Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([O:15][C:16]2[CH:21]=[C:20]([N:22]3[C:27](=[O:28])[CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[N:24]([CH3:33])[C:23]3=[O:34])[C:19]([F:35])=[CH:18][C:17]=2[Cl:36])[N:10]=1)C1C=CC=CC=1.O>FC(F)(F)C(O)=O>[Cl:36][C:17]1[CH:18]=[C:19]([F:35])[C:20]([N:22]2[C:27](=[O:28])[CH:26]=[C:25]([C:29]([F:30])([F:31])[F:32])[N:24]([CH3:33])[C:23]2=[O:34])=[CH:21][C:16]=1[O:15][C:11]1[N:10]=[C:9]([OH:8])[CH:14]=[CH:13][N:12]=1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(Oc3nccc(OCc4ccccc4)n3)c(Cl)cc2F)c1=O
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(Oc3nccc(O)n3)c(Cl)cc2F)c1=O
Temperature: 25 °C
Yield: 36.2 %

Procedure:
A solution of 1 g of 4-benzyloxy-2-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}pyrimidine in trifluoroacetic acid was stirred for 2 hours at 70° C. This reaction solution was cooled to room temperature, then, poured into water, and filterated to obtain 0.3 g of 2-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-4-hydroxy-pyrimidine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:38]=[C:39]([O:43][CH3:44])[C:40]=1[O:41][CH3:42])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([C:27]([C:29]3[NH:33][C:32]4[CH:34]=[CH:35][CH:36]=[CH:37][C:31]=4[N:30]=3)=[O:28])[CH2:23][CH2:22]2)([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:9]1)=[O:7].[CH3:45][C:46]([CH3:53])=[CH:47][CH2:48][O:49][CH2:50][CH2:51]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.CO.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:38]=[C:39]([O:43][CH3:44])[C:40]=1[O:41][CH3:42])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([C:27]([C:29]3[N:30]([CH2:51][CH2:50][O:49][CH2:48][CH:47]=[C:46]([CH3:53])[CH3:45])[C:31]4[CH:37]=[CH:36][CH:35]=[CH:34][C:32]=4[N:33]=3)=[O:28])[CH2:23][CH2:22]2)([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:9]1)=[O:7]
Reactant: CC(C)=CCOCCO
Reactant: COc1cc(C(=O)N2CCC(CCN3CCC(C(=O)c4nc5ccccc5[nH]4)CC3)(c3ccccc3)C2)cc(OC)c1OC
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1cc(C(=O)N2CCC(CCN3CCC(C(=O)c4nc5ccccc5n4CCOCC=C(C)C)CC3)(c3ccccc3)C2)cc(OC)c1OC
Reaction time: 18 h

Procedure:
Combine 1-(3,4,5-trimethoxy-benzoyl)-3-[2-[4-[1H-benzoimidazole-2-carbonyl]-piperidin-1-yl]-ethyl]-3-phenyl-pyrrolidine (0.62 g, 1.0 mmol), and 2-(3,3-dimethylallyloxy)-ethanol (0.14 g, 1.0 mmol), triphenylphosphine (0.33 g, 1.27 mmol) in tetrahydrofuran (2 mL). Add dropwise diethyl azodicarboxylate ((0.2 mL, 1.27.mmol). After 18 hours, evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with 10% methanol/ethyl acetate to give the title compound: Rf=0.35 (silica gel, 10% methanol/ethyl acetate).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][N:5]2[C:10]=1[C:9](=[O:11])[N:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:7]([C@@H:18]([NH:20][C:21]1[C:22]3[C:29]([C:30]4[CH:38]=[C:37]([NH:39][C:40]([NH2:42])=[O:41])[CH:36]=[C:35]5[C:31]=4[CH:32]=[CH:33][NH:34]5)=[CH:28][N:27](COCC[Si](C)(C)C)[C:23]=3[N:24]=[CH:25][N:26]=1)[CH3:19])=[N:6]2.FC(F)(F)C(O)=O.N>>[CH3:1][C:2]1[CH:3]=[CH:4][N:5]2[C:10]=1[C:9](=[O:11])[N:8]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:7]([C@@H:18]([NH:20][C:21]1[C:22]3[C:29]([C:30]4[CH:38]=[C:37]([NH:39][C:40]([NH2:42])=[O:41])[CH:36]=[C:35]5[C:31]=4[CH:32]=[CH:33][NH:34]5)=[CH:28][NH:27][C:23]=3[N:24]=[CH:25][N:26]=1)[CH3:19])=[N:6]2
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3cc(NC(N)=O)cc5[nH]ccc35)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Agent: N
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4[nH]cc(-c5cc(NC(N)=O)cc6[nH]ccc56)c34)n(-c3ccccc3)c(=O)c12
Yield: 77.6 %

