[C:34]([CH3:36])[N:33]=[C:32]([N:37]2[CH2:44][CH:43]3[CH:39]([CH2:40][N:41]([C:68]([C:67]4[CH:71]=[CH:72][CH:73]=[CH:74][C:66]=4[C:64]4[O:63][N:62]=[C:61]([CH3:60])[N:65]=4)=[O:69])[CH2:42]3)[CH2:38]2)[N:31]=1
Reactant: Cc1noc(-c2ccccc2C(=O)O)n1
Reactant: Cc1cc(C)nc(N2CC3CNCC3C2)n1
Agent: CC(C)(C)OC(=O)N1CC2CN(C(=O)c3ccccc3-c3nnc[nH]3)CC2C1
Agent: CC(C)(C)OC(=O)N1CC2CNCC2C1
Agent: O=C(O)c1ccccc1-c1nnc[nH]1
Product: Cc1cc(C)nc(N2CC3CN(C(=O)c4ccccc4-c4nc(C)no4)CC3C2)n1

Procedure:
The title compound was prepared in a manner analogous to Intermediate 59 substituting Intermediate 23 for Intermediate 15 and 2-(3-methyl-1,2,4-oxadiazol-5-yl)benzoic acid for 2-(4H-[1,2,4]triazol-3-yl)benzoic acid. MS (ESI) mass calculated for C22H24N6O2, 404.48; m/z found, 405.2. 1H NMR (500 MHz, CDCl3): 8.10 (dd, J=7.9 Hz, 0.9 Hz, 1H), 7.62 (td, J=7.6 Hz, 1.2 Hz, 1H), 7.53 (td, J=7.7 Hz, 1.3 Hz, 1H), 7.42 (dd, J=7.6 Hz, 1.0 Hz, 1H), 6.28 (s, 1H), 3.99-3.88 (m, 2H), 3.80-3.75 (m, 1H), 3.74-3.65 (m, 2H), 3.53-3.48 (m, 1H), 3.46-3.40 (m, 1H), 3.12-3.04 (m, 2H), 3.01-2.93 (m, 1H), 2.42 (s, 3H), 2.28 (s, 6H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(N(CC)CC)C.Cl.[F:15][C:16]([F:50])([F:49])[C:17]1[CH:22]=[C:21]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=2)[N:20]=[C:19]([C:33]2[CH:38]=[CH:37][N:36]=[C:35]([C:39]3[CH:40]=[C:41]([S:45](Cl)(=[O:47])=[O:46])[CH:42]=[CH:43][CH:44]=3)[CH:34]=2)[N:18]=1>C1COCC1>[F:50][C:16]([F:15])([F:49])[C:17]1[CH:22]=[C:21]([C:23]2[CH:24]=[CH:25][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:27][CH:28]=2)[N:20]=[C:19]([C:33]2[CH:38]=[CH:37][N:36]=[C:35]([C:39]3[CH:40]=[C:41]([S:45]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)(=[O:47])=[O:46])[CH:42]=[CH:43][CH:44]=3)[CH:34]=2)[N:18]=1
Reactant: C1COCCN1
Reactant: O=S(=O)(Cl)c1cccc(-c2cc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)ccn2)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=S(=O)(c1cccc(-c2cc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)ccn2)c1)N1CCOCC1
Temperature: 0 °C
Yield: 91.1 %

