Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][CH:12]=3)=[C:9](Br)[N:8]([C@@H:25]3[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26]3)[C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:37]B(O)O.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][CH:12]=3)=[C:9]([CH3:37])[N:8]([C@@H:25]3[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CB(O)O
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](n2c(Br)c(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)C1
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: Cc1c(-c2ccc(Oc3ccccc3)cc2)c2c(N)ncnc2n1[C@@H]1CCN(C(=O)OC(C)(C)C)C1
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 84.1 %

Procedure:
A mixture of (R)-tert-butyl 3-(4-amino-6-bromo-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidine-1-carboxylate (9) (375 mg, 0.70 mmol), methyl boronic acid (417 mg, 6.96 mmol), Pd2(dba)3 (64 mg, 0.07 mmol), tricyclohexyl phosphine (PCy3) (39 mg, 0.14 mmol) and K3PO43H2O (556 mg, 2.09 mmol) in toluene (10.0 mL) was sealed in microwave tube. The reaction was purged with N2 before heated at 120° C. by microwave for 30 min. Another portion of methyl boronic acid (417 mg, 6.96 mmol) was introduced and the reaction was continued for additional 30 min. After cooled down to r. t., the reaction mixture was partitioned between DCM and water. The layers were separated. The aqueous phase was extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated under reduced pressure to give the crude product which was purified by column chromatographic (silica gel, 50% ethyl acetate in a mixture of petroleum ether and DCM (1:1)) to afford (R)-tert-butyl 3-(4-amino-6-methyl-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidine-1-carboxylate (10) (286 mg, 70% yield) as a yellow oil. LC-MS (ESI): m/z (M+1) 486.3.
Reaction SMILES: [C:1]([NH:4][CH2:5][C:6]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][C:7]=1OCC(N)=O)(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].C[N:27]1CCCC1=O>C(OCC)(=O)C>[C:1]([NH:4][CH2:5][C:6]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][C:7]=1[NH2:27])(=[O:3])[CH3:2]
Reactant: CC(=O)NCc1cc([N+](=O)[O-])ccc1OCC(N)=O
Reactant: CN1CCCC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: CC(=O)NCc1cc([N+](=O)[O-])ccc1N
Temperature: 100 °C

Procedure:
120 g of the 2-(N-acetylaminomethyl)-4-nitrophenoxyacetamide made in step 1 are dissolved in 450 ml of N-methylpyrrolidone, mixed with 155 g of potassium carbonate and heated for 4.5 hours at 100° C. Subsequently the reaction mixture is cooled to room temperature, diluted with 840 ml of ethyl acetate, filtered and the solvent is evaporated in vacuum at 60 to 80° C. The remaining residue is crystallized by addition of ethanol. The product is filtered with suction, taken up in 250 ml ethanol and heated briefly under reflux. Subsequently the solution is cooled, filtered and the residue is dried in vacuum. 46.6 g of a yellow powder are obtained with a melting point of 208 to 210° C.
Reaction SMILES: [B].[NH2:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:13]C)=[CH:10][CH:11]=2)[CH:6]=[C:5]([CH3:15])[N:4]=1>ClCCl>[NH2:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([OH:13])=[CH:10][CH:11]=2)[CH:6]=[C:5]([CH3:15])[N:4]=1
Reactant: COc1ccc2c(N)nc(C)cc2c1
Agent: [B]
Solvent: ClCCl
Product: Cc1cc2cc(O)ccc2c(N)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 86.4 %

Procedure:
Boron tribomide (4 mL) in 6 mL of dichloromethane was added dropwise to a stirred solution of 1-amino-6-methoxy-3-methylisoquinoline (2 g) in 10 mL of dichloromethane at 0° C. After stirring for 16 hours at ambient temperature the reaction mixture was poured on ice, the organic layer removed and the pH of the aqueous layer adjusted to pH 9 by adding concentrated aqueous ammonia. The precipitated material was collected by filtration and dried in vacuo to give 1.6 g of the title compound. ESI-MS: 175 (MH+).
Reaction SMILES: [CH2:1]([CH:4]([CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:5][OH:6])[CH2:2][CH3:3].[C:12](O)(=[O:20])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>O>[C:12]([O:6][CH2:5][CH:4]([CH2:1][CH2:2][CH3:3])[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])(=[O:20])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCCCC(=O)O
Reactant: CCCCCC(CO)CCC
Solvent: O
Product: CCCCCCCC(=O)OCC(CCC)CCCCC
Yield: 99.3 %

