Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([C:8]1[N+:13]([O-])=[CH:12][CH:11]=[C:10]([CH2:15][OH:16])[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17](OC(=O)C)(=[O:19])[CH3:18]>O1CCOCC1>[C:17]([O:16][CH2:15][C:10]1[CH:9]=[C:8]([O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[N:13]=[CH:12][CH:11]=1)(=[O:19])[CH3:18]
Reactant: [O-][n+]1ccc(CO)cc1Oc1ccccc1
Reactant: CC(=O)OC(C)=O
Solvent: C1COCCO1
Product: CC(=O)OCc1ccnc(Oc2ccccc2)c1

Procedure:
In accordance with the process of Example 1, 37 g of 6-phenoxy-4-picoline was oxidized by using hydrogen peroxide-glacial acetic acid to obtain 28.2 g of 6-phenoxypyridine-4-methanol-N-oxide. Then, 28.2 g of 6-phenoxypyridine-4-methanol-N-oxide and 28.6 g of acetic anhydride were added to 400 ml of dioxane and the mixture was refluxed for 5 hours to react them.
Reaction SMILES: C[O:2][C:3](=[O:20])[C:4](=[O:19])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][CH:6]=1.[OH-].[Na+]>CO>[C:13]1([CH2:12][O:11][C:8]2[CH:9]=[CH:10][C:5]([C:4](=[O:19])[C:3]([OH:20])=[O:2])=[CH:6][CH:7]=2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COC(=O)C(=O)c1ccc(OCc2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C(=O)c1ccc(OCc2ccccc2)cc1
Yield: 89.6 %

Procedure:
A mixture of 4-[(phenylmethyl)oxy]-alpha-oxobenzeneacetic acid methyl ester (0.53 g) in methanol (5 mL) and 0. SN sodium hydroxide (8 mL) were heated on the steam bath for 0.5 hours while methanol was distilled out. The resulting mixture containing solid sodium salt was cooled, concentrated to remove the organic solvents, acidified with 1N hydrochloric acid (4 mL), and extracted with diethyl ether (3×25 mL). The organic layers were washed in turn with water (2×10 mL) and the combined organic layers were dried (Na2SO4), filtered, and evaporated to give 0.5 g of crude product. Crystallization from benzene-hexane provided 0.45 g of 4-[(phenylmethyl)oxy]-alpha-oxobenzeneacetic acid, mp 97°-98° C.
Reaction SMILES: C([Li])CCC.[O:6]1CC[CH2:9][CH2:8][CH:7]1OCC#C.[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH:23]=[C:24]([O:28][CH3:29])[C:25]=1[O:26][CH3:27])[CH:21]=[O:22].[Cl-].[NH4+]>O1CCCC1.CCOCC>[OH:6][CH2:7][C:8]#[C:9][C:21]([C:20]1[CH:23]=[C:24]([O:28][CH3:29])[C:25]([O:26][CH3:27])=[C:18]([O:17][CH3:16])[CH:19]=1)=[O:22]
Reactant: COc1cc(C=O)cc(OC)c1OC
Reactant: C#CCOC1CCCCO1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1cc(C(=O)C#CCO)cc(OC)c1OC
Reaction time: 0.5 h

Procedure:
44.6 ml of n-butyllithium solution (1.6M in hexane) were added to a solution of 10.0 g (71.3 mmol) of 3-[(tetrahydro-2H-pyran-2-yl)oxy]1-propyne in 150 ml of absolute tetrahydrofuran at -78° . The reaction mixture was stirred at -40° for 30 minutes and then treated with 14.0 g (71.3 mmol) of 3,4,5-trimethoxybenzaldehyde in 50 ml of tetrahydrofuran. The reaction mixture was subsequently stirred at 0° for 1 hour and then treated with 100 ml of saturated ammonium chloride solution and 200 ml of ether. The aqueous phase was extracted twice with ether, whereupon the combined organic phases were dried over magnesium sulphate and the solvent was distilled off. The residue was dissolved in 150 ml of methylene chloride and added dropwise at 0° to a suspension of 186 g of manganese dioxide in 300 ml of methylene chloride. The reaction mixture was stirred at room temperature for 30 minutes, filtered over magnesium sulphate and evaporated. The residue was dissolved in 300 ml of tetrahydrofuran/ethanol (1:1) and treated with 2.4 g of pyridinium p-toluenesulphonate. The mixture was stirred at room temperature for 24 hours, 100 ml of water and 200 ml of ether were then added, the aqueous phase was extracted twice with ether, the combined organic phases were dried over magnesium sulphate and the solvent was distilled off. Crystallization from ethyl acetate/hexane yielded 4-hydroxy 1-(3,4,5 -trimethoxyphenyl)-2-butyn- 1-one of melting point 104°-105°.
Reaction SMILES: N12CCCN=C1CCCCC2.[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([N:21]2[CH2:26][CH2:25][N:24]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([C:34]([OH:43])([C:39]([F:42])([F:41])[F:40])[C:35]([F:38])([F:37])[F:36])=[CH:30][CH:29]=3)[CH2:23][CH2:22]2)=[O:20])=[CH:15][C:14]=1[F:44].[C:45]([Si:49]([CH3:52])([CH3:51])Cl)([CH3:48])([CH3:47])[CH3:46]>ClCCl>[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([N:21]2[CH2:22][CH2:23][N:24]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([C:34]([O:43][Si:49]([C:45]([CH3:48])([CH3:47])[CH3:46])([CH3:52])[CH3:51])([C:35]([F:36])([F:37])[F:38])[C:39]([F:41])([F:42])[F:40])=[CH:30][CH:29]=3)[CH2:25][CH2:26]2)=[O:20])=[CH:15][C:14]=1[F:44]
Reactant: Nc1ccc(C(=O)N2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1F
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)[Si](C)(C)OC(c1ccc(CN2CCN(C(=O)c3ccc(N)c(F)c3)CC2)cc1)(C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 75 %

