Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([CH:3]([CH3:14])[C:4]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1)=O)=O.O.[NH2:16][NH2:17]>C(O)C>[CH3:13][O:12][C:9]1[CH:10]=[CH:11][C:6]([C:4]2[C:3]([CH3:14])=[CH:1][NH:17][N:16]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(C(=O)C(C)C=O)cc1
Reactant: NN
Solvent: CCO
Solvent: O
Product: COc1ccc(-c2n[nH]cc2C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
9.8 g (51.0 mmol) of the 2-formyl-4′-methoxypropiophenone synthesized in Step 1 was dissolved in 150 ml of ethanol. At room temperature, 3.8 g (61.2 mmol) of 80% hydrazine hydrate was dropwise added to the solution, followed by stirring at the same temperature for 1 hour and further by heating under reflux for 2 hours. After reaction had been completed, the reaction mixture was cooled to room temperature and the solvent was distilled away. As a result, 8.4 g (44.9 mmol) of 3-(4′-methoxyphenyl)-4-methylpyrazole was obtained as an orange oily matter. The yield was 88%. The product synthesized was subjected to the next reaction without purification.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Br:7][C:8]1[CH:9]=[C:10]([N:14]2[CH2:18][CH2:17][CH:16]([C:19]([OH:21])=O)[CH2:15]2)[CH:11]=[CH:12][CH:13]=1.[CH3:22][N:23](C)[CH:24]=O.N(C)C>ClCCCl.C1COCC1.C1(C)C=CC=CC=1>[Br:7][C:8]1[CH:9]=[C:10]([N:14]2[CH2:18][CH2:17][CH:16]([C:19]([N:23]([CH3:24])[CH3:22])=[O:21])[CH2:15]2)[CH:11]=[CH:12][CH:13]=1
Reactant: CN(C)C=O
Reactant: O=C(O)C1CCN(c2cccc(Br)c2)C1
Agent: CNC
Agent: O=C(Cl)C(=O)Cl
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: ClCCCl
Product: CN(C)C(=O)C1CCN(c2cccc(Br)c2)C1
Temperature: 65 °C
Yield: 523.4 %

Procedure:
Oxalyl chloride (104 μL, 1.19 mmol) was added to a mixture of 1-(3-bromophenyl)pyrrolidine-3-carboxylic acid (293 mg, 1.08 mmol) and N,N-dimethylformamide (8.4 μL, 0.108 mmol) in DCE (5 mL). After heating the mixture at 65° C. for 2 hours, the mixture was coevaporated with toluene. The residue was diluted with THF (5 mL) and Me2NH (2M/THF, 2.71 mL, 5.42 mmol) was added to the mixture at 0° C. After stiffing the mixture for 16 hours at room temperature, the mixture was concentrated and the residue was diluted with water and extracted with EtOAc (3×). The combined organic layers were dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel column chromatography (EtOAc/hexane=9:1→4:1→2:1) to afford desired product (168 mg, 48.0%) as orange oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:11]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[C:10](=[O:19])[CH:9]2[CH2:20][CH2:21][CH:22]([O:30][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32])[C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)=[CH:4][CH:3]=1.[CH3:38][N:39]([CH2:47][CH:48]([OH:57])[CH:49]([OH:56])[CH:50]([OH:55])[CH:51]([OH:54])[CH2:52][OH:53])[C:40](=[O:46])[CH2:41][CH2:42][CH2:43][CH:44]=[CH2:45].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(N(CC)CC)C.ClCCl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:38][N:39]([CH2:47][CH:48]([OH:57])[CH:49]([OH:56])[CH:50]([OH:55])[CH:51]([OH:54])[CH2:52][OH:53])[C:40](=[O:46])[CH2:41][CH2:42][CH2:43][CH:44]=[CH:45][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:9]([CH2:20][CH2:21][CH:22]([O:30][Si:31]([C:34]([CH3:35])([CH3:37])[CH3:36])([CH3:32])[CH3:33])[C:23]3[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=3)[C:10](=[O:19])[N:11]2[C:12]2[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=2)=[CH:4][CH:3]=1
Reactant: C=CCCCC(=O)N(C)CC(O)C(O)C(O)C(O)CO
Reactant: CC(C)(C)[Si](C)(C)OC(CCC1C(=O)N(c2ccc(F)cc2)C1c1ccc(Br)cc1)c1ccc(F)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(CC(O)C(O)C(O)C(O)CO)C(=O)CCCC=Cc1ccc(C2C(CCC(O[Si](C)(C)C(C)(C)C)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
110 mg of 4-(4-bromophenyl)-3-[3-(tert-butyldimethylsilanyloxy)-3-(4-fluorophenyl)propyl]-1-(4-fluorophenyl)azetidin-2-one and 136 mg of N-methyl-N-(2,3,4,5,6-pentahydroxyhexyl)hex-5-enamide are initially charged in 300 μl of triethylamine under argon in a closed tube which had been heated thoroughly beforehand. After addition of 6 mg of palladium acetate and 14 mg of triphenylphosphine, the mixture is stirred at 100° C. for 4 h. The reaction mixture is then taken up in dichloromethane, filtered and concentrated using a rotary evaporator. Purification of the residue using an SiO2 cartridge (dichloromethane/methanol 20:1-5:1) gives the product. C43H58F2N2O8Si (796)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH3:8])[CH:5]=[CH:6][CH:7]=1.C([Li])CCC.CN(CCN(CCN(C)C)C)C.CN(C)[CH:28]=[O:29]>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([CH3:8])[CH:5]=[CH:6][C:7]=1[CH:28]=[O:29]
Reactant: CN(C)C=O
Reactant: Cc1cccc(F)c1
Agent: CN(C)CCN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ccc(C=O)c(F)c1
Reaction time: 2 h
Yield: 22.6 %