Procedure:
158.3 g 2-propylheptanol (1 mol) and 144.2 g caprylic acid (1 mol) were heated for 5 h to 220° C. on a water separator together with 0.30 g Fascat® 2001 (Sn oxalate: 0.1% by weight, based on the composition as a whole). After the separation of water had stopped, the crude product was distilled in an oil pump vacuum through a 250 mm Vigreux column (T=92-94° C.). 282.4 g of a colorless oil were obtained: OHV=<1, AV=<0.1.
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: C1CCOC1
Solvent: CCN(CC)CC
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: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[Cl:22][CH2:23][CH2:24][CH2:25][CH2:26]I>>[Cl:22][CH2:23][CH2:24][CH2:25][CH2:26][CH:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[C:9]([OH:11])=[O:10]
Reactant: O=C(O)Cc1ccc(Cl)cc1
Reactant: ClCCCCI
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Product: O=C(O)C(CCCCCl)c1ccc(Cl)cc1
Yield: 90.7 %

Procedure:
Step AH (1): 2-(4-Chlorophenyl)acetic acid (2.5 g, 14.65 mmol) was deprotonated with NaHMDS (1.0 M in THF, 29.3 mL, 29.3 mmol) and reacted with 1-chloro-4-iodobutane (1.80 mL, 14.7 mmol) using a procedure analogous to Step AC (1) to afford 6-chloro-2-(4-chlorophenyl)hexanoic acid (3.47 g, 59% yield). LC-MS (M−H)− 259.1.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]2[N:6]([CH2:10][CH2:11][CH2:12]Cl)[C:7](=[O:9])[S:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH:22]([N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C=O)C>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]2[N:6]([CH2:10][CH2:11][CH2:12][N:38]3[CH2:39][CH2:40][N:35]([CH:22]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[CH2:36][CH2:37]3)[C:7](=[O:9])[S:8][C:4]=2[CH:3]=1
Reactant: O=c1sc2cc(Cl)ccc2n1CCCCl
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1sc2cc(Cl)ccc2n1CCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Yield: 61.7 %

Procedure:
A solution of compound (X) (3.71 g, 20 mmol), K2CO3 (3.31 g, 24 mmol), 4-benzhydrylpiperazine (XId) (6.06 g, 24 mmol), and KI (3.98 g, 24 mmol) in DMF (20 ml) was stirred at 100° C. for 5 hours, concentrated in vacuo and extracted with dichloromethane. The resulting dichloromethane layer was dried over MgSO4, and subjected to column chromatography on silica gel. The eluate eluted with dichloromethane/ethyl acetate (10/1) was recrystallized from ether to obtain compound (XIId) (5.9 g, yield=61.7% ) as colorless prism-shaped crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH:8]([CH2:14]/[CH:15]=[CH:16]/[CH:17]=O)[CH2:7][CH2:6]2.[F:19][C:20]([F:35])([F:34])[C:21]1[CH:22]=[C:23]([CH2:27][NH:28][CH:29]=[CH:30][C:31](=[O:33])[CH3:32])[CH:24]=[CH:25][CH:26]=1>>[C:31]([C:30]1[CH:15]([CH2:14][CH:8]2[CH2:7][CH2:6][C:5]3[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=3)[C:9]2=[O:13])[CH:16]=[CH:17][N:28]([CH2:27][C:23]2[CH:24]=[CH:25][CH:26]=[C:21]([C:20]([F:34])([F:35])[F:19])[CH:22]=2)[CH:29]=1)(=[O:33])[CH3:32]
Reactant: COc1ccc2c(c1)CCC(C/C=C/C=O)C2=O
Reactant: CC(=O)C=CNCc1cccc(C(F)(F)F)c1
Product: COc1ccc2c(c1)CCC(CC1C=CN(Cc3cccc(C(F)(F)F)c3)C=C1C(C)=O)C2=O