Procedure:
1,8-Diazabicyclo[5.4.0]undec-7-ene (1.559 mmol, 0.233 mL, 237 mg) was added to a cooled (ice/slurry) solution of (4-amino-3-fluorophenyl)(4-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzyl)piperazin-1-yl)methanone (1.199 mmol, 575 mg) and tert-butyldimethylchlorosilane (1.559 mmol, 235 mg) in dichloromethane (20 mL) under nitrogen. The resulting solution was stirred for 15 minutes prior to the removal of the external cooling bath. The reaction was allowed to warm to room temperature and stirred for 16 hours. The reaction mixture was diluted with dichloromethane (100 ml) and washed with 0.5M hydrochloric acid (100 ml), 0.5M sodium hydroxide (100 ml) and brine (100 ml). The organic phase was dried on magnesium sulfate, filtered and concentrated under vacuum to give a crude oil. This oil was purified by SCX chromatography to afford the title compound (534 mg). MS (ESI) m/z 594.3 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[N:11][C:10]([O:13][CH:14]([C:16]([O:18]CC)=[O:17])[CH3:15])=[N:9]2)=[CH:4][CH:3]=1.[OH-].[K+]>C(O)C>[C:16]([CH:14]([O:13][C:10]1[N:11]=[CH:12][N:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:9]=1)[CH3:15])([OH:18])=[O:17]
Reactant: CCOC(=O)C(C)Oc1ncn(-c2ccc(Cl)cc2)n1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC(Oc1ncn(-c2ccc(Cl)cc2)n1)C(=O)O

Procedure:
Three g of the compound of Example 12 was refluxed for 2 hours with 1.1 g of potassium hydroxide in 100 ml of ethanol, and the product was collected as shown in Example 22 and was recrystallized from ethyl acetate to obtain 1.9 g of the desired product, m.p. 196°-198°.
Reaction SMILES: [OH:1][CH:2]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=2[C:13]#[N:14])=[CH:7][CH:6]=1)[CH2:3][CH3:4].C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>C1COCC1>[CH3:26][S:27]([O:1][CH:2]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=2[C:13]#[N:14])=[CH:9][N:10]=1)[CH2:3][CH3:4])(=[O:29])=[O:28]
Reactant: CS(=O)(=O)Cl
Reactant: CCC(O)c1ccc(-c2ccccc2C#N)cn1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCC(OS(C)(=O)=O)c1ccc(-c2ccccc2C#N)cn1
Reaction time: 0.08 h
Yield: 71 %

Procedure:
To solution of 2-(6-(1-hydroxypropyl)pyridin-3-yl)benzonitrile (0.05 g) in THF (3 mL) was added triethyl amine (0.042 g), the mixture was stirred for 5 minutes, and then methanesulfonyl chloride was added (0.47 g). The mixture was stirred at room temperature for 90 min. The reaction mixture was quenched with sodium bicarbonate and extracted with ethyl acetate. The organic extracts were dried over sodium sulphate, filtered and concentrated to obtain 1-(5-(2-cyanophenyl)pyridin-2-yl)propyl methanesulfonate (0.050 g, 71% yield), which was used directly in the next step.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([C:34]1([C:39]([NH2:41])=[O:40])[CH2:38][CH2:37][CH2:36][CH2:35]1)(=[O:33])=[O:32]>>[NH2:23][C:20]1[N:21]=[CH:22][C:17]([C:3]2[CH:4]=[CH:5][C:6]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[S:31]([C:34]3([C:39]([NH2:41])=[O:40])[CH2:38][CH2:37][CH2:36][CH2:35]3)(=[O:33])=[O:32])=[CH:7][C:2]=2[F:1])=[N:18][CH:19]=1
Reactant: NC(=O)C1(S(=O)(=O)c2ccccc2Br)CCCC1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Product: NC(=O)C1(S(=O)(=O)c2ccccc2-c2ccc(-c3cnc(N)cn3)c(F)c2)CCCC1