Procedure:
The solution of 3-fluorotoluene (2.91 g, 0.0266 mol) in anhydrous tetrahydrofuran was cooled to −78° C. and a 1.4M solution of n-butyllithium in hexanes (19 mL, 0.0266 mol) was added dropwise keeping the reaction mixture temperature below −75° C. Upon the completion of the addition, N,N,N′,N′,N″-pentamethyldiethylenetriamine was added dropwise and the stirring at −78° C. was continued under an atmosphere of nitrogen for an additional 2 hours. N,N-dimethylformamide (3.89 g, 0.0532 mol) was added dropwise and the reaction mixture was slowly warmed up while stirring for 0.5 hours. It was quenched by dropwise addition of 1N hydrochloric acid and the layers were separated. The aqueous phase was further extracted with ethyl acetate (2×150 mL) and the combined organic extracts were dried with magnesium sulfate. The organic phase was concentrated under reduced pressure and the residue was purified by flash chromatography on silica using ethyl acetate/n-heptane (5:95) as mobile phase to yield 2-fluoro-4-methylbenzaldehyde (0.83 g, 0.006 mol) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5](I)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[CH3:12][CH:13]([OH:16])[C:14]#[CH:15].CCN(CC)CC>[Cl-].[Cl-].[Zn+2].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.CN(C=O)C>[F:1][C:2]1[CH:10]=[C:6]2[C:5]([CH:15]=[C:14]([CH:13]([OH:16])[CH3:12])[O:9][C:7]2=[O:8])=[CH:4][CH:3]=1
Reactant: C#CC(C)O
Reactant: O=C(O)c1cc(F)ccc1I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(O)c1cc2ccc(F)cc2c(=O)o1
Temperature: 100 °C
Reaction time: 2 h
Yield: 83.8 %

