Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]([C:5]1[CH:39]=[CH:38][C:8]([C:9]([NH:11][C:12]2[CH:17]=[C:16]([C:18]3[CH:27]=[C:26]4[C:21]([CH2:22][CH2:23][N:24](C(OC(C)(C)C)=O)[CH2:25]4)=[CH:20][CH:19]=3)[N:15]3[N:35]=[CH:36][CH:37]=[C:14]3[N:13]=2)=[O:10])=[CH:7][CH:6]=1)([CH3:4])[CH3:3].[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43]>C(Cl)Cl>[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43].[OH:1][C:2]([C:5]1[CH:6]=[CH:7][C:8]([C:9]([NH:11][C:12]2[CH:17]=[C:16]([C:18]3[CH:27]=[C:26]4[C:21]([CH2:22][CH2:23][NH:24][CH2:25]4)=[CH:20][CH:19]=3)[N:15]3[N:35]=[CH:36][CH:37]=[C:14]3[N:13]=2)=[O:10])=[CH:38][CH:39]=1)([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(-c3cc(NC(=O)c4ccc(C(C)(C)O)cc4)nc4ccnn34)cc2C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(O)c1ccc(C(=O)Nc2cc(-c3ccc4c(c3)CNCC4)n3nccc3n2)cc1
Reaction time: 0.5 h
Yield: 41 %

Procedure:
tert-Butyl 7-(5-(4-(2-hydroxypropan-2-yl)benzamido)pyrazolo[1,5-a]pyrimidin-7-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate from Step A was dissolved in CH2Cl2 (2 ml). Trifluoroacetic acid (2 ml) was then added at 0° C. The mixture was stirred for 30 minutes at that temperature before being concentrated in vacuo. Residual trifluoroacetic acid was removed azeotropically with toluene twice. The residue was then dissolved in acetonitrile before being purified by preparatory HPLC (20-30% MeCN/H2O gradient+0.01% TFA) to give the titled compound as a white powder (50 mg, 41% yield). 1H NMR (400 MHz, DMSO-d6) δ=11.30 (s, 1 H), 9.14 (br. s., 2 H), 8.21 (d, J=2.5 Hz, 1 H), 8.07 (s, 1 H), 8.05-8.01 (m, 2 H), 8.00-7.95 (m, 1 H), 7.65-7.60 (m, 2 H), 7.50 (d, J=8.1 Hz, 1 H), 6.60 (d, J=2.3 Hz, 1 H), 4.47-4.40 (m, 2 H), 3.47 (br. s., 2 H), 3.13 (t, J=6.2 Hz, 2 H), 1.46 (s, 6 H).
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[NH:13][CH:12]=3)[CH2:7][CH2:6]2)[O:4]CC1.CN(C=O)C.Cl>O>[NH:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11]([CH:8]2[CH2:7][CH2:6][C:5](=[O:4])[CH2:10][CH2:9]2)=[CH:12]1
Reactant: c1ccc2c(C3CCC4(CC3)OCCO4)c[nH]c2c1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: O=C1CCC(c2c[nH]c3ccccc23)CC1
Temperature: 50 °C
Reaction time: 24 h

Procedure:
To a 3-L, four-neck round bottom flask equipped with an overhead stirrer, temperature probe, addition funnel, was added 3-(1,4-dioxaspiro[4.5]decan-8-yl)-1H-indole (as prepared in the previous step, 143.2 g, 0.56 mol) and DMF (190 mL). The suspension was heated to 50° C., and aqueous HCl (2M, 290 mL) was charged to the addition funnel and added dropwise and after about 5 mins, a precipitate formed. The reaction was stirred at 30° C. for 24 h. HPLC showed there was <2% of the acetal remaining. The suspension was chilled in an ice bath to 6° C., water (1.2 L) was added, and the suspension stirred at ambient temperature for 15 mins. The solid was filtered, washed with water (250 mL), and dried in a vacuum oven at 50° C. overnight. 1H NMR (400 MHz, CHLOROFORM-d) δ: 8.16 (br. s., 1H), 7.65 (d, J=7.6 Hz, 1H), 7.35 (d, J=8.1 Hz, 1H), 7.15-7.26 (m, 1H), 7.08-7.16 (m, 1H), 6.95 (d, J=2.0 Hz, 1H), 3.33 (tt, J=3.3, 11.6 Hz, 1H), 2.28-2.66 (m, 6H), 1.88-2.06 (m, 2H).
Reaction SMILES: [C:1]([C:4]1[S:5]C(Cl)=C[CH:8]=1)(=O)[CH3:2].[Cl:10][C:11]1[S:15][C:14]([C:16]([CH2:18][C:19]#[N:20])=[O:17])=[CH:13][CH:12]=1.N1CCOCC1.[S]>CC(=O)CC>[NH2:20][C:19]1[S:5][C:4]([CH3:8])=[C:1]([CH3:2])[C:18]=1[C:16]([C:14]1[S:15][C:11]([Cl:10])=[CH:12][CH:13]=1)=[O:17]
Reactant: CC(=O)c1ccc(Cl)s1
Reactant: N#CCC(=O)c1ccc(Cl)s1
Agent: [S]
Solvent: CCC(C)=O
Solvent: C1COCCN1
Product: Cc1sc(N)c(C(=O)c2ccc(Cl)s2)c1C
Yield: 46 %