Procedure:
(S)-1-(4-(4-((1-(5-Methyl-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)ethyl)amino)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-1H-indol-6-yl)urea (40 mg, 0.06 mmol) was treated with trifluoroacetic acid (800 μl, 10.38 mmol) and a solution of ammonia (7N in methanol, 800 μl, 5.60 mmol) according to the method described in Example 27. The residue was purified using SP1® Purification System (0% to 20% dichloromethane methanol) to obtain 26 mg (80% yield) of the title compound.
Reaction SMILES: Cl.[O:2]=[C:3]1[CH:8]=[C:7]([CH2:9][N:10]2[C:14]([CH2:15][C:16]3[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=3)=[CH:13][N:12]=[CH:11]2)[CH:6]=[CH:5][N:4]1C1C=CC=CC=1.Cl[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[N:32]=1.IC1C=CC=CC=1>>[F:38][C:37]([F:40])([F:39])[C:33]1[N:32]=[C:31]([N:4]2[CH:5]=[CH:6][C:7]([CH2:9][N:10]3[C:14]([CH2:15][C:16]4[CH:17]=[CH:18][C:19]([C:20]#[N:21])=[CH:22][CH:23]=4)=[CH:13][N:12]=[CH:11]3)=[CH:8][C:3]2=[O:2])[CH:36]=[CH:35][CH:34]=1
Reactant: FC(F)(F)c1cccc(Cl)n1
Reactant: N#Cc1ccc(Cc2cncn2Cc2ccn(-c3ccccc3)c(=O)c2)cc1
Agent: Cl
Solvent: Ic1ccccc1
Product: N#Cc1ccc(Cc2cncn2Cc2ccn(-c3cccc(C(F)(F)F)n3)c(=O)c2)cc1

Procedure:
4-[3-(6-'Triflouromethyl-2-oxo-2H-[1,2']bipyridinyl-4-ylmethyl)-3H-imidazol-4-ylmethyl]-benzonitrile was prepared in a manner substantially similar to the procedure described above for 4-[3-(2-oxo-1-phenyl-1,2-dihydropyridin-4-ylmethyl)-3H-imidazol-4-ylmethyl]benzonitrile, hydrochloride, but substituting 2-chloro-6-trifluoromethylpyridine for the iodobenzene in Step 3.
Reaction SMILES: [NH2:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]([S:16]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[C@H:8]([CH2:12][CH:13]([CH3:15])[CH3:14])[C:9]([NH2:11])=[O:10])=[CH:4][CH:3]=1.CCN(CC)CC.[Br:35][CH2:36][C:37](Cl)=[O:38]>C(Cl)Cl>[Br:35][CH2:36][C:37]([NH:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]([S:16]([C:19]2[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=2)(=[O:18])=[O:17])[C@H:8]([CH2:12][CH:13]([CH3:15])[CH3:14])[C:9]([NH2:11])=[O:10])=[CH:4][CH:3]=1)=[O:38]
Reactant: O=C(Cl)CBr
Reactant: CC(C)C[C@H](C(N)=O)N(Cc1ccc(N)cc1)S(=O)(=O)c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)C[C@H](C(N)=O)N(Cc1ccc(NC(=O)CBr)cc1)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.7 %