Procedure:
A mixture of 5-fluoro-2-iodobenzoic acid (9.04 g, 34.0 mmol), but-3-yn-2-ol (5.7 mL, 5.46 g, 78.0 mmol), ZnCl2 (4.62 g, 34.0 mmol), Pd(Ph3P)4 (1.96 g, 1.7 mmol), Et3N (14.2 mL, 10.3 g, 102.0 mmol) and DMF (50 mL) was stirred under argon at 100° C. for 2 hours. After the removal of the volatiles under vacuum, the residue was chromatographed (silica gel, ethyl acetate in hexanes, 0-50%) to provide intermediate 7-fluoro-3-(1-hydroxyethyl)-1H-isochromen-1-one as a brown oil (5.93 g, 84%). MS m/z 209.2 [M+H]+; 1H NMR (500 MHz, CDCl3-d): 6 ppm 7.91-7.96 (1H, m), 7.43-7.47 (2H, m), 6.55-6.59 (1H, m), 4.67 (1H, q, J=6.52 Hz), 1.57 (3H, d, J=6.62 Hz).
Reaction SMILES: CO[C:3]1[CH:31]=[CH:30][C:6]([C:7]([NH:9][C:10]2[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[CH:24]=[CH:23][C:11]=2[C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[O:13])=[O:8])=[C:5]([O:32][CH:33]2[CH2:38][CH2:37][N:36]([CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=3[O:46][CH3:47])[CH2:35][CH2:34]2)[CH:4]=1.[CH3:48][O:49]C1C=CC(C(NC2C=C([N+]([O-])=O)C=CC=2C(NC2C=CC(OC)=CC=2)=O)=O)=C(OC2CCNCC2)C=1.COC1C=CC=CC=1C=O>>[CH3:48][O:49][C:33]1([O:32][C:5]2[CH:4]=[CH:3][CH:31]=[CH:30][C:6]=2[C:7]([NH:9][C:10]2[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[CH:24]=[CH:23][C:11]=2[C:12]([NH:14][C:15]2[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=2)=[O:13])=[O:8])[CH2:38][CH2:37][N:36]([CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=2[O:46][CH3:47])[CH2:35][CH2:34]1
Reactant: COc1ccc(NC(=O)c2ccc([N+](=O)[O-])cc2NC(=O)c2ccc(OC)cc2OC2CCNCC2)cc1
Reactant: COc1ccc(NC(=O)c2ccc([N+](=O)[O-])cc2NC(=O)c2ccc(OC)cc2OC2CCN(Cc3ccccc3OC)CC2)cc1
Agent: COc1ccccc1C=O
Product: COc1ccc(NC(=O)c2ccc([N+](=O)[O-])cc2NC(=O)c2ccccc2OC2(OC)CCN(Cc3ccccc3OC)CC2)cc1

Procedure:
Using methods substantially equivalent to those described in Example 94-E, 2-[4-methoxy-2-[1-(2-methoxybenzyl)piperidin-4-yloxy]benzoylamino]-N-(4-methoxy-phenyl)-4-nitrobenzamide (83 mg, 0.13 mmol, 86%) was prepared from 2-[4-methoxy-2-(piperidin-4-yloxy)benzoylamino]-N-(4-methoxyphenyl)-4-nitrobenzamide and 2-methoxybenzaldehyde.
Reaction SMILES: [CH3:1][C:2]1[C:8]([CH3:9])=[C:7](O)[C:6]([CH3:11])=[CH:5][C:3]=1[OH:4].[CH:12]1[CH:17]=[CH:16][C:15]([CH2:18]Br)=[CH:14][CH:13]=1.[C:20]([O-:23])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:18]([O:4][C:3]1[C:2]([CH3:1])=[C:8]([CH3:9])[C:7]([O:23][CH2:20][C:2]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:3]=2)=[C:6]([CH3:11])[CH:5]=1)[C:15]1[CH:16]=[CH:17][CH:12]=[CH:13][CH:14]=1
Reactant: BrCc1ccccc1
Reactant: Cc1cc(O)c(C)c(C)c1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(OCc2ccccc2)c(C)c(C)c1OCc1ccccc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 161.2 %