Procedure:
The title compound 65 is prepared according to the procedure reported in step D of Example 8 with aldehyde 54 (100 mg, 0.41 mmol) and enamine 66 (100 mg, 0.41 mmol) as reactants. Purification by column chromatography on SiO2 (Petroleum Ether/EtOAc=2:1) afford the title compound 65 as a pale yellow solid. (Yield 65 mg, 39%).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([N:9]2[C:13](=[O:14])[CH2:12][CH:11]([C:15]([O:17][CH3:18])=[O:16])[CH2:10]2)[CH:6]=[CH:7][CH:8]=1)=O.[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1.CC(O)=O>COC(OC)OC>[O:14]=[C:13]1[N:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([CH2:1][NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)[CH:4]=2)[CH2:10][CH:11]([C:15]([O:17][CH3:18])=[O:16])[CH2:12]1
Reactant: COC(=O)C1CC(=O)N(c2cccc(C=O)c2)C1
Reactant: Nc1ccccn1
Solvent: CC(=O)O
Solvent: COC(OC)OC
Product: COC(=O)C1CC(=O)N(c2cccc(CNc3ccccn3)c2)C1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A solution of methyl (3-formylphenyl)-5-oxopyrrolidine-3-carboxylate, 2-aminopyridine, and AcOH in trimethylorthoformate was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo and the residue was re-dissolved in methanol. The solution was then cooled to 0° C. AcOH was added followed by NaBH3CN solid in portions. The reaction was allowed to stirred at room temperature for 8 hours. The reaction solution was then concentrated in vacuo. The residue was dissolved in EtOAc and organic solution was washed with saturated NaHCO3 twice. The organic layer was dried over Na2SO4 and concentrated in vacuo. The crude product was purified by silica gel chromatograph (10% meOH/EtOAc) to provide an orange oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:15][CH2:14][N:13](CC3C=CC=CC=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[C:29](Cl)(=[O:33])[O:30][CH2:31][CH3:32]>CC1C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:10]2([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:15][CH2:14][N:13]([C:29]([O:30][CH2:31][CH3:32])=[O:33])[CH2:12][CH2:11]2)=[O:9])=[CH:6][CH:7]=1
Reactant: O=C(c1ccc(F)cc1)C1(c2ccccc2)CCN(Cc2ccccc2)CC1
Reactant: CCOC(=O)Cl
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CCC(C(=O)c2ccc(F)cc2)(c2ccccc2)CC1
Reaction time: 5 h

Procedure:
To a stirred mixture of 79 parts of (4-fluorophenyl) [4-phenyl-1-(phenylmethyl)-4-piperidinyl]methanone and 630 parts of methylbenzene were added dropwise 32 parts of ethyl carbonochloridate at room temperature. Upon completion, stirring was continued for 5 hours at reflux temperature. The reaction mixture was evaporated and the (chloromethyl)benzene was distilled in vacuo (pump). The oily residue was purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (98:2 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from a mixture of 2,2'-oxybispropane and a small amount of petroleumether, yielding 35.5 parts of ethyl 4-(4-fluorobenzoyl)-4-phenyl-1-piperidinecarboxylate; mp. 91.7° C. (intermediate 15).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)=[N:10][NH:11][CH:12]=2)[CH:5]=[CH:4][N:3]=1.[CH3:20][O:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH2:27])=[CH:24][CH:23]=1>>[F:19][C:16]1[CH:17]=[CH:18][C:13]([C:9]2[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:27][CH2:26][C:25]4[CH:28]=[CH:29][C:22]([O:21][CH3:20])=[CH:23][CH:24]=4)[N:7]=3)=[CH:12][NH:11][N:10]=2)=[CH:14][CH:15]=1
Reactant: Fc1ccc(-c2n[nH]cc2-c2ccnc(Cl)n2)cc1
Reactant: COc1ccc(CN)cc1
Product: COc1ccc(CNc2nccc(-c3c[nH]nc3-c3ccc(F)cc3)n2)cc1
Yield: 80 %

