Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[C:5](=[O:17])[C:6]2[CH:11]=[CH:10][C:9]([C:12]3[O:16][CH:15]=[N:14][CH:13]=3)=[CH:8][CH:7]=2)[CH2:3][CH2:2]1.Cl[C:25]1[N:30]=[CH:29][C:28]([C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=2)=[CH:27][N:26]=1>>[Cl:37][C:34]1[CH:33]=[CH:32][C:31]([C:28]2[CH:29]=[N:30][C:25]([N:21]3[CH2:22][CH2:23][CH:18]([N:4]([CH:1]4[CH2:3][CH2:2]4)[C:5](=[O:17])[C:6]4[CH:7]=[CH:8][C:9]([C:12]5[O:16][CH:15]=[N:14][CH:13]=5)=[CH:10][CH:11]=4)[CH2:19][CH2:20]3)=[N:26][CH:27]=2)=[CH:36][CH:35]=1
Reactant: O=C(c1ccc(-c2cnco2)cc1)N(C1CCNCC1)C1CC1
Reactant: Clc1ccc(-c2cnc(Cl)nc2)cc1
Product: O=C(c1ccc(-c2cnco2)cc1)N(C1CC1)C1CCN(c2ncc(-c3ccc(Cl)cc3)cn2)CC1

Procedure:
The title compound is prepared from N-cyclopropyl-4-oxazol-5-yl-N-piperidin-4-yl-benzamide and 2-chloro-5-(4-chloro-phenyl)-pyrimidine following a procedure analogous to that described in Example 19. LC (method 9): tR=2.42 min; Mass spectrum (ESI+): m/z=500/502 (Cl) [M+H]+.
Reaction SMILES: [C:1]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[C:12](=[O:13])[C:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=3)=[N:10][C:9]3[CH:22]=[CH:23][CH:24]=[N:25][C:8]2=3)[CH:2]=1.C(N(CC)CC)C.[C:39](OC(=O)C)(=[O:41])[CH3:40].C(=O)(O)[O-].[Na+]>CN(C)C1C=CN=CC=1.O1CCOCC1.C(OCC)(=O)C>[C:39]([O:21][C:18]1[CH:17]=[CH:16][C:15]([CH2:14][C:11]2[C:12](=[O:13])[N:7]([C:3]3[CH:2]=[C:1]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH:6]=[CH:5][CH:4]=3)[C:8]3[N:25]=[CH:24][CH:23]=[CH:22][C:9]=3[N:10]=2)=[CH:20][CH:19]=1)(=[O:41])[CH3:40]
Reactant: O=c1c(Cc2ccc(O)cc2)nc2cccnc2n1-c1cccc(-c2ccccc2)c1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(=O)Oc1ccc(Cc2nc3cccnc3n(-c3cccc(-c4ccccc4)c3)c2=O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 4-(3-biphenylyl)-2-(4-hydroxybenzyl)-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (76 mg), triethylamine (0.05 ml) and 4-dimethylaminopyridine (3 mg) in 1,4-dioxane (2 ml) was added acetic anhydride (0.035 ml). The mixture was stirred at room temperature for 1 hour, then poured into a mixture of ethyl acetate and aqueous sodium bicarbonate. The organic phase was separated, washed with aqueous sodium bicarbonate and brine, dried over magnesium sulfate and concentrated to give 2-(4-acetoxybenzyl)-4-(3-biphenylyl)-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (58 mg).