Procedure:
A solution of 2,3,5-trimethylhydroquinone (15.2 g, 100 mmol) in DMF (150 mL) was treated with BnBr (35.7 mL, 51.6 g, 300 mmol, 3 equiv.) and anhydrous K2CO3 (55.3 g, 400 mmol, 4 equiv.). The brown suspension was heated to 60° C. for 48 h at which time the reaction was judged incomplete by HPLC. Additional BnBr (37 mL, 300 mmol, 3 equiv.) and K2CO3 (50 g, 362 mmol, 3.6 equiv.) were added and heated to 60° C. for an additional 48 h. The reaction was cooled, filtered through Celite, the filter cake rinsed 2×100 mL EtOAc and the combined filtrates washed with 500 mL H2O. The aqueous layer was extracted 4×250 mL EtOAc and concentrated at 80° C. by rotary evaporation. The brown residue was poured onto 300 mL water which precipitated a light brown solid and the resulting suspension stirred overnight. The brown solid was collected by filtration, washed with 2×50 mL H2O and dried, yielding 26.8 g of 1,4-bis(benzyloxy)-3,5,6-trimethylbenzene as a brown solid 1H NMR (400 MHz, CDCl3) d=7.50-7.34 (m, 10H), 6.64 (s, 1H), 5.03 (s, 2H), 4.74 (s, 2H), 2.30 (s, 3H), 2.25 (s, 3H), 2.20 (s, 3H) ppm.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:11][O:12][CH3:13])=[C:6]([CH:9]=1)[CH2:7]Cl.[C-:14]#[N:15].[Na+].ClCCl.CS(C)=O>O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:11][O:12][CH3:13])=[C:6]([CH:9]=1)[CH2:7][C:14]#[N:15]
Reactant: COCOc1ccc(Br)cc1CCl
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: O
Product: COCOc1ccc(Br)cc1CC#N
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.9 %

Procedure:
To a mixture of 5-bromo-2-methoxymethoxybenzyl chloride (21.6 g), sodium cyanide (8.33 g) and dichloromethane (10 ml) was added, at 15° to 20° C., DMSO (80 ml), followed by stirring for 3 hours at room temperature. The mixture was poured into water, which was subjected to extraction with ethyl acetate. The extract solution was washed with water, dried (anhydrous magnesium sulfate) and concentrated to leave an oily product. The oily product was purified by means of a silica gel column chromatography (eluted with ethyl acetate/hexane) to give 5-bromo-2-methoxymethoxybenzyl cyanide (20.4 g), whose spectrum data are shown below.
Reaction SMILES: [C:1]([C:3]1[C:8]2[N:9]=[C:10]([C:12](=[O:16])[N:13]([CH3:15])[CH3:14])[O:11][C:7]=2[C:6]([C:17]2[CH2:21]C[CH:19]([CH2:22][NH:23][C:24](=O)OC(C)(C)C)[CH:18]=2)=[C:5]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:4]=1[CH3:37])#[N:2]>Cl.O1CCOCC1>[C:1]([C:3]1[C:8]2[N:9]=[C:10]([C:12]([N:13]([CH3:15])[CH3:14])=[O:16])[O:11][C:7]=2[C:6]([CH:17]2[CH2:18][CH2:19][C:22]([NH:23][CH3:24])=[CH:21]2)=[C:5]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:4]=1[CH3:37])#[N:2]
Reactant: Cc1c(-c2ccccc2)c(C2=CC(CNC(=O)OC(C)(C)C)CC2)c2oc(C(=O)N(C)C)nc2c1C#N
Agent: Cl
Solvent: C1COCCO1
Product: CNC1=CC(c2c(-c3ccccc3)c(C)c(C#N)c3nc(C(=O)N(C)C)oc23)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.6 %