Procedure:
This compound was synthesized by refluxing 2-chloro-4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]pyrimidine prepared in accordance with Example A-299 in 4-methoxybenzylamine overnight. The product, 4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-N-[(4-methoxyphenyl)methyl]-2-pyrimidinamine, was obtained as a off-white solid in 80% yield, mp: 183-185° C.; Anal. Calc'd for C21H18FN5O: C, 67.19; H, 4.83; N, 18.66. Found: C, 67.01; H, 5.11; N, 18.93.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][CH:9]=2)[CH:5]=[CH:4][CH:3]=1.[F:16][C:17]([F:29])([F:28])[O:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>CCOCC.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>[F:16][C:17]([F:28])([F:29])[O:18][C:19]1[CH:24]=[CH:23][C:22]([C:2]2[N:7]=[C:6]([C:8]3[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][CH:9]=3)[CH:5]=[CH:4][CH:3]=2)=[CH:21][CH:20]=1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: O=Cc1ccc(-c2cccc(Br)n2)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: [K+]
Solvent: CCOCC
Solvent: C1COCCO1
Product: O=Cc1ccc(-c2cccc(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Yield: 75.2 %

Procedure:
4-(6-Bromo-pyridin-2-yl)-benzaldehyde (0.31 mmol), 4-trifluoromethoxyphenyl boronic acid (0.46 mmol), tetrakis(triphenylphosphine)palladium(0) (0.003 mmol), 2 M potassium carbonate (0.31 mL) and dioxane (2 mL) were combined in a vial and irradiated by microwave for 10 min at 150° C. The reaction mixture was taken up in ether and washed with brine. The organic layer was dried over magnesium sulfate, was filtered and the solvent removed in vacuo. Purification by silica gel chromatography (EtOAc/hexanes) yielded the product (80 mg) as an off-white solid: mp 109-112° C.; 1H NMR (400 MHz, CDCl3) δ 10.11 (s, 1H), 8.32 (d, J=8.5 Hz, 2H), 8.19 (d, J=8.1 Hz, 2H), 8.03 (d, J=8.4 Hz, 2H), 7.89 (t, J=7.9 Hz, 1H), 7.79 (d, J=7.7 Hz, 1H), 7.74 (d, J=8.0 Hz, 1H), 7.35 (d, J=8.3 Hz, 2H); EIMS m/z 343 (M+).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]=1[N+:17]([O-:19])=[O:18])(=O)=O.[NH2:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:25][CH:24]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>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.C1(C)C=CC=CC=1>[N+:17]([C:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:15]=[CH:16][C:7]=1[NH:22][C:23]1[CH:24]=[CH:25][C:26]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:34])([CH3:33])[CH3:35])=[CH:27][CH:28]=1)([O-:19])=[O:18]
Reactant: CC(C)(C)OC(=O)Nc1ccc(N)cc1
Reactant: O=[N+]([O-])c1c(OS(=O)(=O)C(F)(F)F)ccc2ccccc12
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: [K+]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)Nc1ccc(Nc2ccc3ccccc3c2[N+](=O)[O-])cc1
Yield: 78 %

Procedure:
1-Nitro-2-naphthyl trifluoromethanesulfonate (20.26 g, 63.07 mmol), tert-butyl 4-aminophenylcarbamate (13.13 g, 63.07 mmol), triphenylphosphine (1.65 g, 6.31 mmol), tetrakis(triphenylphosphine)palladium(0) (3.64 g, 3.15 mmol), potassium carbonate (8.72 g, 63.07 mmol), and dry toluene (600 mL) were mixed, and the mixture was refluxed by heating for 6 hours under a nitrogen atmosphere. After the reaction mixture was left to cool, the insoluble matter was separated by filtration, and washed off with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogencarbonate, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=4/1), and then recrystallized from ethyl acetate/hexane to obtain the title compound (18.67 g, yield 78%) as yellow crystals.
Reaction SMILES: Br[CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:14])[CH3:13])=[CH:7][CH:6]=1)[OH:4].[CH3:15][NH2:16]>>[OH:4][CH:3]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:14])[CH3:13])=[CH:7][CH:6]=1)[CH2:2][NH:16][CH3:15]
Reactant: CC(=O)Nc1ccc(C(O)CBr)cc1
Reactant: CN
Product: CNCC(O)c1ccc(NC(C)=O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of N-[4-(2-bromo-1-hydroxyethyl)phenyl]acetamide (0.40 g, in 10 mL of methanol) was introduced methylamine (10 mL, 2.0 M in methanol) at 0° C. The reaction mixture was warmed to room temperature after 30 minutes, and stirred at that temperature for 2 hours. The solvent and excess methylamine was evaporated. The residue was dissolved in methanol (5 mL) and stirred with resin (BioRad 50W×2, 0.5 g) overnight. The resin was collected by filtration, washed with methanol. The product on the resin was washed off with NH4OH/CH3OH (10% NH4OH aqueous solution (Aldrich, 29.4% NH3) in methanol, v/v). The solution was concentrated to give the title compound as a white solid (0.16 g).
Reaction SMILES: C([O:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][Si:11]([C:24]([CH3:27])([CH3:26])[CH3:25])([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:6][C:5]=1[Cl:28])=O.[OH-].[K+]>CO>[Si:11]([O:10][C:7]1[CH:8]=[CH:9][C:4]([OH:3])=[C:5]([Cl:28])[CH:6]=1)([C:24]([CH3:27])([CH3:26])[CH3:25])([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CC(C)(C)[Si](Oc1ccc(OC=O)c(Cl)c1)(c1ccccc1)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)[Si](Oc1ccc(O)c(Cl)c1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.8 %