Reaction SMILES: Br[C:2]1[CH:23]=[CH:22][C:5]2[C:6]3[N:7]=[C:8]([C:14]4[N:15]([CH:19]([CH3:21])[CH3:20])[N:16]=[CH:17][N:18]=4)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1.[CH3:24][C:25]([OH:42])([CH3:41])[CH2:26][N:27]1[CH:31]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:29]=[N:28]1>>[CH:19]([N:15]1[C:14]([C:8]2[S:9][C:10]3[CH2:11][CH2:12][O:13][C:4]4[CH:3]=[C:2]([C:30]5[CH:29]=[N:28][N:27]([CH2:26][C:25]([CH3:41])([OH:42])[CH3:24])[CH:31]=5)[CH:23]=[CH:22][C:5]=4[C:6]=3[N:7]=2)=[N:18][CH:17]=[N:16]1)([CH3:21])[CH3:20]
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(Br)ccc1-2
Reactant: CC(C)(O)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(-c3cnn(CC(C)(C)O)c3)ccc1-2

Procedure:
Similar to as described in General Procedure C, 8-Bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene 27 was reacted with 2-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-2-ol. Purification of the crude reaction mixture by reverse phase HPLC gave 367. LCMS: 451.1
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([NH:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34][O:35][CH2:36][CH2:37][O:38][CH2:39][CH2:40][O:41][CH2:42][CH2:43][O:44][CH2:45][CH2:46][O:47][CH2:48][CH2:49][C:50]([O:52][CH3:53])=[O:51])[CH:6]=[C:7]([CH2:9][OH:10])[CH:8]=1.IC.[C:56](=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[OH:1][CH2:2][C:3]1[CH:4]=[C:5]([N:11]([CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34][O:35][CH2:36][CH2:37][O:38][CH2:39][CH2:40][O:41][CH2:42][CH2:43][O:44][CH2:45][CH2:46][O:47][CH2:48][CH2:49][C:50]([O:52][CH3:53])=[O:51])[CH3:56])[CH:6]=[C:7]([CH2:9][OH:10])[CH:8]=1
Reactant: COC(=O)CCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCNc1cc(CO)cc(CO)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: COC(=O)CCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCN(C)c1cc(CO)cc(CO)c1
Temperature: 82 °C
Reaction time: 18 h
Yield: 91.1 %

Procedure:
To a stirred solution of methyl 1-(3,5-bis(hydroxymethyl)phenylamino)-3,6,9,12,15,18,21,24,27,30,33,36-dodecaoxanonatriacontan-39-oate (265c) (67 mg, 0.087 mmol) in anhydrous DMF (1.0 ml) was added iodomethane (7.06 μl, 0.113 mmol) and potassium carbonate (14.47 mg, 0.105 mmol). The reaction was stirred at 82° C. for 18 hours. The mixture was cooled to room temperature, diluted with water and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Purification by preparative TLC (10% MeOH/CH2Cl2) gave methyl 2-(3,5-bis(hydroxymethyl)phenyl)-5,8,11,14,17,20,23,26,29,32,35,38-dodecaoxa-2-azahentetracontan-41-oate (265d) (62 mg, 92%). 1H NMR (400 Hz, CDCl3): δ 6.65 (s, 3H), 4.59 (d, J=5.6 Hz, 4H), 3.74 (t, J=6.4 Hz, 2H), 3.67 (s, 3H), 3.61 (m, 46H), 3.54 (t, J=6.0 Hz, 2H) 2.98 (s, 3H), 2.59 (t, J=6.4 Hz, 2H), 2.55 (m, 2H); MS (m/z): found 820.5 (M+K)+.
Reaction SMILES: [OH:1][C@@H:2]1[C@@H:7]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4](C(OC(C)(C)C)=O)[CH2:3]1.[ClH:22]>CO.O1CCOCC1>[ClH:22].[OH:14][C:11]1[CH:12]=[CH:13][C:8]([C@H:7]2[CH2:6][CH2:5][NH:4][CH2:3][C@@H:2]2[OH:1])=[CH:9][CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](c2ccc(O)cc2)[C@@H](O)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Oc1ccc([C@H]2CCNC[C@@H]2O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (3R,4R)-tert-butyl 3-hydroxy-4-(4-hydroxyphenyl)piperidine-1-carboxylate (1.5 g, 5.1 mmol, E-2 from example 46 step E) in methanol (50 mL) under nitrogen was added 12.8 mL of 4 M HCl in dioxane and the reaction was stirred for 1 h at rt. The mixture was then evaporated under reduced pressure to dryness and the residue was washed twice with 20 mL of diethyl ether. The solid residue was dried under vacuum to give (3R,4R)-4-(4-hydroxyphenyl)-piperidin-3-ol hydrochloride E-2a (950 mg, 4.1 mmol). LCMS (method F) RT: 0.17 min, m/z 194 (M+H+). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.74-1.93 (m, 2H) 2.61-2.68 (m, 1H) 2.81-2.93 (m, 1H) 3.21-3.33 (m, 2H) 3.78-3.90 (m, 1H) 6.72 (d, J=8.53 Hz, 2H) 7.00 (d, J=8.53 Hz, 2H) 9.14-9.25 (m, 1H) 9.27-9.44 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](Cl)[CH:5]=[C:6]([CH:10]=1)[C:7](O)=[O:8].O.[ClH:13]>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:13])=[C:6]([CH2:7][OH:8])[CH:10]=1
Reactant: O=C(O)c1cc(Cl)cc(Br)c1
Reactant: Cl
Solvent: C1CCOC1
Solvent: O
Product: OCc1cc(Br)ccc1Cl
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
10 g (42.5 mmol) of 5-bromo-3-chlorobenzoic acid are dissolved in 135 ml of THF. At 0° C., 4.2 g (55.2 mmol, 5.24 ml) of borane-dimethyl sulfide complex are added dropwise. The mixture is then stirred at RT for 25 min and under reflux for 30 min. 40 ml of water and 15 ml of 2N hydrochloric acid are successively added dropwise while cooling in ice, followed by stirring at RT for 45 min. After a renewed addition of 15 ml of 2N hydrochloric acid the mixture is extracted several times with diethyl ether. The combined organic phase is washed successively with 1N hydrochloric acid, water, a saturated sodium bicarbonate solution and a saturated sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo. The solid is dried under high vacuum to constant weight.