Procedure:
tert-Butyl {3-[4-cyano-2-dimethylcarbamoyl-5-methyl-6-phenyl-1,3-benzoxazol-7-yl]cyclopent-2-enyl}methylcarbamate (I-340-2) (154 mg, 0.31 mmol) was dissolved in 4 N hydrochloric acid/1,4-dioxane solution (3 ml), and stirred at room temperature for 1 hour. The solvent was evaporated away under reduced pressure, then ethanol was added to the resulting residue, followed by concentration under reduced pressure. This operation was repeated once again. The residue was dissolved in chloroform (15 ml) and an aqueous saturated sodium hydrogencarbonate solution (15 ml), and vigorously stirred for 10 minutes. The aqueous layer was separated, extracted twice with chloroform. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The insoluble matter was separated by filtration, the solvent was evaporated away, and the resulting residue was purified by preparative TLC (eluent, chloroform:methanol=9:1, v/v), and this was further purified by preparative TLC (eluent, chloroform:7 N ammonia-containing methanol solution=93:7, v/v) to obtain a brown solid (74 mg). The solid was washed in slurry with diisopropyl ether, and a pale brown solid was collected by filtration. The solid was dried at 60° C. under reduced pressure for 48 hours to obtain the entitled compound (57 mg, 46%).
Reaction SMILES: [CH2:1]([C:5]1[C:9](/[CH:10]=[CH:11]/[C:12]2[S:13][C:14]([C:18]([OH:20])=O)=[C:15]([CH3:17])[N:16]=2)=[C:8]([CH3:21])[O:7][N:6]=1)[CH2:2][CH2:3][CH3:4].Cl.[F:23][C:24]1([F:28])[CH2:27][NH:26][CH2:25]1.ON1C(=O)CCC1=O.C(N(CC)CC)C>CN(C=O)C.O>[CH2:1]([C:5]1[C:9](/[CH:10]=[CH:11]/[C:12]2[S:13][C:14]([C:18]([N:26]3[CH2:27][C:24]([F:28])([F:23])[CH2:25]3)=[O:20])=[C:15]([CH3:17])[N:16]=2)=[C:8]([CH3:21])[O:7][N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1noc(C)c1/C=C/c1nc(C)c(C(=O)O)s1
Reactant: FC1(F)CNC1
Agent: Cl
Agent: O=C1CCC(=O)N1O
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCCc1noc(C)c1/C=C/c1nc(C)c(C(=O)N2CC(F)(F)C2)s1
Reaction time: 20 h
Yield: 29.4 %

Procedure:
To a stirred solution of 2-[(E)-2-(3-butyl-5-methyl-isoxazol-4-yl)-vinyl]-4-methyl-thiazole-5-carboxylic acid (200 mg, 0.65 mmol), 3,3-difluoroazetidine hydrochloride (93 mg, 0.72 mmol) and N-hydroxysuccinimide (86 mg, 0.74 mmol) in DMF (1 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarboiimide (144 mg, 0.75 mmol) and DMF (1 mL) followed by triethylamine (0.29 mL, 2.1 mmol) and DMF (2 mL). The resulting mixture was stirred under argon for 20 h and then water added and the mixture extracted with ethyl acetate. The combined organic extracts were dried, filtered and concentrated. Purification by chromatography (silica, 40% ethyl acetate in heptane) gave the title compound (73 mg, 29%) as pale yellow oil. MS: m/e=382.1 [M+H]+.
Reaction SMILES: [N:1]1([C:7]2[S:8][CH:9]=[C:10]([CH2:12][OH:13])[N:11]=2)[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1.C(N(CC)CC)C>CS(C)=O>[N:1]1([C:7]2[S:8][CH:9]=[C:10]([CH:12]=[O:13])[N:11]=2)[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1
Reactant: OCc1csc(N2CCSCC2)n1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=Cc1csc(N2CCSCC2)n1

Procedure:
The reaction described in Preparation 44 was repeated, but using 1.2 g of 2-(thiomorpholin-4-yl)thiazol-4-ylmethanol, 2.65 g of sulfur trioxide pyridine complex, 1.68 g of triethylamine and 30 ml of dimethyl sulfoxide, giving the title compound as a colorless powder.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[Mg+2].[Cl-].[Cl-].[C:15]1([C:21]2([C:27](O)=[O:28])[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.S(Cl)(Cl)=O>C(#N)C.CCOC(C)=O>[C:15]1([C:21]2([C:27]([CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8])=[O:28])[CH2:22][CH2:23][O:24][CH2:25][CH2:26]2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: O=C(O)C1(c2ccccc2)CCOCC1
Agent: [Cl-]
Agent: [Mg+2]
Solvent: O=S(Cl)Cl
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C(=O)OCC)C(=O)C1(c2ccccc2)CCOCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of diethyl malonate (3.96 mL, 26.2 mmol) in ACN (52.4 mL) at 0° C. was added MgCl2 (2.74 g, 28.8 mmol) in one portion. TEA (7.30 mL, 52.4 mmol) was added dropwise, and the reaction mixture was allowed to warm to ambient temperature and stirred for 3 hours. 4-Phenyl-tetrahydro-2H-pyran-4-carboxylic acid (5.13 g, 24.9 mmol) was converted to the acid chloride by addition of thionyl chloride and reaction at 65° C. for 1 hour. The resulting acid chloride solution was then concentrated in vacuo, dissolved in ACN, and added to the initial reaction mixture. The resulting mixture was stirred at ambient temperature for 2 hours and then diluted with 200 mL of EtOAc, added to a separatory funnel, partitioned with water, washed 2 times with 75 mL of water, separated, dried over Na2SO4, and concentrated in vacuo to give the title compound without further purification. MS m/e=349 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5].[H-].[Na+].F[C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[C:16]#[N:17]>CN(C=O)C>[Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][O:5][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[C:16]#[N:17]
Reactant: OCc1ccccc1Br
Reactant: COc1ccc(C#N)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(C#N)cc1OCc1ccccc1Br
Temperature: 90 °C
Yield: 71.4 %