Procedure:
To a solution of (2R)-2-[(4-aminobenzyl)-(4-chloro-benzenesulfonyl)amino]-4-methyl-pentanoic acid amide (248 mg, 0.56 mmol) and Et3N (176 mg, 1.74 mmol) in CH2Cl2 (3 mL) was added bromoacetylchloride (105 mg, 0.67 mmol). The reaction mixture was stirred overnight at rt. The reaction mixture was diluted with CH2Cl2 (5 mL), washed with 1 N HCl, brine, and dried through a cotton plug. The solvent was removed in vacuo. Purification by flash chromatography (SiO2, 10% acetone/CH2Cl2) afforded the title compound (124 mg) in 42% yield. MS (ESI), (M+H)+ 531.86, 1H NMR (CDCl3, 400 MHz) δ 8.78 (br s, NH), 7.95 (d, 2H, J=8.0), 7.82 (d, 2H, J=8.0), 7.42 (d, 2H, J=8.0), 7.33 (d, 2H, J=8.0), 6.20 (br s, 1H), 5.20 (br s, 1H), 4.30 (s, 2H), 4.22 (d, 1H, Jab=16), 4.14 (d, 1H, Jab=16), 3.25 (t, 1H, J=6.0), 1.95 (m, 1H), 1.60 (m, 2H), 0.98 (d, 3H, J=7.0), 0.94 (d, 3H, J=7.0)
Reaction SMILES: [OH:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[C:16]([CH3:17])[C:11]3=[N:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[CH2:20]([N:24]([CH2:29][CH2:30][CH2:31]Cl)[CH2:25][CH2:26][CH2:27][CH3:28])[CH2:21][CH2:22][CH3:23].[OH-].[K+]>CO>[CH2:25]([N:24]([CH2:29][CH2:30][CH2:31][O:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[C:16]([CH3:17])[C:11]3=[N:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1)[CH2:20][CH2:21][CH2:22][CH3:23])[CH2:26][CH2:27][CH3:28]
Reactant: Cc1cccn2c(C(=O)c3ccc(O)cc3)cnc12
Reactant: CCCCN(CCCC)CCCCl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CCCCN(CCCC)CCCOc1ccc(C(=O)c2cnc3c(C)cccn23)cc1

Procedure:
A mixture of 3-(4-hydroxybenzoyl)-8-methylimidazo[1,2-a]-pyridine (2.3 g, 9.6 mmol), dibutylaminopropyl chloride (6.8 g, 33 mmol) and potassium hydroxide (1.3 g, 23 mmol) in methanol (60 ml) was stirred at reflux for 96 hours. The mixture was concentrated and the resulting oil was flash chromatographed (silica gel, 2.5% methanol in diethyl ether) to give 1.3 g (31% yield) of the free base of the title compound. The HCl salt was prepared by dropwise addition of concentrated hydrochloric acid to a solution of the free base in methanol, concentrated and recrystallized from acetone-ether to give the HCl salt of the title compound as an off-white solid, mp 105° C. to 107° C. lR(KBr): 3440, 2640, 1645, 1605 cm-1. MS: 421 (M+). 1H NMR (CD3OD): δ9.66 (d, J=8 Hz, 1H), 8.74 (s, 1H), 8.00-7.61 (m, 4H), 7.20 (d, J=7.2 Hz, 2H), 4.29 (t, J=5 Hz, 2H), 3.41-3.15 (m, 6H), 2.75 (s, 3H), 2.31 (m, 2H), 1.80-1.42 (m, 8H), 1.02 (m, 6H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][NH2:8])([O-:3])=[O:2].[CH3:12][O:13][C:14](=[O:34])[C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:22]=[C:23](Cl)[C:24]3[CH:29]=[C:28]([N+:30]([O-:32])=[O:31])[S:27][C:25]=3[N:26]=2)=[CH:17][CH:16]=1>>[CH3:12][O:13][C:14](=[O:34])[C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:22]=[C:23]([NH:8][CH2:7][C:6]3[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)[C:24]3[CH:29]=[C:28]([N+:30]([O-:32])=[O:31])[S:27][C:25]=3[N:26]=2)=[CH:17][CH:16]=1
Reactant: NCc1cccc([N+](=O)[O-])c1
Reactant: COC(=O)c1ccc(-c2nc(Cl)c3cc([N+](=O)[O-])sc3n2)cc1
Product: COC(=O)c1ccc(-c2nc(NCc3cccc([N+](=O)[O-])c3)c3cc([N+](=O)[O-])sc3n2)cc1