Reaction SMILES: [N:1]1[C:10]2[C@H:9]([NH:11]C(=O)C)[CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>Cl.C(Cl)Cl>[NH2:11][C@H:9]1[C:10]2[N:1]=[CH:2][CH:3]=[CH:4][C:5]=2[CH2:6][CH2:7][CH2:8]1
Reactant: CC(=O)N[C@@H]1CCCc2cccnc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: N[C@@H]1CCCc2cccnc21
Yield: 79.7 %

Procedure:
A stirred solution of (R)-(−)-N-(5,6,7,8-tetrahydroquinolin-8-yl)-acetamide (230 mg, 1.21 mmol, 97% ee) in 6 N aqueous HCl (4.0 mL) was heated to 130° C. for 2 h. At this time, the reaction mixture was cooled to room temperature and cautiously rendered basic with a minimum amount of saturated aqueous NaOH, then diluted with CH2Cl2 (10 mL). The phases were separated and the aqueous phase was washed with CH2Cl2 (5×20 mL), then the combined organic phases were dried (MgSO4) and concentrated. Flash chromatography through a plug of silica gel (elution with 20:2:1 CH2Cl2—MeOH—NH4OH) afforded 143 mg (80%) of (R)-(−)-8-amino-5,6,7,8-tetrahydroquinoline in 96% ee (separated by chiral GC, J&W CycloSil B column, initial temperature: 160° C., initial time: 0 min, rate: 1° C./min, final temperature: 130° C., final time: 0 min, (S)-(+)-enantiomerrt=12.43 min, (R)-(−)-enantiomerrt=13.13 min). [α]D=−125.7 (c 0.56, CHCl3); 1H NMR (CDCl3) δ 1.52–1.62 (m, 2H), 1.78–1.85 (m, 1H), 1.91 (br s, 2H), 2.02–2.06 (m, 1H), 2.60–2.65 (m, 2H), 3.83–3.87 (m, 2H), 6.91 (dd, 1H, J=8, 5 Hz), 7.21 (dd, 1H, J=8, 1 Hz), 8.26 (d, 1H, J=5 Hz); 13C NMR (CDCl3) δ 19.6, 28.7, 31.7, 51.0, 121.3, 131.2, 136.4, 146.7, 159.2. ES-MS m/z 149 (M+H).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17]([NH:19][NH:20][C:21](=[O:23])[CH3:22])=O)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=P(Cl)(Cl)Cl>C(#N)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][CH:14]([C:17]2[O:23][C:21]([CH3:22])=[N:20][N:19]=2)[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)NNC(=O)C1CCN(C(=O)OCc2ccccc2)CC1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: Cc1nnc(C2CCN(C(=O)OCc3ccccc3)CC2)o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.6 %

Procedure:
A suspension of 2.00 g (6.26 mmol) of 4-(N′-acetyl-hydrazinocarbonyl)-piperidine-1-carboxylic acid benzyl ester in 30 ml acetonitril was treated at RT with 0.69 ml (7.51 mmol) of phosphoroxychloride. The suspension was stirred 1 h at RT and the refluxed for 2 h, evaporated, dissolved in CH2Cl2 and neutralized with aqueous saturated NaHCO3 solution. The aqueous phase was extracted with CH2Cl2 (2×). The organic phase was dried (Na2SO4) and and evaporated to give after flash silica gel column (EtOAc) 1.69 g (89%) of the title compound as light yellow oil. MS: 302.1 (MH+).