Procedure:
The procedure of Example 1 was followed except that 2-acetyl-5-chlorothiophene (Aldrich) was used in place of acetophenone to prepare the corresponding 2-(5-chlorothiophene-2-carbonyl)acetonitrile (Steps A and B). 2-Butanone (Aldrich), 2-(5-chlorothiophene-2-carbonyl)acetonitrile, morpholine, and sulfur were reacted according to the procedure of Step C, Example 1, to afford the desired compound. Yield: 46%; IR (KBr) cm−1: 3377, 3259, 2918, 1551, 1424, 1326, 1266, 1003, 764; 1H NMR (CDCl3):δ 1.90 (s, 3H), 2.17 (s, 3H), 5.77 (bs, 2H), 6.89 (d, 1H, J=4 Hz), 7.16 (d, 1H, J=4 Hz); red solid, mp: 125–127° C. (petroleum ether).
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@H:13]2[CH2:27][O:26][C:16]3[CH:17]=[CH:18][C:19]4[C:20](=[O:25])[CH2:21][CH2:22][O:23][C:24]=4[C:15]=3[O:14]2)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+].[NH:34]1[CH2:39][CH:38]=[C:37]([C:40]2[C:48]3[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=3)[NH:42][CH:41]=2)[CH2:36][CH2:35]1>O1CCCC1.CN(C)C=O>[NH:42]1[C:43]2[C:48](=[CH:47][CH:46]=[CH:45][CH:44]=2)[C:40]([C:37]2[CH2:38][CH2:39][N:34]([CH2:12][CH:13]3[O:14][C:15]4[C:16](=[CH:17][CH:18]=[C:19]5[C:24]=4[O:23][CH2:22][CH2:21][C:20]5=[O:25])[O:26][CH2:27]3)[CH2:35][CH:36]=2)=[CH:41]1
Reactant: C1=C(c2c[nH]c3ccccc23)CCNC1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc4c(c3O2)OCCC4=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C1CCOc2c1ccc1c2OC(CN2CC=C(c3c[nH]c4ccccc34)CC2)CO1

Procedure:
To a mixture of [(2R)-7-oxo-2,3,8,9-tetrahydro-7H-[1,4]dioxino[2,3-h]-chromen-2-yl]methyl 4-methylbenzenesulfonate (0.60 g, 1.54 mmole) and potassium carbonate (0.22 g, 1.55 mmole) in 1:1 tetrahydrofuran/dimethyl-formamide (20 mL) was added 0.91 g (4.61 mmole) of 3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole. The reaction mixture was refluxed under nitrogen for 6 hours. After the reaction was complete, the mixture was evaporated to dryness under reduced pressure and the residue was column chromatographed on silica gel with methylene chloride to remove impurities and with 3% methanol/methylene chloride to elute the desired product. Evaporation of the product-containing fractions in vacuum gave 0.12 g (18%) of the (S)-enantiomer of the title compound as an off-white solid, m.p. 210° C.
Reaction SMILES: [CH:1]1[C:17]2=[C:18]3[C:8]([C:9]([C:11]4[C:16]2=[CH:15][CH:14]=[CH:13][CH:12]=4)=[O:10])=[CH:7][CH:6]=[CH:5][C:4]3=[CH:3][CH:2]=1.O.[Cl:20]([O-])(=O)=O.[K+].Cl>C(O)(=O)C>[Cl:20][C:3]1[CH:2]=[CH:1][C:17]2[C:16]3[C:11]([C:9](=[O:10])[C:8]4[C:18]=2[C:4]=1[CH:5]=[CH:6][CH:7]=4)=[CH:12][CH:13]=[CH:14][CH:15]=3
Reactant: O=C1c2ccccc2-c2cccc3cccc1c23
Reactant: [O-][Cl+2]([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: O=C1c2ccccc2-c2ccc(Cl)c3cccc1c23
Reaction time: 2 h