Procedure:
The reaction procedure as above wherein 3-nitrobenzylamine is reacted with 4-(4-chloro-6-nitro-thieno-[2,3-d]-pyrimidin-2-yl)-benzoic acid methylester yields 4-[4-(3-nitrobenzylamino)-6-nitro-thieno-[2,3-d]-pyrimidin-2-yl]-benzoic acid methylester.
Reaction SMILES: C[N:2]([CH3:4])Cl.[Cl-].[Al+3].[Cl-].[Cl-].C(OCC)C.[CH2:14]=[CH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]C.Cl>C(Cl)Cl.O>[CH2:4]([NH2:2])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH3:14]
Reactant: C=CCCCCCCCCCCCC
Reactant: CN(C)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOCC
Solvent: ClCCl
Solvent: O
Product: CCCCCCCCCCCCCCN
Temperature: -35 °C
Reaction time: 0.08 h
Yield: 6.7 %

Procedure:
To a reactor of the type used in Example 1 is charged a cold solution of N,N-dimethylchloramine (0.87 moles), chilled to -77° C, in 300 ml of methylene chloride, followed by aluminum chloride (0.3 moles). The mixture is stirred for 5 minutes and then diethyl ether (0.4 moles) is added. After stirring for an additional 5 minutes, an additional portion of diethyl ether (0.4 moles) and 1-tetradecene (0.3 mol) is added to the stirred solution. The chilled reaction mixture is heated to -35° C and the reaction mixture stirred for one hour. At the end of this time an 80 g portion of hydrochloric acid (28% by weight) and 100-300 g of water are added to the reaction mixture and stirred for a half hour. The organic and water layers are then separated and the organic layer is stirred for an additional half-hour with 80 g of the same strength hydrochloric acid used previously. Again the organic and water layers are separated. The organic layer is filtered to yield 0.02 mol of tetradecyl amine salt. This represents a 6.68% yield based on the amount of 1-tetradecene charged.
Reaction SMILES: O.[OH-].[Li+].[C:4]([O:8][C:9]([NH:11][CH2:12][C:13]1([C:28]([O:30]CC)=[O:29])[CH2:18][CH2:17][N:16]([C:19]2[C:20]3[CH:27]=[CH:26][NH:25][C:21]=3[N:22]=[CH:23][N:24]=2)[CH2:15][CH2:14]1)=[O:10])([CH3:7])([CH3:6])[CH3:5]>O.C1COCC1.C(O)C.CCOC(C)=O>[C:4]([O:8][C:9]([NH:11][CH2:12][C:13]1([C:28]([OH:30])=[O:29])[CH2:14][CH2:15][N:16]([C:19]2[C:20]3[CH:27]=[CH:26][NH:25][C:21]=3[N:22]=[CH:23][N:24]=2)[CH2:17][CH2:18]1)=[O:10])([CH3:7])([CH3:5])[CH3:6]
Reactant: CCOC(=O)C1(CNC(=O)OC(C)(C)C)CCN(c2ncnc3[nH]ccc23)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(C)OC(=O)NCC1(C(=O)O)CCN(c2ncnc3[nH]ccc23)CC1
Temperature: 20 °C
Reaction time: 24 h
Yield: 63.1 %

Procedure:
Lithium hydroxide monohydrate (0.556 g, 13.26 mmol) was added to ethyl 4-((tert-butoxycarbonylamino)methyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxylate (Intermediate 11) (1.07 g, 2.65 mmol) in water (6.25 ml), THF (25 ml) and ethanol (25.00 ml). The resulting solution was stirred at 20° C. for 1 day. The reaction mixture was diluted with EtOAc (20 mL) and washed with water (20 mL). The aqueous was adjusted to pH5 with 1M citric acid solution then extracted with EtOAc (3×50 mL). The organic extracts were washed with saturated brine (25 mL) then dried over MgSO4, filtered and evaporated to afford desired product 4-((tert-butoxycarbonylamino)methyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid (0.628 g, 63.1%) as a white foam.
Reaction SMILES: C(Cl)Cl.[H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:10]([C:13]1([CH2:24][C@H:25]2[C@:27]([CH3:34])([CH2:28][CH2:29][CH:30]=[C:31]([CH3:33])[CH3:32])[O:26]2)[C:18]([O:19][CH3:20])=[CH:17][C:16](=O)[CH:15]=[C:14]1[O:22][CH3:23])[CH:11]=[CH2:12].CCCCCC>CCOC(C)=O>[CH2:10]([C:13]1([CH2:24][C@@H:25]2[O:26][C@@:27]2([CH3:34])[CH2:28][CH2:29][CH:30]=[C:31]([CH3:33])[CH3:32])[C:14]([O:22][CH3:23])=[CH:15][CH2:16][CH:17]=[C:18]1[O:19][CH3:20])[CH:11]=[CH2:12]
Reactant: C=CCC1(C[C@@H]2O[C@@]2(C)CCC=C(C)C)C(OC)=CC(=O)C=C1OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: C=CCC1(C[C@@H]2O[C@@]2(C)CCC=C(C)C)C(OC)=CCC=C1OC
Temperature: -78 °C
Reaction time: 0.42 h
Yield: 45.2 %