Reaction SMILES: [CH2:1]([O:3][CH2:4][N:5]1[CH:12]=[C:11](I)[C:9](=[O:10])[NH:8][C:6]1=[O:7])[CH3:2].[C:14]([O:18][CH2:19][CH3:20])(=[O:17])[CH:15]=[CH2:16].C(N(CC)CC)C>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:14](/[CH:15]=[CH:16]/[C:11]1[C:9](=[O:10])[NH:8][C:6](=[O:7])[N:5]([CH2:4][O:3][CH2:1][CH3:2])[CH:12]=1)([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOCn1cc(I)c(=O)[nH]c1=O
Reactant: C=CC(=O)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOCn1cc(/C=C/C(=O)OCC)c(=O)[nH]c1=O
Temperature: 70 °C
Reaction time: 5 h
Yield: 74.4 %

Procedure:
Then, 1.184 g (4 mmol) of 1-(ethoxymethyl)-5-iodouracil, 870 μg (8 mmol) of ethyl acrylate, 45 mg of palladium acetate and 0.6 ml of triethylamine were dissolved in 40 ml of dimethylformamide, heated and stirred for 5 hours at 70° C. After the solvent was evaporated under reduced pressure, the residue was adsorbed on a silica gel column, eluted with a solution of dichloromethan/ethyl acetate (1:1 v/v) to recover the desired fraction, from which the solvent was evaporated under reduced pressure to obtain 798 mg of 5-(2-(E)-carboethoxyvinyl) -1-(ethoxymethyl)uracil as crystals.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27](Br)=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][CH:10]=1)([CH3:7])[CH3:6])[CH3:2].[CH3:32][C:33]1[C:37](B(O)O)=[C:36]([CH3:41])[O:35][N:34]=1.C(O)C.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.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.C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:31])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27]([C:37]4[C:33]([CH3:32])=[N:34][O:35][C:36]=4[CH3:41])=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][CH:10]=1)([CH3:7])[CH3:6])[CH3:2]
Reactant: Cc1noc(C)c1B(O)O
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccc(Br)cc3)oc2C)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccc(-c4c(C)noc4C)cc3)oc2C)cc1
Temperature: 25 °C
Yield: 92 %

Procedure:
A solution of 2-(4-{2-[2-(4-bromophenyl)-5-methyloxazol-4-yl]ethoxy}phenoxy)-2-methyl-propionic acid ethyl ester (907 mmol) (see Ex. 2, part B) and 3,5-dimethylisoxazole-4-boronic acid (0.998 mmol) in toluene:ethanol (18.2 mL of a 1:1 solution) was treated with Na2CO3(aq) (0.906 mL of a 2M solution). A nitrogen atmosphere was applied, Pd(PPh3)4 (52.5 mg) was added, and the orange mixture was heated at reflux for 2 h. After cooling to room temperature, the mixture was partitioned between ethyl acetate (20 mL) and H2O (30 mL). The layers were separated, and the aqueous phase was back-extracted with ethyl acetate (2×10 mL). Combined organic phases were washed with brine (20 mL), dried over Na2SO4, and concentrated. The product was purified by silica gel chromatography (20 g SiO2, 3:7 ethyl acetate:hexanes) to yield the product in 92% yield as an oil; Rf=0.16 in 1:4 ethyl acetate:hexanes; 1H NMR (400 MHz, CDCl3) δ7.99 (d, J=8.4 Hz, 2H), 7.27 (d, J=8.4 Hz, 2H), 6.78 (d, J=8.8 Hz, 2H), 6.73 (d, J=8.8 Hz, 2H), 7.06-7.01 (m, 2H), 4.8 (q, J=7.2 Hz, 2H), 4.15 (t, J=6.4 Hz, 2H), 2.92 (t, J=6.4 Hz, 2H), 2.39 (s, 3H), 2.33 (s, 3H), 2.25 (s, 3H), 1.48 (s, 6H), 1.23 (t, J=7.2 Hz, 3H); MS (EI) 528.2 (M+Na)+5.05.2 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([O:12][C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=2[OH:20])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O:23][C:24]([C:26]1[CH:30]=[C:29]([CH2:31]Br)[O:28][C:27]=1[C:33]([F:36])([F:35])[F:34])=[O:25])C.C([O-])([O-])=O.