Procedure:
A 10g amount of benzanthrone was dissolved in a solvent mixture of 100g acetic acid and 100 g of water. 6 g of potassium chlorate was added to the solution and the mixture was heated and stirred at 90°-95° C for 2 hours. 12 g of conc. hydrochloric acid was added dropwise to the mixture during 1 hour and 20 minutes. After the addition, the mixture was stirred for 1 hour to complete the reaction. The reaction mixture was cooled, filtered, washed with water and dried. The product was recrystallized from chlorobenzene to obtain 3-chlorobenzanthrone having a melting point of 179°-190° C (orange needle crystals).
Reaction SMILES: [CH3:1][N:2]([CH:4]=O)[CH3:3].[CH2:6]([O:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:20]=[CH:21][C:22]3[N:28]([CH2:29][C:30]4[S:31][CH:32]=[CH:33][CH:34]=4)[CH2:27][CH2:26][C:25]([C:35](O)=[O:36])=[CH:24][C:23]=3[CH:38]=2)=[CH:15][CH:14]=1)[CH2:7][CH3:8].S(Cl)(Cl)=O>O1CCCC1>[CH3:3][N:2]([CH2:4][C:19]1[CH:20]=[CH:21][C:22]([NH:28][C:35]([C:25]2[CH2:26][CH2:27][N:28]([CH2:29][C:30]3[S:31][CH:32]=[CH:33][CH:34]=3)[C:22]3[CH:21]=[CH:20][C:19]([C:16]4[CH:17]=[CH:18][C:13]([O:12][CH2:11][CH2:10][O:9][CH2:6][CH2:7][CH3:8])=[CH:14][CH:15]=4)=[CH:38][C:23]=3[CH:24]=2)=[O:36])=[CH:23][CH:38]=1)[CH:1]1[CH2:7][CH2:6][O:9][CH2:10][CH2:11]1
Reactant: CN(C)C=O
Reactant: CCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3Cc2cccs2)cc1
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: CCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCN3Cc2cccs2)cc1
Reaction time: 1 h

Procedure:
One droplet of DMF was added to a solution of 7-(4-propoxyethoxyphenyl)-1-(2-thienylmethyl)-2,3-dihydro-1-benzazepine-4-carboxylic acid (240 mg) in tetrahydrofuran (10 ml). Then, thionyl chloride (184 mg) was added at 0° C., the temperature was returned to room temperature, and the mixture was stirred under nitrogen atmosphere for 1 hour. The solvent and excess thionyl chloride were evaporated under reduced pressure, the resulting residue was suspended in tetrahydrofuran (30 ml), and the suspension was added to a solution of 4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]aniline (137 mg) and triethylamine (629 mg) in tetrahydrofuran (10 ml) at 0° C. The suspension was stirred under nitrogen atmosphere at room temperature overnight, to the mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with magnesium sulfate. The solvent was evaporated under reduced pressure, the resulting residue was separated and purified with silica gel column chromatography (methanol:ethyl acetate=1:8), which was recrystallized from hexane-ethyl acetate to give N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-7-(4-propoxyethoxyphenyl)-1-(2-thienylmethyl)-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 59) (152 mg) as yellow crystals.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl:5][CH2:6][CH:7]([CH3:11])[C:8](Cl)=[O:9].Cl.[CH2:13]([C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>C(Cl)Cl>[Cl:5][CH2:6][CH:7]([CH3:11])[C:8]([C:17]1[CH:18]=[CH:19][C:14]([CH2:13][C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)=[CH:15][CH:16]=1)=[O:9]
Reactant: c1ccc(Cc2cccnc2)cc1
Reactant: CC(CCl)C(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: CC(CCl)C(=O)c1ccc(Cc2cccnc2)cc1
Reaction time: 1 h
Yield: 96 %