Procedure:
To a solution of 2-bromobenzyl alcohol (16.50 g, 88.2 mmol) in DMF (100 ml) was added sodium hydride (60% dispersion in mineral oil, 2.94 g, 73.5 mmol) and this was followed by 3-fluoro-4-methoxybenzonitrile (8.88 g, 58.8 mmol) and the resulting mixture was heated to 90° C. for 2 h under N2. After cooling, the mixture was partitioned between ether and H2O, the organic layer washed sequentially with 0.5N HCl and saturated brine and then dried over MgSO4. Trituration with ether/pentane (1/3, v/v) afforded the subtitle compound as an off-white solid (13.35 g, 71%). Rf 0.27 (hexane/EtOAc 5/1, v/v). MS m/z 318, 320 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([O:13][CH3:14])[CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[C:7]2[CH3:12].Br[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][N:22]1[C:26](=[O:27])[C:25]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:24]2[C:23]1=[O:32].C(N(CC)CC)C>CC(C)=O>[CH3:14][O:13][C:4]1[CH:5]=[C:6]2[C:11](=[C:2]([NH:1][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][N:22]3[C:26](=[O:27])[C:25]4=[CH:28][CH:29]=[CH:30][CH:31]=[C:24]4[C:23]3=[O:32])[CH:3]=1)[N:10]=[CH:9][CH:8]=[C:7]2[CH3:12]
Reactant: O=C1c2ccccc2C(=O)N1CCCCCCBr
Reactant: COc1cc(N)c2nccc(C)c2c1
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: COc1cc(NCCCCCCN2C(=O)c3ccccc3C2=O)c2nccc(C)c2c1
Reaction time: 0.5 h

Procedure:
A stirred mixture of 20.9 g (0.111 mole) of 8-amino-6-methoxy-4-methylquinoline and 34.5 g (0.111 mole) of N-(6-bromohexyl)phthalimide was heated in an oil bath (130° ) while 11.2 g (15.4 ml; 0.111 mole) of triethylamine was added dropwise over a period of 45 minutes. The temperature of the bath was kept at 130° for 60 minutes, at 150° for 60 minutes, between 150° and 190° for 30 minutes, and at 190° for 30 minutes. The mixture was cooled then diluted with acetone (100 ml). The precipitate as collected on a filter, washed with acetone (2×50 ml), dried, then discarded. The filtrate was concentrated in vacuo to a dark oil; yield 53 g. The oil was dissolved in 100 ml of dischloromethane, and the solution was chromatographed on a column (40 cm× 8 cm dia) of silica gel (1000 g; activity III) using dichloromethane (1.5 l) as the eluent. Fractions containing the product were combined then concentrated in vacuo; yield 35.5 g (83.7%). That material was satisfactory for conversion to the target compound, however a 93% recovery of analytically pure material (mp 84°-85° ) could be obtained by crystallization from ethanol.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:3]=1[CH2:4][O:5][C:6]1[CH:12]=[CH:11][C:9]([NH2:10])=[C:8]([N+:13]([O-])=O)[CH:7]=1.[OH-].[Na+].ClCCl>CO.C(O)(=O)C.[Fe]>[Cl:1][C:2]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([NH2:13])[C:9]([NH2:10])=[CH:11][CH:12]=1
Reactant: Nc1ccc(OCc2c(Cl)cccc2Cl)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CO
Product: Nc1ccc(OCc2c(Cl)cccc2Cl)cc1N
Reaction time: 0.25 h
Yield: 87.7 %