Procedure:
To a cooled (ice-water bath) and stirred mixture of morpholine (0.063 g, 0.72 mmol), triethylamine (0.07 ml, 0.5 mmol) and THF (1 ml) was added drop wise a solution of 3-{4-[4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidin-2-yl]-pyridin-2-yl}-benzenesulfonyl chloride hydrochloride (example I.1) (0.14 g, 0.24 mmol) in THF (2 ml). The mixture was allowed to stir at room temperature for 16 h. Purification of the reaction mixture by flash chromatography on silica gel (ethyl acetate/hexane) and crystallization (dichloromethane/hexane) yielded the title compound as a white solid (0.13 g, 91%). MS (ISP) 595.2 [(M+H)+]; mp 202° C.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[N:6]=1.[F:11][C:12]1[CH:17]=[C:16]([OH:18])[CH:15]=[C:14]([F:19])[C:13]=1B(O)O.[F-].[K+]>O1CCCC1.O.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[F:11][C:12]1[CH:17]=[C:16]([OH:18])[CH:15]=[C:14]([F:19])[C:13]=1[C:2]1[S:3][CH:4]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[N:6]=1
Reactant: OB(O)c1c(F)cc(O)cc1F
Reactant: COC(=O)c1csc(Br)n1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [F-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1csc(-c2c(F)cc(O)cc2F)n1
Temperature: 120 °C
Yield: 41.1 %

Procedure:
To a suspension of methyl 2-bromothiazole-4-carboxylate (500 mg, 2.16 mmol), 2,6-difluoro-4-hydroxyphenylboronic acid (2 equiv., 767 mg) and potassium fluoride (3.3 equiv., 414 mg) in tetrahydrofuran (10 mL) and water (1 mL) was added bis(tri-tert-butylphosphine)palladium(0) (0.1 equiv., 110 mg) and the mixture was heated to 120° C. for 15 min in the microwave reactor. After in vacuo concentration, the reaction mixture was purified by CombiFlash (0 to 100% EtOAc in heptane) to provide 241 mg of the title compound as a ˜1:1 mixture with methyl 2-bromothiazole-4-carboxylate, which was used directly without further purification.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][O:5][CH2:6][CH:7]=[CH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.P(Br)(Br)[Br:16].[Cl-].[Na+]>N1C=CC=CC=1>[Br:16][CH2:2][CH2:3][CH2:4][O:5][CH2:6][CH:7]=[CH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: BrP(Br)Br
Reactant: OCCCOCC=Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: c1ccncc1
Product: BrCCCOCC=Cc1ccccc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
192 g (1.2 mol) of the obtained 3-hydroxypropoxy methylstyrene and 55 ml of dehydrated and purified pyridine were charged into a 300 ml four-necked flask, and 108 g (0.4 mol) of phosphorus tribromide was dropwise added thereto while maintaining the mixture at -10° C. with dry ice ethanol. After completion of the dropwise addition, the mixture was stirred at room temperature for 15 hours. The reaction mixture was poured into 250 ml of an aqueous sodium chloride solution (20 wt %) and extracted with toluene. The organic layer was washed with water and a 8% sodium hydrogencarbonate aqueous solution and dried over magnesium sulfate. Then, toluene was distilled off under reduced pressure. The solution thereby obtained was subjected to vacuum distillation (b.p. 90° to 91° C./54 Pa) in the presence of DPPH to obtain 3-bromopropoxymethylstyrene as the desired product. The yield was 35%. The obtained solution was analyzed by 1H-NMR and IR spectrum.
Reaction SMILES: [C:1](OCC)(OCC)(OCC)[CH2:2][CH2:3][CH3:4].[CH3:14][S:15]([CH2:18][CH2:19][O:20][CH2:21][CH2:22][NH:23][C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[N:27]=[CH:26][C:25]=1[NH2:34])(=[O:17])=[O:16].Cl.N1C=CC=CC=1>C(#N)C>[CH3:14][S:15]([CH2:18][CH2:19][O:20][CH2:21][CH2:22][N:23]1[C:24]2[C:33]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[N:27]=[CH:26][C:25]=2[N:34]=[C:1]1[CH2:2][CH2:3][CH3:4])(=[O:17])=[O:16]
Reactant: CCCC(OCC)(OCC)OCC
Reactant: CS(=O)(=O)CCOCCNc1c(N)cnc2ccccc12
Agent: Cl
Solvent: c1ccncc1
Solvent: CC#N
Product: CCCc1nc2cnc3ccccc3c2n1CCOCCS(C)(=O)=O
Reaction time: 0.67 h
Yield: 85.3 %