[Cs+].[Cs+].[OH-].[Na+]>CN(C=O)C.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]([O:12][C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=2[O:20][CH2:31][C:29]2[O:28][C:27]([C:33]([F:35])([F:34])[F:36])=[C:26]([C:24]([OH:25])=[O:23])[CH:30]=2)[CH2:11]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC(Oc2cc(Cl)ccc2O)C1
Reactant: CCOC(=O)c1cc(CBr)oc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC(Oc2cc(Cl)ccc2OCc2cc(C(=O)O)c(C(F)(F)F)o2)C1

Procedure:
The title compound was prepared as described in Example 1 Step D using 3-(5-chloro-2-hydroxy-phenoxy)-azetidine-1-carboxylic acid tert-butyl ester (0.15 g, 0.50 mmol), the title compound of Step A (0.18 g, 0.60 mmol), Cs2CO3 (0.41 g, 1.2 mmol), KI (0.12 g, 0.70 mmol) in DMF, except upon completion of the reaction 1N NaOH and EtOAc were added. The organic layer was washed with 1N NaOH and dried. The crude material was purified by RP HPLC to provide the title compound. 1H NMR (CDCl3): 7.20-6.92 (m, 1H), 6.91-6.80 (m, 2H), 6.77-6.69 (m, 1H), 6.53 (d, J=2.1 Hz, 1H), 4.87 (s, 2H), 4.79-4.69 (m, 1H), 4.27-4.12 (m, 2H), 4.00-3.88 (m, 2H), 1.38 (s, 9H).
Reaction SMILES: [C:1]1([CH3:16])[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[C:15]3[CH2:14][CH2:13][NH:12][CH2:11][C:10]=3[N:9]=[CH:8]2)[CH:2]=1.Cl[C:18]1[NH:27][C:26](=[O:28])[C:25]2[C:20](=[CH:21][C:22]([O:31][CH3:32])=[C:23]([O:29][CH3:30])[CH:24]=2)[N:19]=1.C(N(CC)CC)C.C(O)C>COC(O)C>[CH3:30][O:29][C:23]1[CH:24]=[C:25]2[C:20](=[CH:21][C:22]=1[O:31][CH3:32])[N:19]=[C:18]([N:12]1[CH2:13][CH2:14][C:15]3[N:7]([C:3]4[CH:2]=[C:1]([CH3:16])[CH:6]=[CH:5][CH:4]=4)[CH:8]=[N:9][C:10]=3[CH2:11]1)[NH:27][C:26]2=[O:28]
Reactant: COc1cc2nc(Cl)[nH]c(=O)c2cc1OC
Reactant: Cc1cccc(-n2cnc3c2CCNC3)c1
Agent: COC(C)O
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1cc2nc(N3CCc4c(ncn4-c4cccc(C)c4)C3)[nH]c(=O)c2cc1OC
Temperature: 100 °C
Yield: 56.9 %

Procedure:
A mixture of 1-m-tolyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine 18a (100 mg, 0.5 mmol), 2-chloro-6,7-dimethoxy-3H-quinazolin-4-one 1b (100 mg, 0.4 mmol), and triethylamine (140 μL, 1.0 mmol) in 10 mL methoxyethanol was heated at 100° C. under nitrogen for 12 hr. The mixture was pumped to constant weight. The resulting residue was slurried with hot ethanol and allowed to reach ambient temperature. Vacuum filtration provided 95 mg of 6,7-dimethoxy-2-(1-m-tolyl-1,4,6,7-tetrahydro-imidazo[4,5-c]pyridin-5-yl)-3H-quinazolin-4-one, 601, [M+H]+=418, as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2/[C:11](=[CH:14]/[C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)/[C:12]#[N:13].[O-]P([O-])([O-])=O.[K+].[K+].[K+].C(Cl)Cl.[F:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(OCC)C.C1COCC1>[F:32][C:33]1[CH:38]=[CH:37][C:36]([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[C:5]3/[C:11](=[CH:14]/[C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)/[C:12]#[N:13])=[CH:35][CH:34]=1