Procedure:
A DCM (0.5 mL) slurry of lithium aluminum hydride (23 mg, 0.61 mmol, 2 equiv.) was cooled to −78° C. in a 10-mL recovery flask, and a DCM (0.5 mL) solution of 7 (106 mg, 0.31 mmol, 1 equiv.) was added via cannula, followed by a DCM (0.5 mL) rinse. The slurry was stirred at −78° C. for 25 min, Et2O (0.5 mL), and the reaction was warmed to 0° C. After stirring for 75 min, the reaction was quenched sequentially with H2O (23 μL), 15 wt % NaOHaq (23 μL), and H2O (63 μL). The reaction was then warmed to room temperature, diluted with H2O, and extracted four times with EtOAc. The organic extracts were combined, washed with H2O and brine, dried over Na2SO4, filtered, and concentrated in vacuo to a brown residue. Flash column chromatography (30 mL SiO2, 19:1 hexane:EtOAc) afforded 45 mg (0.14 mmol, 44% yield) of 8 as a clear, colorless oil. TLC Rf 0.74 (1:1 hexane:EtOAc). 1H NMR (600 MHz; CDCl3): δ 5.57 (ddt, J=17.1, 10.1, 7.1 Hz, 1H), 5.05 (t, J=7.2 Hz, 1H), 4.94-4.88 (m, 2H), 4.80 (t, J=3.5 Hz, 1H), 4.76 (t, J=3.5 Hz, 1H), 3.54 (s, 3H), 3.49 (s, 3H), 2.78 (app q, J=3.5 Hz, 2H), 2.64 (dd, J=8.0, 4.0 Hz, 1H), 2.39 (qd, J=12.7, 7.2 Hz, 2H), 2.03 (dd, J=13.7, 4.0 Hz, 1H), 1.97 (q, J=7.9 Hz, 2H), 1.76 (dd, J=13.7, 8.0 Hz, 1H), 1.67 (s, 3H), 1.58 (s, 3H), 1.57-1.54 (m, 1H), 1.29 (dt, J=13.5, 8.4 Hz, 1H), 1.18 (s, 3H). 13C NMR (125 MHz; CDCl3): δ 153.80, 153.73, 135.3, 131.8, 124.2, 116.1, 93.23, 93.17, 61.25, 61.09, 54.6, 54.2, 46.2, 40.2, 39.4, 34.2, 25.8, 24.2, 24.0, 17.8, 16.8. IR (NaCl, thin film, cm−1) 2932, 2831, 1694, 1659, 1451, 1381, 1223, 1206, 1139, 908. HRMS-ESI (m/z): [M+H]+ calculated for C21H32O3, 333.2424. found, 333.2425.
Reaction SMILES: CS(C)=O.[CH3:5][C:6]([O:9][C:10]([NH:12][CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)=[O:11])([CH3:8])[CH3:7].[F:19][C:20]1[CH:25]=[C:24](F)[CH:23]=[C:22]([F:27])[CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>O>[F:19][C:20]1[CH:25]=[C:24]([N:16]2[CH2:15][CH2:14][CH:13]([NH:12][C:10](=[O:11])[O:9][C:6]([CH3:5])([CH3:7])[CH3:8])[CH2:18][CH2:17]2)[CH:23]=[C:22]([F:27])[CH:21]=1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: Fc1cc(F)cc(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)NC1CCN(c2cc(F)cc(F)c2)CC1
Temperature: 100 °C
Yield: 73 %