Procedure:
Triethyl orthobutyrate (2.2 mL, 14 mmol) was added to a stirred solution of N4-{2-[2-(methylsulfonyl)ethoxy]ethyl}quinoline-3,4-diamine (3.6 g, 12 mmol) in acetonitrile (60 mL). Pyridine hydrochloride (0.3 g) was added and the reaction mixture was heated to reflux with the volatiles being collected in a Dean Stark trap. After 40 minutes analysis by TLC indicated that the starting material was consumed. The reaction mixture was concentrated under reduced pressure to provide 3.7 g of 1-{2-[2-(methylsulfonyl)ethoxy]ethyl}-2-propyl-1H-imidazo[4,5-c]quinoline as a white solid.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=1)[N:7]=[C:6]2[CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.[N+]([NH:31][C:32](N)=[O:33])([O-])=O.O>CN(C=O)C>[F:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]1[CH:13]=[CH:14][C:15]([C:18]([F:19])([F:20])[F:21])=[CH:16][CH:17]=1)[N:7]=[C:6]2[CH:22]1[CH2:27][CH2:26][N:25]([C:32]([NH2:31])=[O:33])[CH2:24][CH2:23]1
Reactant: Fc1ccc2c(c1)c(C1CCNCC1)nn2-c1ccc(C(F)(F)F)cc1
Reactant: NC(=O)N[N+](=O)[O-]
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)N1CCC(c2nn(-c3ccc(C(F)(F)F)cc3)c3ccc(F)cc23)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 39.8 %

Procedure:
To a solution of 5-fluoro-1-[4-(trifluoromethyl)phenyl]-3-(4-piperidinyl)-1H-indazole free base of Example 124 (6.3 g, 0.017 moles) in DMF (100 ml) was added nitrourea (2.2 g, 0.021 moles). The mixture was warmed on a steam bath until gas began to evolve and was then stirred at ambient temperature for 4 hours. The mixture was then poured into H2O and the product extracted (dichloromethane), dried (MgSO4), and concentrated to yield 6.9 of an oil. The oil was triturated with water to produce 6.9 of a solid. The product was purified by high pressure liquid chromatography (silica gel 100% ethyl acetate) followed by recrystallization from isopropyl alcohol to yield 2.75 g (39%) of 4-[5-fluoro-1-[4-(trifluoromethyl)phenyl]-1H-indazol-3-yl]piperidine-1-carboxamide, mp 172°-174°.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[C:24]1[CH:25]=[CH:26][C:27]([Cl:32])=[C:28]([CH:31]=1)[CH:29]=O)(=[O:3])[CH3:2].[CH2:33]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH2:35][NH:34]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>ClCCCl.C(O)(=O)C>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[C:24]1[CH:25]=[CH:26][C:27]([Cl:32])=[C:28]([CH2:29][N:34]2[CH2:35][C:36]3[C:41](=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH2:33]2)[CH:31]=1)(=[O:3])[CH3:2]
Reactant: c1ccc2c(c1)CNC2
Reactant: CC(=O)OC[C@H]1O[C@@H](c2ccc(Cl)c(C=O)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CC(=O)OC[C@H]1O[C@@H](c2ccc(Cl)c(CN3Cc4ccccc4C3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 59.1 %