Reactant: N#C/C(=C\c1cccnc1)c1c[nH]c2ccc(Br)cc12
Reactant: OB(O)c1ccc(F)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: ClCCl
Solvent: CCOCC
Solvent: C1CCOC1
Product: N#C/C(=C\c1cccnc1)c1c[nH]c2ccc(-c3ccc(F)cc3)cc12
Temperature: 50 °C

Procedure:
To a solution of (Z)-2-(5-bromo-1H-indol-3-yl)-3-pyridin-3-yl-acrylonitrile (180 mg, 0.56 mmol, 1.0 eq.) in anhydrous and degazed THF (6.0 mL) were added, under an argon atmosphere, K3PO4 (236 mg, 1.11 mmol, 2.0 eq.), PdCl2(dppf).CH2Cl2 (41 mg, 0.056 mmol, 0.1 eq.) and 4-fluorophenylboronic acid (155 mg, 1.11 mmol, 2.0 eq.). The reaction apparatus was protected from light and the mixture was heated at 50° C. for 16 hours, and then, quenched with a saturated aqueous ammonium chloride solution, after cooling to room temperature. The mixture was extracted with ethyl acetate and the organic layer was washed with water, dried over MgSO4, and then, evaporated under reduced pressure. The residue was purified by silica gel flash-column chromatography (eluent: heptane/AcOEt, 50/50 to 30/70) to afford, after trituration with diethyl ether, the compound (39) as an orange solid (175 mg, 92%). IR νmax (cm−1): 2217 (νCN); 1H NMR (DMSO, 500 MHz) δ (ppm): 7.29 (2H, t, J10′-9′=J12′-13′=J10′-F=J12′-F=8.5 Hz, H10′ and H12′), 7.52 (1H, dm, J6′-7′=8.9 Hz, H6′), 7.55 (1H, dd, J5″-4″=7.9 Hz, J5″-6″=4.9 Hz, H5″), 7.59 (1H, d, J7′-6′=8.9 Hz, H7′), 7.78 (2H, dd, J9′-10′=J13′-12′=8.5 Hz et J9′-F=J13′-F=5.5 Hz, H9′ and H13′), 7.89 (1H, m, H4′), 7.91 (1H, s, H3), 8.23 (1H, s, H2′), 8.34 (1H, d, J4″-5″=7.9 Hz, H4″), 8.60 (1H, d, J6″-5″=4.9 Hz, H6″), 9.01 (1H, s, H2″), 11.86 (1H, s, indolic H); 13C NMR (DMSO, 75.5 MHz) δ (ppm): 108.4 (C2), 111.4 (C3′), 113.4 (C7′), 116.0 (2C, d, 2JC—F=21 Hz, C10′ and C12′), 118.1 (C2′), 118.6 (C1), 122.6 (C6′), 124.1 (C5″), 124.7 (C3a′), 128.4 (C4′), 129.4 (2C, d, 3JC—F=8 Hz, C9′ and C13′), 131.4 (C3″), 132.9 (C7a′), 133.8 (C3), 135.2 (C4″), 137.2 (C5′), 138.4 (C8′), 150.1 (C6″), 150.5 (C2″), 162.0 (1C, d, 1JC—F=244 Hz, C4″); ESI-MS: m/z 340.1 ([M+H]+); HRESI-MS: m/z 340.1241 (calcd for C22H15N3F, 340.1250).
Reaction SMILES: [OH-].[Na+].[Br:3][C:4]1[C:5]([C:15]#[C:16][Si](C)(C)C)=[C:6]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[NH2:7]>CO>[Br:3][C:4]1[C:5]([C:15]#[CH:16])=[C:6]([CH:8]=[C:9]([C:11]([F:12])([F:13])[F:14])[CH:10]=1)[NH2:7]
Reactant: C[Si](C)(C)C#Cc1c(N)cc(C(F)(F)F)cc1Br
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C#Cc1c(N)cc(C(F)(F)F)cc1Br
Reaction time: 0.5 h

Procedure:
Sodium hydroxide (3.17 mL, 31.7 mmol) was added to a solution of 3-bromo-5-(trifluoromethyl)-2-((trimethylsilyl)ethynyl)aniline (10.67 g, 31.7 mmol) in methanol (200 mL) and was stirred for 30 min. The solvent was evaporated. The residue was taken up in brine (30 mL) and extracted with ethyl acetate (3×100 mL). The combined organic layers were dried with magnesium sulfate and evaporated. The residue was purified on silica gel with 10% ethyl acetate/hexanes to give 7.54 g (90%) as a tan solid. 1H-NMR (CDCl3, 400 MHz) δ 7.15 (s, 1H), 6.85 (s, 1H), 4.58 (bs, 2H), 3.77 (s, 1H); LC/MS (HPLC method 4): tR=3.186 min, 263.89(MH)+.