Procedure:
add 1.75 g of iron powder to a solution of 1.4 g of 4-[(2,6-dichlorobenzyl)oxy]-2-nitroaniline in 80 cm3 of methanol and 7 cm3 of glacial acetic acid. The reaction mixture is refluxed for three hours. The mixture is concentrated under reduced pressure (0.2 kPa). The residue is taken up in 30 cm3 of water and the pH of the suspension thus obtained is adjusted to 10-11 by adding 2N aqueous solution of sodium hydroxide; 350 cm3 of dichloromethane is then added. After vigorous stirring for 15 min, the insoluble matter is filtered. The filtrate is decanted, then the organic phase is dried over magnesium sulphate, filtered and concentrated under reduced pressure (0.2 kPa). We obtain 1.11 g of 4-[(2,6-dichlorobenzyl)oxy]benzene-1,2-diamine in the form of a black resin, which has the following characteristics:
Reaction SMILES: O=P(Cl)(Cl)[Cl:3].[CH3:6][N:7]1[C:15]2[C:10](=[CH:11][C:12]([CH3:16])=[CH:13][CH:14]=2)[CH2:9][C:8]1=O.CN([CH:21]=[O:22])C>>[CH3:6][N:7]1[C:15]2[C:10](=[CH:11][C:12]([CH3:16])=[CH:13][CH:14]=2)[C:9]([CH:21]=[O:22])=[C:8]1[Cl:3]
Reactant: CN(C)C=O
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1ccc2c(c1)CC(=O)N2C
Product: Cc1ccc2c(c1)c(C=O)c(Cl)n2C
Yield: 78 %

Procedure:
Prepared from POCl3 (1.7 ml), DMF (1.6 ml), 1,5-dimethyl-1,3-dihydroindol-2-one (1.0 g) yielding (46) 1.0 g (78%). M.p. 120°-121° C. as crude product sufficiently pure for the next synthesis.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[N:5]2[N:14]=[C:15]([C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=3)[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[C:19](S(C)=O)[N:18]=3)=[C:4]2[CH:3]=1.C(OCC)(=O)C.[CH:40]1([NH2:43])[CH2:42][CH2:41]1>>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[N:5]2[N:14]=[C:15]([C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=3)[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:43][CH:40]4[CH2:42][CH2:41]4)[N:18]=3)=[C:4]2[CH:3]=1
Reactant: COc1ccc(-c2nn3c(NC4CCCC4)cc(Cl)cc3c2-c2ccnc(S(C)=O)n2)cc1
Reactant: NC1CC1
Solvent: CCOC(C)=O
Product: COc1ccc(-c2nn3c(NC4CCCC4)cc(Cl)cc3c2-c2ccnc(NC3CC3)n2)cc1
Temperature: 25 °C
Yield: 83 %

Procedure:
A solution of N-{5-chloro-2-(4-methoxyphenyl)-3-[2-(methylsulfinyl)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-7-yl}-N-cyclopentylamine (118 mg, 0.24 mmol) in cyclopropylamine (5 mL) was heated at 45° C. in a sealed tube for 5 hours. The reaction mixture was cooled to room temperature and ethyl acetate was added to the reaction mixture. The organic phase was washed with water, brine and dried over magnesium sulfate. Filtration and concentration followed by chromatography (7:3 hexanes:ethyl acetate) gave N-{4-[5-chloro-7-(cyclopentylamino)-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinyl}-N-cyclopropylamine (96 mg, 83%) as a yellow solid. 1H NMR (CDCl3) δ 8.10 (broad s, 1H), 8.00 (d, 1H), 7.55 (d, 2H), 6.98 (d, 2H), 6.33 (d, 1H), 6.09 (d, 1H), 5.98 (d, 1H), 5.68 (s, 1H), 3.93 (m, 1H), 3.86 (s, 3H), 2.84 (m, 1H), 2.10 (m, 2H), 1.78-1.65 (m, 6H), 0.90 (m, 2H), 0.63 (m, 2H). MS m/z 475 (M+1).