Procedure:
To a mixed solution of the above 5-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-2-chlorobenzaldehyde 83 (325 mg), 2,3-dihydro-1H-isoindole (98 mg), acetic acid (82 mg) in 1,2-dichloroethane (5 ml) was added sodium triacetoxyborohydride (219 mg). The mixture was stirred at room temperature for 3 hours, and cooled to 0° C. A saturated aqueous sodium hydrogen carbonate solution was added thereto to basify the reaction mixture. The mixture was extracted with ethyl acetate, and the extract was washed with brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:0-1:1) to give 1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-4-chloro-3-(1,3-dihydro-isoindol-2-ylmethyl)benzene 84 (234 mg) as a colorless solid. APCI-Mass m/Z 574/576 (M+H).
Reaction SMILES: [CH:1]1([OH:10])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[H-].[Na+].Cl[C:14]1[C:15]2[CH:24]=[CH:23][N:22]([C:25]3[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][C:26]=3[CH3:32])[C:16]=2[C:17](=[O:21])[N:18]([CH3:20])[N:19]=1>CN(C=O)C.O>[CH:1]1([O:10][C:14]2[C:15]3[CH:24]=[CH:23][N:22]([C:25]4[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][C:26]=4[CH3:32])[C:16]=3[C:17](=[O:21])[N:18]([CH3:20])[N:19]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: OC1CCc2ccccc21
Reactant: Cc1ccc(-n2ccc3c(Cl)nn(C)c(=O)c32)c(C)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(-n2ccc3c(OC4CCc5ccccc54)nn(C)c(=O)c32)c(C)c1
Temperature: 60 °C
Reaction time: 3 h
Yield: 48.4 %

Procedure:
To a solution of 1-indanol (60 mg, 0.45 mmol) in DMF (1 ml) was added sodium hydride (60% in oil, 18 mg, 0.45 mmol). The mixture was stirred for 10 min before addition of 4-chloro-1-(2,4-dimethylphenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-d]pyridazin-7-one (43.2 mg, 0.15 mmol). The mixture was stirred at 60° C. for 3 hours, then diluted with water (30 ml) and extracted with ethyl acetate (30 ml×2). The extract were combined, washed with water, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with hexane/ethyl acetate (10:1) to give 28 mg (48%) of the title compounds as an oil.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:13]=[CH:12][C:8]([C:9](O)=[O:10])=[CH:7][CH:6]=1)=[N+:2]=[N-:3].S(Cl)([Cl:16])=O>C(Cl)Cl.CN(C=O)C>[N:1]([CH2:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([Cl:16])=[O:10])=[CH:7][CH:6]=1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=NCc1ccc(C(=O)O)cc1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: [N-]=[N+]=NCc1ccc(C(=O)Cl)cc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of p-azidomethylbenzoic acid (1.063 g, 6.00 mmol) in CH2Cl2 (60 ml) at room temperature were added dropwise thionyl chloride (1 ml, excess) and DMF (5 drops). The mixture was stirred at room temperature for 2.5 h and evaporated, yielding 1.13 g of title compound as a light yellow oil: 1Hmr (CDCl3) δ: 4.48 (2H, s, --CH2N3), 7.38-7.52-8.07-8.22 ppm (4H, A2 'B2 ', aromatic Hs); ir (neat) νmax : 2090 (--N3) and 1750 cm-1 (br. --COCl). This material was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4](Cl)=[O:5].[Cl-:14].[Al+3].[Cl-].[Cl-]>ClC1C=CC=CC=1>[Cl:1][C:2]1[CH:10]=[C:9]([Cl:14])[C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:3]=1)=[O:5]
Reactant: [Cl-]
Reactant: O=C(Cl)c1cc([N+](=O)[O-])ccc1Cl
Agent: [Al+3]
Solvent: Clc1ccccc1
Product: O=C(c1ccccc1)c1cc([N+](=O)[O-])c(Cl)cc1Cl

Procedure:
The reaction is carried out as in Example 10 a) by reacting chlorobenzene with 2-chloro-5-nitrobenzoyl chloride in the presence of aluminium chloride.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:12][C:11]2[C:6](=[C:7]([O:15][CH3:16])[CH:8]=[CH:9][C:10]=2[O:13][CH3:14])[CH2:5][C@H:4]1[OH:17].[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[OH-].[Na+]>O.C1C=CC=CC=1>[C:18]([NH:2][C@@H:3]1[CH2:12][C:11]2[C:6](=[C:7]([O:15][CH3:16])[CH:8]=[CH:9][C:10]=2[O:13][CH3:14])[CH2:5][C@H:4]1[OH:17])(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COc1ccc(OC)c2c1C[C@@H](N)[C@H](O)C2
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Solvent: O
Product: COc1ccc(OC)c2c1C[C@@H](O)[C@H](NC(=O)c1ccccc1)C2
Reaction time: 2 h
Yield: 84.3 %