Procedure:
In 25 ml of methylene chloride was suspended 13.3 g of anhydrous aluminum chloride, and 7.3 g of 3-chloro-2-methylpropionyl chloride was added to the suspension with ice-cooling, after which 8.2 g of 3-benzylpyridine hydrochloride was added in small portions to the suspension. The resulting mixture was subjected to reaction with ice-cooling for 2 hours and then at room temperature for one hour. The reaction mixture was added in small portions to a mixture of 246 ml of iced water and 49 ml of methylene chloride, and the organic layer was separated, while the aqueous layer was extracted with 40 ml of methylene chloride. The organic layers were combined and then 80 ml of water was added thereto after which the resulting mixture was neutralized with sodium hydrogencarbonate. The organic layer was separated, washed with 50 ml of water, and thereafter dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the residue thus obtained was purified by a column chromatography [Wako Silica Gel C-200, eluant: chloroform:ethyl acetate (1:1 by volume)] to obtain 10.53 g (yield 96.0%) of colorless, oily 3-[p-(3-chloro-2-methylpropionyl)benzyl]pyridine.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][C:5](=[O:7])[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[C:3]1[CH:18]=CC1C=CC=CC=1.I([O-])(=O)(=O)=[O:27].[Na+]>O1CCOCC1.[Os](=O)(=O)(=O)=O>[CH:18]([C:3]1[CH:2]([OH:1])[CH2:6][C:5](=[O:7])[C:4]=1[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[O:27]
Reactant: COC(=O)CCCCCCC1=C(C=Cc2ccccc2)C(O)CC1=O
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: C1COCCO1
Product: COC(=O)CCCCCCC1=C(C=O)C(O)CC1=O

Procedure:
The 2-formyl compounds useful in this invention are then conveniently prepared by cleaving the glycol structure of the corresponding 2-(α,β-dihydroxyphenethyl) substances. Methyl 3-hydroxy-5-oxo-2-(αβ-dihydroxyphenethyl)cyclopent-1-eneheptanoate in ethanol is contacted with aqueous sodium periodate, thus affording methyl 3-hydroxy-2-formyl-5-oxocyclopent-1-eneheptanoate. The 2-formyl compounds are alternatively produced from the corresponding 2-styryl derivatives by combining the hydroxylation and cleavage processes. Methyl 3-hydroxy-5-oxo-2-styrylcyclopent-1-eneheptanoate in aqueous dioxane is thus allowed to react with osmium tetroxide and sodium periodate to afford methyl 2-formyl-3-hydroxy-5-oxocyclopent-1-eneheptanoate.
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:32])[C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:22]=[C:23](Cl)[C:24]3[CH:29]=[C:28]([Cl:30])[S:27][C:25]=3[N:26]=2)=[CH:17][CH:16]=1>>[CH3:12][O:13][C:14](=[O:32])[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]([Cl:30])[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(Cl)sc3n2)cc1
Product: COC(=O)c1ccc(-c2nc(NCc3cccc([N+](=O)[O-])c3)c3cc(Cl)sc3n2)cc1

Procedure:
The reaction procedure as above wherein 3-nitrobenzylamine is reacted with 4-(4-chloro-6-chloro-thieno-[2,3-d]-pyrimidin-2-yl)-benzoic acid methylester yields 4-[4-(3-nitrobenzylamino)-6-chloro-thieno-[2,3-d]-pyrimidin-2-yl]-benzoic acid methylester.
Reaction SMILES: Br[C:2]1[C:3](=[O:33])[C:4]2[C:9]([C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=1[F:18])=[CH:8][CH:7]=[C:6]([O:19][CH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][N:26]([S:29]([CH3:32])(=[O:31])=[O:30])[CH2:25][CH2:24]1)[CH:5]=2.O1CCN(CCOC2C=C3C(C(C4C=CC=CC=4)=C(Br)C3=O)=CC=2)CC1.[F:60][C:61]1[CH:62]=[C:63](B(O)O)[CH:64]=[CH:65][C:66]=1[O:67][CH3:68]>>[F:60][C:61]1[CH:62]=[C:63]([C:2]2[C:3](=[O:33])[C:4]3[C:9]([C:10]=2[C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=2[F:18])=[CH:8][CH:7]=[C:6]([O:19][CH2:20][CH2:21][CH2:22][N:23]2[CH2:24][CH2:25][N:26]([S:29]([CH3:32])(=[O:31])=[O:30])[CH2:27][CH2:28]2)[CH:5]=3)[CH:64]=[CH:65][C:66]=1[O:67][CH3:68]
Reactant: CS(=O)(=O)N1CCN(CCCOc2ccc3c(c2)C(=O)C(Br)=C3c2ccc(F)cc2F)CC1
Reactant: COc1ccc(B(O)O)cc1F
Agent: O=C1C(Br)=C(c2ccccc2)c2ccc(OCCN3CCOCC3)cc21
Product: COc1ccc(C2=C(c3ccc(F)cc3F)c3ccc(OCCCN4CCN(S(C)(=O)=O)CC4)cc3C2=O)cc1F
Yield: 77 %