Procedure:
4-{[t-butyl(diphenyl)silyl]oxy}-2-chlorophenyl formate (9.42 g, 22.4 mmol) was dissolved in methanol (50 mL). 10% KOH (15 mL) was added. The solution was stirred for 30 minutes at ambient temperature. The solvent was removed in vacuo and the solid partitioned between ethyl acetate and water. The aqueous phase was acidified with HCl and extracted three times with ethyl acetate. The organic layers were combined and the solvent dried over anhydrous magnesium sulfate. The solution was filtered and the solvent evaporated to dryness in vacuo to yield crude title compound (8.04 g, 21 mmol).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[C:10]([O:11][CH2:12][CH2:13][CH:14]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH3:15])=[C:9]([O:23][CH3:24])[C:8]([Cl:25])=[C:7]([CH3:26])[C:6]=1[C:27](=[O:29])[CH3:28].Cl.[F:31][C:32]1([F:37])[CH2:36][CH2:35][NH:34][CH2:33]1>>[Cl:25][C:8]1[C:7]([CH3:26])=[C:6]([C:27](=[O:29])[CH3:28])[C:5]([O:4][CH2:3][CH2:2][N:34]2[CH2:35][CH2:36][C:32]([F:37])([F:31])[CH2:33]2)=[C:10]([O:11][CH2:12][CH2:13][CH:14]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH3:15])[C:9]=1[O:23][CH3:24]
Reactant: COc1c(Cl)c(C)c(C(C)=O)c(OCCBr)c1OCCC(C)c1ccc(F)cc1
Reactant: FC1(F)CCNC1
Agent: Cl
Product: COc1c(Cl)c(C)c(C(C)=O)c(OCCN2CCC(F)(F)C2)c1OCCC(C)c1ccc(F)cc1
Yield: 54 %

Procedure:
Example 8a (83 mg, 0.17 mmol) was reacted with 3,3-difluoropyrrolidine hydrochloride (2.5 eq.) as described under General Procedure K and the crude mixture was purified by flash chromatography (silica gel, hexane/Et2O 70:30) to afford the title compound as a pale yellow oil (47 mg, 54%). 1H NMR (300 MHz, CDCl3) δ 7.20-7.15 (m, 2H), 7.01-6.95 (m, 2H), 4.03 (t, J=5.6 Hz, 2H), 3.95 (dt, J=2.1, 6.8 Hz, 2H), 3.83 (s, 3H), 2.97 (m, 1H), 2.95 (t, J=13.4 Hz, 2H), 2.79-2.71 (m, 4H), 2.49 (s, 3H), 2.33-2.21 (m, 2H), 2.18 (s, 3H), 2.06-1.98 (m, 2H), 1.30 (d, J=6.9 Hz, 3H). MS (ES+) m/z 514.2 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][CH:7]2[CH2:10][N:9]([C:11](Cl)=[O:12])[CH2:8]2)=[CH:4][CH:3]=1.[OH-].[NH4+:17]>O1CCCC1.O>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][CH:7]2[CH2:10][N:9]([C:11]([NH2:17])=[O:12])[CH2:8]2)=[CH:4][CH:3]=1
Reactant: [NH4+]
Reactant: O=C(Cl)N1CC(Oc2ccc(Cl)cc2)C1
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: NC(=O)N1CC(Oc2ccc(Cl)cc2)C1
Reaction time: 18 h
Yield: 52.9 %