Procedure:
A DMSO (25 mL, 0.1M) solution containing 4-N—BOC-aminopiperidine (500 mg, 2.5 mmol, 1.0 eq), 1,3,5-trifluorobenzene (256 μL, 2.5 mmol, 1.0 eq), and potassium carbonate (691 mg, 5.0 mmol, 2.0 eq) was heated to 100° C. for 18 h. The resulting mixture was cooled to RT, poured in H2O (ca 50 mL), and extracted (3×) with EtOAc. The combined extracts were washed (2×) with H2O, dried over MgSO4, and concentrated in vocuo. The resulting solid was purified via flash chromatography using 1:1 Hexane/EtOAc as the mobile phase. Isolated 572 mg (1.83 mmol, 73% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](Br)=[CH:5][C:4]=1[C:10]([CH3:14])([CH3:13])[CH:11]=[O:12].[CH3:15][N:16](C)C=O.C(OCC)C>O.Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:15]#[N:16])=[CH:5][C:4]=1[C:10]([CH3:14])([CH3:13])[CH:11]=[O:12]
Reactant: CN(C)C=O
Reactant: COc1ccc(Br)cc1C(C)(C)C=O
Agent: Cl
Solvent: O
Solvent: CCOCC
Product: COc1ccc(C#N)cc1C(C)(C)C=O
Reaction time: 3 h

Procedure:
2-(2-Methoxy-5-bromophenyl)-2-methyl-1-propanal (9.5 g), prepared as in Example 5(d), cuprous cyanide (4.0 g) and dimethylformamide (20 ml) were heated under reflux with stirring for 3 hours. A solution of ferric chloride (7.3 g) in water (25 ml) and hydrochloric acid (3.5 ml conc) was added to the cooled reaction mixture which was then heated at 60°-70° C. for 5 minutes. Isolation of the product through diethyl ether yielded, after recrystallisation from ethanol, 3 g of pure product, mp 115°-117° C.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]([OH:26])([CH3:25])[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[CH:12]=[CH:13][C:14]3[CH:19]=[N:18][C:17](S(C)(=O)=O)=[N:16][C:15]=3[N:24]=2)[CH:8]=[N:7]1.[CH3:27][N:28]1[C:32]([C:33]2[CH:38]=[CH:37][C:36]([NH:39]C=O)=[C:35]([O:42][CH3:43])[CH:34]=2)=[CH:31][N:30]=[C:29]1[CH3:44]>CN1C(=O)CCC1.C1COCC1>[CH3:27][N:28]1[C:32]([C:33]2[CH:38]=[CH:37][C:36]([NH:39][C:17]3[N:18]=[CH:19][C:14]4[CH:13]=[CH:12][C:11]([C:9]5[CH:8]=[N:7][N:6]([CH2:5][C:4]([CH3:25])([OH:26])[CH3:3])[CH:10]=5)=[N:24][C:15]=4[N:16]=3)=[C:35]([O:42][CH3:43])[CH:34]=2)=[CH:31][N:30]=[C:29]1[CH3:44]
Reactant: COc1cc(-c2cnc(C)n2C)ccc1NC=O
Reactant: CC(C)(O)Cn1cc(-c2ccc3cnc(S(C)(=O)=O)nc3n2)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Product: COc1cc(-c2cnc(C)n2C)ccc1Nc1ncc2ccc(-c3cnn(CC(C)(C)O)c3)nc2n1
Temperature: 160 °C
Reaction time: 2 h
Yield: 13.8 %