Procedure:
The procedure of Step 7 of Example 1 was repeated except for using 2-bromo-3-(2,4-difluorophenyl)-6-[3-(4-(methylsulfonyl)piperazin-1-yl)propoxy]-1H-inden-1-one obtained in Step 1 of Example 108 as a starting material instead of 6-(2-morpholinoethoxy)-2-bromo-3-phenyl-1H-inden-1-one and 3-fluoro-4-methoxyphenylboronic acid instead of 3-pyridinylboronic acid to obtain the title compound (77%).
Reaction SMILES: C1O[C:4]([CH:17](Br)[CH3:18])([CH2:5][N:6]2[C:10](=[O:11])[C:9]3=[CH:12][CH:13]=[CH:14][CH:15]=[C:8]3[C:7]2=[O:16])[O:3]C1.[N-:21]=[N+:22]=[N-:23].[Na+]>CS(C)=O>[C:10]1(=[O:11])[N:6]([CH2:5][C:4](=[O:3])[CH:17]([N:21]=[N+:22]=[N-:23])[CH3:18])[C:7](=[O:16])[C:8]2=[CH:15][CH:14]=[CH:13][CH:12]=[C:9]12
Reactant: [N-]=[N+]=[N-]
Reactant: CC(Br)C1(CN2C(=O)c3ccccc3C2=O)OCCO1
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(N=[N+]=[N-])C(=O)CN1C(=O)c2ccccc2C1=O

Procedure:
In the manner given in example 3, 1-phthalimido-3-bromo-2-butanone ethyleneketal in dimethyl sulfoxide is heated with sodium azide to give 1-phthalimido-3-azido-2-butanone, ethylene ketal.
Reaction SMILES: [NH2:1][C:2]([CH:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)=[O:3].[CH2:10]([O:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20]Cl)=[CH:16][CH:15]=1)[CH2:11][CH3:12].C(=O)(O)[O-].[K+].O>C1(C)C=CC=CC=1>[NH2:1][C:2]([CH:4]1[CH2:9][CH2:8][N:7]([CH2:20][C:17]2[CH:18]=[CH:19][C:14]([O:13][CH2:10][CH2:11][CH3:12])=[CH:15][CH:16]=2)[CH2:6][CH2:5]1)=[O:3]
Reactant: CCCOc1ccc(CCl)cc1
Reactant: NC(=O)C1CCNCC1
Agent: O=C([O-])O
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCCOc1ccc(CN2CCC(C(N)=O)CC2)cc1
Yield: 79.1 %

Procedure:
The method taught by R. A. Farr et al, J. Org. Chem. 1981, 46, 1212-1215, was used in the following two-step preparation. A vigorously stirred solution of 16.5 grams (0.129 mole) of 4-aminocarbonylpiperidine, 25.0 grams (0.135 mole) of 4-propoxyphenylmethyl chloride, and 19.4 grams (0.193 mole) of potassium bicarbonate in 200 mL of toluene was heated at reflux for 6.5 hours. The reaction mixture was then cooled, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with two portions of an aqueous solution saturated with sodium chloride. The organic layer was dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to a solid residue, which was slurried in pentane and collected by filtration, yielding 28.2 grams of 4-aminocarbonyl-N-(4-propoxyphenylmethyl)piperidine, mp 142°-146° C. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:18][C:19]([O:21][CH3:22])=[O:20]>>[CH3:22][O:21][C:19]([CH2:18][O:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=1)=[O:20]
Reactant: COC(=O)CBr
Reactant: OCCc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)COc1ccc(CCO)cc1