Procedure:
A solution of 74.8 g of trans-3-amino-1,2,3,4-tetrahydro-5,8-dimethoxy-2- naphthalenol, hydrochloride in 2 liters of water is cooled in an ice bath and a solution of 40 g of benzoyl chloride in 300 ml of benzene is added. While stirring vigorously a solution of 23 g of sodium hydroxide in 100 ml of water is added dropwise at 0°-5° C over a period of 30 minutes. Semi-solid material begins adhering to the sides of the flask almost immediately. The mixture is stirred at 0°-5° C for an additional 2 hours. The solid is removed by filtration, washed with a small amount of water, then washed with chloroform and dried in vacuo over phosphorous pentoxide to give 78.5 g of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH3:9])[CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[C:17]1[C:22]([C:23]2[CH:28]=[CH:27][N:26]=[C:25]([NH:29][CH3:30])[N:24]=2)=[CH:21][CH:20]=[CH:19][N:18]=1>CN1C(=O)CCC1>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:17]2[C:22]([C:23]3[CH:28]=[CH:27][N:26]=[C:25]([NH:29][CH3:30])[N:24]=3)=[CH:21][CH:20]=[CH:19][N:18]=2)=[C:4]([CH3:9])[CH:3]=1
Reactant: CNc1nccc(-c2cccnc2Cl)n1
Reactant: Cc1cc(N)ccc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: CNc1nccc(-c2cccnc2Oc2ccc(N)cc2C)n1
Temperature: 100 °C

Procedure:
4-Amino-2-methyl-phenol (84 mg, 0.68 mmol), Cs2CO3 (665 mg, 2.04 mmol) and NMP (2.5 mL) were combined. The mixture was heated for 5 minutes at 100° C., cooled to RT and [4-(2-chloro-pyridin-3-yl)-pyrimidin-2-yl]-methyl-amine (150 mg, 0.68 mmol) was added. The mixture was heated in the microwave to 210° C. for 20 minutes, cooled, filtered through a plug of cotton and purified by reverse-phase HPLC (Gilson, acidic mobile phase) to yield the title compound. MS m/z=308 [M+1]+. Calc'd for C17H17N5O: 307.36.
Reaction SMILES: [C:1]([C:4]1[C:5]([O:27][CH2:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=2)=[C:6]([O:15][CH2:16][CH2:17][CH:18]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[CH3:19])[C:7]2[O:11][C:10]([CH3:12])=[N:9][C:8]=2[C:13]=1[CH3:14])(=[O:3])[CH3:2].[OH:36]O>C(O)(=O)C>[C:1]([C:4]1[C:5]([O:27][CH2:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N+:31]=2[O-:36])=[C:6]([O:15][CH2:16][CH2:17][CH:18]([C:20]2[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=2)[CH3:19])[C:7]2[O:11][C:10]([CH3:12])=[N:9][C:8]=2[C:13]=1[CH3:14])(=[O:3])[CH3:2]
Reactant: CC(=O)c1c(OCCc2ccccn2)c(OCCC(C)c2ccc(F)cc2)c2oc(C)nc2c1C
Reactant: OO
Solvent: CC(=O)O
Product: CC(=O)c1c(OCCc2cccc[n+]2[O-])c(OCCC(C)c2ccc(F)cc2)c2oc(C)nc2c1C
Temperature: 100 °C