Procedure:
A solution of 5 g (0.02 mole) of 3-(4-chlorophenoxy)-1-azetidinecarbonyl chloride in 20 ml of tetrahydrofuran was stirred while 4 ml (0.06 mole) of 57% ammonium hydroxide was added all at once. After stirring for 18 hr, the reaction mixture was diluted with 200 ml of water and the solid which separated was collected by filtration, 10.5 g. Recrystallization from isopropanol yielded 2.4 g (52.9%) of gray crystalline powder, m.p. 187°-188° C.
Reaction SMILES: NC1C=CNN=1.O/[CH:8]=[C:9]1\[C:10](=[O:18])[NH:11][C:12]2[C:17]\1=[CH:16][CH:15]=[CH:14][CH:13]=2.[N:19]1([CH2:25][CH2:26][CH2:27][O:28][C:29]2[CH:41]=[CH:40][C:32]([CH2:33][C:34]3[CH:35]=[C:36]([NH2:39])[NH:37][N:38]=3)=[CH:31][CH:30]=2)[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>O1CCCC1>[N:19]1([CH2:25][CH2:26][CH2:27][O:28][C:29]2[CH:30]=[CH:31][C:32]([CH2:33][C:34]3[CH:35]=[C:36]([NH:39][CH:8]=[C:9]4[C:17]5[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=5)[NH:11][C:10]4=[O:18])[NH:37][N:38]=3)=[CH:40][CH:41]=2)[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1
Reactant: Nc1cc(Cc2ccc(OCCCN3CCOCC3)cc2)n[nH]1
Reactant: O=C1Nc2ccccc2/C1=C/O
Agent: Nc1cc[nH]n1
Solvent: C1CCOC1
Product: O=C1Nc2ccccc2C1=CNc1cc(Cc2ccc(OCCCN3CCOCC3)cc2)n[nH]1

Procedure:
The named compound is prepared by substituting 5-[4-(3-morpholin-4-yl-propoxy)-benzyl]-2H-pyrazol-3-ylamine for 3-aminopyrazole in the reaction of Example 1. Specifically, E & Z-3-[(hydroxy)-methylene]-1,3-dihydro-indol-2-one (0.017 gms.) is reacted with 0.048 gms. of 5-[4-(3-morpholin-4-yl-propoxy)-benzyl]-2H-pyrazol-3-ylamine by refluxing in tetrahydrofuran (1.0 mL). Recrystallization from a mixture of ethyl acetate and hexanes affords the named compound.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][C:9]2=O)=[CH:4][CH:3]=1.C([SiH](CC)CC)C>FC(F)(F)C(O)=O>[Br:1][C:2]1[CH:11]=[C:10]2[C:5](=[CH:4][CH:3]=1)[CH2:6][CH2:7][CH2:8][CH2:9]2
Reactant: O=C1CCCc2ccc(Br)cc21
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: Brc1ccc2c(c1)CCCC2
Reaction time: 1.5 h
Yield: 94.3 %

Procedure:
To 7.50 g of 7-bromo-3,4-dihydronaphthalen-1(2H)-one in trifluoroacetic acid (60 ml), 15.5 g of triethylsilane was added dropwise over 30 minutes at room temperature (the temperature of the reaction solution exothermically elevated from 27° C. to 50° C.). After the dropwise addition, the reaction solution was allowed to react at room temperature for 2 hours and then on a water bath at 50° C. for 1.5 hours. The reaction mixture was concentrated under reduced pressure, and the residue was poured into 400 ml of saturated aqueous sodium hydrogen carbonate, extracted with ethyl acetate (200 ml×1, 100 ml×1). The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane) to obtain 6.63 g of the desired product (yield 94%).