Procedure:
Prepared from 2-(4-hydroxyphenyl)-ethanol, potassium carbonate and methyl bromoacetate analogously to Example XXXVa.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[C:5]#[N:6].O.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:19]([F:24])([F:23])C([O-])=O.[Na+]>CN(C)C=O>[F:23][CH:19]([F:24])[O:10][C:9]1[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[CH:3][C:2]=1[F:1]
Reactant: N#Cc1ccc(O)c(F)c1
Reactant: O=C([O-])C(F)(F)Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(OC(F)F)c(F)c1
Temperature: 110 °C
Reaction time: 2 h
Yield: 96.7 %

Procedure:
To a mixed solution of 3-fluoro-4-hydroxybenzonitrile (3.10 g) in N,N-dimethylformamide (31 ml)/water (3.1 ml) were successively added cesium carbonate (10.3 g) and sodium chlorodifluoroacetate (7.93 g). After stirring at 110° C. for 2 hr, the reaction mixture was partitioned by adding toluene and water. The aqueous layer was extracted with toluene, and the combined organic layer was washed with water. The organic layer was dried over anhydrous magnesium sulfate, filtrated, and concentrated under reduced pressure to give the title compound (4.09 g).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11](=[O:19])OC2C=CC=CC=2)[N:7]([CH2:20][CH:21]([CH3:23])[CH3:22])[N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.[CH3:33][O:34][C:35]1[CH:36]=[C:37]2[C:42](=[CH:43][C:44]=1[O:45][CH3:46])[N:41]=[CH:40][N:39]=[C:38]2[S:47][C:48]1[CH:49]=[C:50]([CH:52]=[CH:53][CH:54]=1)[NH2:51]>C1COCC1>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:51][C:50]2[CH:52]=[CH:53][CH:54]=[C:48]([S:47][C:38]3[C:37]4[C:42](=[CH:43][C:44]([O:45][CH3:46])=[C:35]([O:34][CH3:33])[CH:36]=4)[N:41]=[CH:40][N:39]=3)[CH:49]=2)=[O:19])[N:7]([CH2:20][CH:21]([CH3:22])[CH3:23])[N:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: COc1cc2ncnc(Sc3cccc(N)c3)c2cc1OC
Reactant: CC(C)Cn1nc(C(C)(C)C)cc1NC(=O)Oc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2ncnc(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C)nn4CC(C)C)c3)c2cc1OC
Temperature: 60 °C
Yield: 32 %

Procedure:
A stirred solution of phenyl 3-tert-butyl-1-isobutyl-1H-pyrazol-5-ylcarbamate described in Example 332A (150 mg, 0.47 mmol), N,N-diisopropylethylamine (80 mg, 0.62 mmol) and 3-(6,7-dimethoxyquinazolin-4-ylthio)aniline (prepared as described in Example 115B) (100 mg, 0.31 mmol) in THF (1.0 mL) was heated at 60° C. for 15 h. After cooling to rt, the reaction solution was partitioned between dichloromethane and a saturated aqueous solution of sodium carbonate. The organic phase was separated and concentrated under reduced pressure. The crude product was purified via silica gel column chromatography (eluting with a gradient of 40:1 to 20:1 dichloromethane:methanol) then reverse-phase preparative HPLC to afford 1-(3-tert-butyl-1-isobutyl-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)urea (52 mg, 32%) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 9.07 (s, 1H), 8.70 (s, 1H), 8.48 (s, 1H), 7.85 (s, 1H), 7.24-7.53 (m, 5H), 6.07 (s, 1H), 4.00 (s, 6H), 3.72 (d, J=7.2 Hz, 2H), 2.07 (m, 1H), 1.20 (s, 9H), 0.83 (d, J=6.8 Hz, 6H); LC-MS (ESI) m/z 535 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[NH:10][N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].[Cl:17][C:18]1[CH:25]=[CH:24][CH:23]=[C:22](F)[C:19]=1[CH:20]=[O:21].C(=O)([O-])[O-].[Cs+].[Cs+].C(O[Si](C)(C)C)C>CN(C=O)C>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:22]1[CH:23]=[CH:24][CH:25]=[C:18]([Cl:17])[C:19]=1[CH:20]=[O:21])[N:9]=[CH:8]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=Cc1c(F)cccc1Cl
Reactant: CC(C)(C)c1cc(F)c2c(=O)[nH]ncc2c1
Agent: CCO[Si](C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)c1cc(F)c2c(=O)n(-c3cccc(Cl)c3C=O)ncc2c1
Temperature: 60 °C
Reaction time: 4 h
Yield: 49.9 %