Procedure:
To a stirred solution of Example 8) (24 mg, 0.05 mmol) in acetic acid (0.5 mL) at room temperature was added H2O2 (30% aq.) and the solution heated to 100° C. for 23 h. The acetic acid was removed in vacuo and the brown oil partitioned between NaHCO3 (20 mL) and EtOAc (20 mL). The aqueous phase (pH=10) was extracted with EtOAc (2×10 mL). The combined extracts were dried (MgSO4) and concentrated in vacuo. The product was purified by column chromatography (silica gel, hexane/Et2O (1:4) to Et2O to MeOH/DCM (1:19)). The title compound (10 mg, 41%) eluted from the column with MeOH/DCM (1:19) as a pale yellow oil. 1H NMR (CDCl3): δ 8.26-8.24 (m, 1H), 7.41-7.38 (m, 1H), 7.21 (m, 4H), 7.00-6.94 (m, 2H), 4.44 (t, J=6 Hz, 2H), 4.22-4.15 (m, 2H), 3.32 (t, J=6 Hz, 2H), 3.05-2.95 (m, 1H), 2.57 (s, 3H), 3.37 (s, 3H), 2.34 (s, 3H), 2.10-1.90 (m, 2H), 1.30 (d, J=6.9 Hz, 3H), ESIMS m/z [M+H]+ 493.2.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5](I)=[CH:4][N:3]=1.CC1(C)C(C)(C)OB([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[S:24][CH3:25])O1>C1COCC1.O.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>[Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[S:24][CH3:25])=[CH:4][N:3]=1
Reactant: CSc1ccccc1B1OC(C)(C)C(C)(C)O1
Reactant: Clc1ncc(I)c(Cl)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CSc1ccccc1-c1cnc(Cl)nc1Cl
Temperature: 70 °C
Yield: 71.9 %

Procedure:
A solution of 2,4-dichloro-5-iodopyrimidine (50.15 g, 182 mmol), 4,4,5,5-tetramethyl-2-(2-(methylthio)phenyl)-1,3,2-dioxaborolane (47.9 g, 192 mmol) in THF (1368 ml) and water (456 ml) was degassed with nitrogen. Pd(PPh3)4 (10.54 g, 9.12 mmol) was added and degassing continued for several minutes. The mixture was then heated to reflux at 70° C. overnight. After 24 hrs the reaction was cooled to room temperature, the aqueous layer was removed, and the organic layer was washed with brine. The aqueous layer was extracted once with EtOAc, and the combined organic layers were dried over sodium sulfate, filtered and concentrated. The crude material was purified by column chromatography in 10-15% DCM 1-2% EtOAc/heptanes (v/v/v). The product was further purified by dissolving in EtOH and precipitating with heptanes, yielding 35.5 g (72% yield) of 2,4-dichloro-5-(2-(methylthio)phenyl)pyrimidine as white solids.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][C:7]2=[O:12].[Cl:13]N1C(=O)CCC1=O.O>CN(C)C=O>[NH2:1][C:2]1[CH:11]=[CH:10][C:9]([Cl:13])=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][C:7]2=[O:12]
Reactant: O=C1CCC(=O)N1Cl
Reactant: Nc1cccc2c1CCCC2=O
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ccc(Cl)c2c1CCCC2=O
Reaction time: 60 h

Procedure:
A solution of 5-amino-1-tetralone (Itoh, K. Chem. Pharm. Bull. (1984), 32, 130-151) (0.50 g, 3.1 mmol) in dimethylformamide (15 mL) was treated with N-chlorosuccinimide (0.49 g, 3.7 mmol), stirred for 60 hours, treated with water and extracted with ether (4×30 mL). The combined ether extracts were washed with brine, dried (Na2SO4) and concentrated. Purification of the residue on silica gel with ethyl acetate:hexanes 1:1 provided the desired product.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[N:9][CH:10]=1.C1C=C(Cl)C=C(C(OO)=[O:24])C=1>C(Cl)Cl>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[N+:9]([O-:24])[CH:10]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COCOc1ccc(CC(C)(C)C)nc1
Solvent: ClCCl
Product: COCOc1ccc(CC(C)(C)C)[n+]([O-])c1
Reaction time: 4 h
Yield: 99.6 %