Reaction SMILES: CCCCO[C:6]1[CH:7]=[CH:8][C:9]([CH2:12][C:13](NO)=O)=[CH:10][CH:11]=1.[C:17]([O-])(=O)C(C)=C.COCC(O)C.NC(OCC)=O>>[CH3:17][CH:13]=[CH:12][C:9]1[CH:10]=[CH:11][CH:6]=[CH:7][CH:8]=1
Reactant: C=C(C)C(=O)[O-]
Reactant: CCCCOc1ccc(CC(=O)NO)cc1
Agent: CCOC(N)=O
Solvent: COCC(C)O
Product: CC=Cc1ccccc1
Reaction time: 2 h

Procedure:
Functionalized zirconia nanoparticles in which 50%, 25%, and 25% of the surface sites reacted with bufexamac, 2a (Preparatory Example 1), and 2b (Preparatory Example 2), respectively, were prepared as follows. A clean vial was charged with 10 grams of ZrO2 sol (47.3% weight) followed by 20 grams of 1-methoxy-2-propanol. Then 0.739 grams (0.70 mmol/g ZrO2) of bufexamac, 0.383 grams (0.35 mmol/g ZrO2) of 2a and 0.243 grams (0.35 mmol/g ZrO2) 2b were added to the vial. The content of the vial was stirred for 2 hours. The solution was then dried down to a powder, under vacuum, at 70° C. A total of 4.93 grams of zirconia nanoparticle powder was recovered. The powder was placed in a clean vial and redispersed in 4.93 grams of ultra-pure THF to yield a clear, slightly yellow solution. To this solution 0.48 grams of 3-isopropenyl-α,α-dimethylbenzyl isocyanine was added. The vial was sealed and stirred for 12 hours at room temperature. An FT-IR was taken of the sample, and an IR peak was observed at 1751 cm−1 and attributed to the ν(C═O) stretch in the urethane.
Reaction SMILES: I[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]([OH:12])[O:7][C:8]2=[O:11])=[CH:4][CH:3]=1.[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[CH2:20])=[CH:17][CH:16]=1.CCN(CC)CC>CS(C)=O>[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[CH:20][C:2]2[CH:10]=[C:9]3[C:5]([CH:6]([OH:12])[O:7][C:8]3=[O:11])=[CH:4][CH:3]=2)=[CH:17][CH:16]=1
Reactant: C=Cc1ccc(OC)cc1
Reactant: O=C1OC(O)c2ccc(I)cc21
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: COc1ccc(C=Cc2ccc3c(c2)C(=O)OC3O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 1.38 g (5 mmol) of 6-iodo-3-hydroxyisobenzofuranone, 0.74 g (5.5 mmol) of p-methoxystyrene, 0.83 ml (5.5 mmol) Et3N, 0.01 g of Pd (OAc)2 and 1 ml of DMSO was prepared in a 10 ml flask. The flask was surmounted with a reflux condenser and the solution was heated to 95° (oil bath) with stirring under N2 for 1 hour. The dark solution was allowed to cool to RT and poured onto 75 ml of ice/H2O with stirring. After standing overnight, the solid which had formed was collected, washed well with cold H2O and air dried. It was then heated with 50 ml of 95% EtOH, charcoaled and filtered. The reddish filtrate was cooled in ice and deposited 100 mg of reddish-brown solid which was found to be impurity and was discarded. The filtrate was evaporated at reduced pressure and the residual orange-yellow solid was triturated with 25 ml of Et2O and filtered to afford 860 mg (60.9%) of the desired coupling product as a yellow solid; homogeneous by TLC--used as is for the next reaction.