Procedure:
To a 10 mL round bottom flask were added 6-tert-butyl-8-fluoro-2H-phthalazin-1-one 101h (640 mg, 2.9 mmol), 2-chloro-6-fluorobenzaldehyde (506 mg, 3.2 mmol), and cesium carbonate (488 mg, 1.5 mmol). The flask was evacuated and backfilled with nitrogen three times then ethoxytrimethylsilane (684 mg, 5.8 mmol) and DMF (5 mL) were added to the reaction flask. The resulting mixture was heated to 60° C. After 4 h of stirring, the solution was allowed to cool down to ambient temperature and the reaction was quenched by addition of 2 mL of H2O drop-wise. The desired product started to precipitate from the DMF and water mixture. The solid was collected by filtration after cooling down to 5° C., and washed with DMF/water (2/1, 2 mL, pre-cooled to 6° C.) and H2O (2 mL). The filter cake was dried under vacuum oven at 65° C. for overnight to afford 519 mg (52%) of 101i as a yellow solid. MS: [M+H]+: 359
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[C:19]([CH:31]=[CH:32][CH:33]=2)[C:20]([NH:22][C:23]2[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=2[F:30])=[O:21])[CH:5]=[CH:4][N:3]=1.[CH3:34][O:35][C:36]1[CH:42]=[C:41]([N:43]2[CH2:48][CH2:47][CH:46]([N:49]3[CH2:54][CH2:53][O:52][CH2:51][CH2:50]3)[CH2:45][CH2:44]2)[CH:40]=[CH:39][C:37]=1[NH2:38].C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(O)C.C(Cl)Cl>[F:30][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]([F:29])[C:23]=1[NH:22][C:20](=[O:21])[C:19]1[CH:31]=[CH:32][CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:38][C:37]3[CH:39]=[CH:40][C:41]([N:43]4[CH2:48][CH2:47][CH:46]([N:49]5[CH2:54][CH2:53][O:52][CH2:51][CH2:50]5)[CH2:45][CH2:44]4)=[CH:42][C:36]=3[O:35][CH3:34])[N:7]=2)[CH:18]=1
Reactant: O=C(Nc1c(F)cccc1F)c1cccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)c1
Reactant: COc1cc(N2CCC(N3CCOCC3)CC2)ccc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)O
Solvent: ClCCl
Product: COc1cc(N2CCC(N3CCOCC3)CC2)ccc1Nc1nccc(-c2c(-c3cccc(C(=O)Nc4c(F)cccc4F)c3)nc3ccccn23)n1
Temperature: 180 °C
Yield: 66.7 %

Procedure:
A mixture of 3-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-benzamide (Intermediate Example 1) (139 mg, 0.30 mmol), 2-(methyloxy)-4-[4-(4-morpholinyl)-1-piperidinyl]aniline (79 mg, 0.27 mmol) and p-toluenesulfonic acid (137 mg, 0.71 mmol) in iPrOH was heated in the microwave at 180° C. for 13.5 min. The mixture was dissolved in DCM and concentrated onto silica gel. The crude material was purified by flash column chromatography to give 129 mg (60%) of the title compound. 1H NMR (400 MHz, DMSO-d6) δ 10.22 (s, 1H), 9.38 (br s, 1H), 8.44 (s, 1H), 8.31 (s, 1H), 8.18 (d, J=5.2 Hz, 1H), 8.03 (d, J=8.0 Hz, 1H), 7.80 (d, J=8.0 Hz, 1H), 7.71 (d, J=9.2 Hz, 1H), 7.59 (t, J=7.8 Hz, 1H), 7.46-7.35 (m, 2H), 7.19 (t, J=8.0 Hz, 1H), 6.96 (t, J=6.8 Hz, 1H), 6.65 (m, 1H), 6.48-6.43 (m, 2H), 3.77 (s, 3H), 3.71 (d, J=12.4 Hz, 2H), 3.56-3.54 (M, 4H), 2.67-2.62 (m, 2H), 2.49-2.46 (m under DMSO peak, 4H), 2.27-2.22 (m, 1H), 1.86-1.83 (m, 2H), 1.52-1.44 (m, 2H). MS (ESI) m/z=717 [M+H]+.