Procedure:
5-(Methoxymethoxy)-2-neopentylpyridine (11.0 g, 52.6 mmol) was dissolved in CH2Cl2 (200 mL) to which mCPBA (18.1 g, 105 mmol) was added, and the mixture was stirred under N2 for about 4 h. The mixture was quenched with 1M NaOH (200 mL) and stirring was continued vigorously for 10 min. The mixture was extracted with CH2Cl2 (2×300 ML), the combined organic layers were washed with saturated NaCl, dried (Na2SO4), and evaporated to give 5-(methoxymethoxy)-2-neopentylpyridine-N-oxide (11.8 g, 99.7% yield) as a brown oil which was used without purification in the next step.
Reaction SMILES: C([Li])CCC.[CH2:6]([O:8][C:9]([N:11]1[CH2:16][CH2:15][C:14](=[O:17])[CH2:13][CH2:12]1)=[O:10])[CH3:7].Cl.[CH2:19]([O:26][C:27]1[CH:32]=[C:31]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:30]=[CH:29][C:28]=1Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O1CCCC1.CCCCCC>[CH2:6]([O:8][C:9]([N:11]1[CH2:12][CH2:13][C:14]([C:30]2[CH:29]=[CH:28][C:27]([O:26][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:32][C:31]=2[O:33][CH2:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)([OH:17])[CH2:15][CH2:16]1)=[O:10])[CH3:7]
Reactant: CCOC(=O)N1CCC(=O)CC1
Reactant: Brc1ccc(OCc2ccccc2)cc1OCc1ccccc1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC(=O)N1CCC(O)(c2ccc(OCc3ccccc3)cc2OCc2ccccc2)CC1
Temperature: -70 °C
Reaction time: 1 h

Procedure:
In a 500 ml three-necked flask, 20 g of 2,4-bis(benzyloxy)-1-bromobenzene are dissolved in 240 ml of tetrahydrofuran. The mixture is cooled to −70° C. and then 26 ml of 2.5M n-butyllithium in hexane are added. The reaction medium is stirred at −70° C. for 1 hour, and then 11.1 g of 4-oxo-piperidine-1-carboxylic acid ethyl ester are added dropwise. The reaction medium is stirred at −70° C. for 2 hours and then left at ambient temperature overnight. The reaction medium is poured into 100 ml of a 2M solution of hydrochloric acid and then extracted with 400 ml of ethyl acetate. The organic phases are combined, washed with 150 ml of water and then dried over magnesium sulphate and evaporated.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]([CH2:15][CH2:16][CH:17]=[C:18]([CH3:20])[CH3:19])=[CH:5][CH2:6][CH2:7][C:8](=[O:14])[CH2:9][C:10](OC)=[O:11].O.Cl.[CH:23]([OH:26])([CH3:25])[CH3:24]>>[CH3:3][C:4]([CH2:15][CH2:16][CH:17]=[C:18]([CH3:20])[CH3:19])=[CH:5][CH2:6][CH2:7][C:8](=[O:14])[CH2:9][C:10]([O:26][CH:23]([CH3:25])[CH3:24])=[O:11]
Reactant: CC(C)O
Reactant: COC(=O)CC(=O)CCC=C(C)CCC=C(C)C
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CC(C)=CCCC(C)=CCCC(=O)CC(=O)OC(C)C

Procedure:
A solution of 1.92 g of sodium hydride in 200 ml of isopropanol was added to a boiling mixture of 10 g of the product of Example 3 and 200 ml of isopropanol and the volume was held constant by replacing proportionately the distillate with isopropanol for 2 hours. After cooling, the mixture was poured into water and acidified with concentrated hydrochloric acid. The mixture was extracted with ethyl acetate and the extract was washed with water, dried over sodium sulfate and evaporated to dryness. The residue was chromatographed over silica and was eluted with a 9-1 petroleum ether (b.p.= 40°-75° C.)-ethyl ether mixture to obtain 7.05 g of isopropyl 7,11dimethyl-3-oxo-6,10-dodecadienoate in the form of an amber oil with a refractive index of nD24 = 1.467.