Procedure:
A suspension of NaH (4.3 mg), 2-methyl-1-(4-(2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7-yl)-1H-pyrazol-1-yl)propan-2-ol (Preparation 69, 15.5 mg, 0.045 mmol), N-(4-(1,2-dimethyl-1H-imidazol-5-yl)-2-methoxyphenyl)formamide (Preparation 74, 16.4 mg, 0.067 mmol) in NMP/THF (1/3 mL) was stirred at 160° C. under microwave irradiation for 2 hours. The reaction mixture was filtered, diluted with NaCl solution and extracted with EtOAc. The EtOAc portion was purified by elution through an SCX-2 column using 2M NH3/MeOH to give the title compound as yellow oil (3 mg, 14%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([CH:11]=O)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4].C([O-])(=O)C.[Na+].Cl.[CH2:19]([O:26][NH2:27])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CO>[CH3:1][O:2][C:3]([C:5]1([CH:11]=[N:27][O:26][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]1)=[O:4]
Reactant: COC(=O)C1(C=O)CCCCC1
Reactant: NOCc1ccccc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)C1(C=NOCc2ccccc2)CCCCC1
Yield: 87.9 %

Procedure:
A mixture of 1-formyl-cyclohexanecarboxylic acid methyl ester (1.23 g, 7.23 mmol), sodium acetate (1.0 g, 14.5 mmol) and O-benzylhydroxylamine hydrochloride (2.3 g, 14.5 mmol) were stirred in methanol (40 mL) for 18 h. The methanol was removed in vacuo and the residue partitioned between water and EtOAc. The aqueous phase was extracted with EtOAc (50 mL×2). The combined organic extracts were dried (MgSO4) and were evaporated in vacuo to provide the title compound as a clear colorless liquid (1.75 g, 88%). MH+276.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].C([O-])([O-])=O.[Na+].[Na+].O[CH2:23][CH:24]1[O:28][C:27](=[O:29])[C:26]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:25]1>C(Cl)Cl>[F:1][C:2]([F:15])([F:14])[S:3]([O:6][CH2:23][CH:24]1[O:28][C:27](=[O:29])[C:26]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:25]1)(=[O:5])=[O:4]
Reactant: O=C1OC(CO)CC1(c1ccccc1)c1ccccc1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: O=C1OC(COS(=O)(=O)C(F)(F)F)CC1(c1ccccc1)c1ccccc1
Temperature: -40 °C
Reaction time: 2 h

Procedure:
Trifluoromethanesulfonic anhydride, 5.5 mL (32.5 mmol.), was added to 14 mL dry methylene chloride under argon at room temperature. The solution was cooled to -40° C. and 2.3 g (22 mmol.) of finely powdered, oven dried Na2CO3 was added. To the stirred mixture 6.7 g (25 mmol.) of 5-(hydroxymethyl)-4,5-dihydro-3,3-diphenyl-2(3H)furanone in 15 mL of methylene chloride was added dropwise, stirring 2 hours at -40° C. before warming to 0° C. for 0.5 hours. The reaction was quenched at 0° C. by adding 10 mL of water dropwise with vigorous stirring. The layers were separated, the organics washed with brine, dried (MgSO4), and evaporated at reduced pressure to a solid. This material was used as received and usually contained 5 to 15% of unreacted alcohol. 1H NMR (CDCl3)δ 2.77-2.83 (m, 1H), 3.05-3.14 (m, 1H), 4.51-4.71 (m, 2H), 4.7-4.75 (m, 1H), 7.25-7.45 (m, 10H).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][N:7]1[C:12]2=[CH:13][NH:14][C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:11]2[C:10](=[O:22])[N:9]([CH3:23])[C:8]1=[O:24].CN([CH:28]=[O:29])C>>[CH3:6][N:7]1[C:12]2=[C:13]([CH:28]=[O:29])[NH:14][C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:11]2[C:10](=[O:22])[N:9]([CH3:23])[C:8]1=[O:24]
Reactant: Cn1c(=O)c2c(-c3ccccc3)[nH]cc2n(C)c1=O
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: Cn1c(=O)c2c(-c3ccccc3)[nH]c(C=O)c2n(C)c1=O
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Phosphorous oxychloride (1.081 mL, 11.60 mmol) was added slowly to a solution of 1,3-dimethyl-5-phenyl-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione (2.96 g, 11.60 mmol) in DMF (40 mL) at 0° C. The mixture was stirred at 0° C. for 15 mins. The reaction was quenched with 2M HCl(aq), diluted with EtOAc, and the mixture stirred overnight. The mixture was then extracted with EtOAc (3×) and the combined organic phases washed with brine, dried over sodium sulphate and evaporated under vacuum. The residue was triturated with diethyl ether/hexane to afford the title compound.