Procedure:
The title compound was prepared using conditions analogous to those used to make Example 6 utilizing 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazin-2-amine and 1-(2-bromophenylsulfonyl)cyclopentanecarboxamide. MS (ESI): mass calcd. for C22H21FN4O3S, 440.13; m/z found, 441.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.40 (s, 1H), 8.05 (s, 1H), 7.98 (d, J=7.8, 1H), 7.86 (m, 1H), 7.76 (m, 1H), 7.65 (m, 1H), 7.46 (s, 1H), 7.37 (d, J=7.4, 2H), 7.26-7.23 (m, 2H), 6.77 (s, 2H), 2.20 (s, 2H), 2.05-1.88 (m, 2H), 1.56 (s, 2H), 1.43 (s, 2H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:18]=[C:17]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:16]([O:23][CH:24]([CH3:26])[CH3:25])=[C:15]([CH2:27]Br)[C:14]=2[CH3:29])=[CH:7][CH:6]=1.[CH3:31][Si:32]([C:35]#[CH:36])([CH3:34])[CH3:33].C(OCC)(=O)C>C(N(CC)CC)C.CN(C)C=O.CCCCCC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:30])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:18]=[C:17]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:16]([O:23][CH:24]([CH3:26])[CH3:25])=[C:15]([CH2:27][C:36]#[C:35][Si:32]([CH3:34])([CH3:33])[CH3:31])[C:14]=2[CH3:29])=[CH:7][CH:6]=1
Reactant: C#C[Si](C)(C)C
Reactant: COC(=O)Cc1ccc(C#Cc2cc(C(C)(C)C)c(OC(C)C)c(CBr)c2C)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCCCCC
Solvent: CCN(CC)CC
Product: COC(=O)Cc1ccc(C#Cc2cc(C(C)(C)C)c(OC(C)C)c(CC#C[Si](C)(C)C)c2C)cc1
Temperature: 85 °C
Yield: 31.1 %

Procedure:
A solution of [4-(3-bromomethyl-5-tert-butyl-4-isopropoxy-2-methyl-phenylethynyl)-phenyl]-acetic acid methyl ester (Intermediate 148, 0.12 g, 0.25 mmol) in triethyl amine (1 mL) and N,N-dimethylformamide (4 mL) was sparged with argon and treated with trimethylsilylacetylene (0.5 mL, 3.5 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.025 g, 0.036 mmol). The resulting reaction mixture was heated at 85° C. overnight at the end of which it was cooled to ambient temperature and subjected to flash column chromatography over silica gel (230-400 mesh) using 4% ethyl acetate in hexane as the eluent followed by preparative normal phase HPLC using 3% ethyl acetate in hexane as the mobile phase to afford the title compound as an oil (0.038 g, 31%).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:7]=[C:8]([CH2:14][OH:15])[CH:9]=[C:10]([CH2:12][OH:13])[CH:11]=1)[CH2:2][CH2:3][CH3:4].C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O>C(Cl)Cl>[CH2:1]([O:5][C:6]1[CH:11]=[C:10]([CH:12]=[O:13])[CH:9]=[C:8]([CH:7]=1)[CH:14]=[O:15])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1cc(CO)cc(CO)c1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CCCCOc1cc(C=O)cc(C=O)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 75.9 %

Procedure:
(5-Butoxy-1,3-phenylene)dimethanol (0.24 g, 1.15 mmol) and CH2Cl2 (10 mL) were added to a round-bottom flask. To the solution was added PCC (0.74 g, 3.45 mmol), and the reaction was stirred at rt for 16 h. The reaction mixture was concentrated under reduced pressure. Purification by column chromatography (90% hexanes/EtOAc) afforded the desired product (0.18 g, 44%, 3 steps) as a white semi-solid. 1H NMR (300 MHz, CDCl3) δ ppm 9.99 (s, 2H), 7.89 (s, 1H), 7.58 (s, 21-1), 4.03 (t, J=6.6 Hz, 2H), 1.77 (quint, J=6.6 Hz, 2H), 1.47 (sext, J=7.2 Hz, 2H), 0.94 (t, J=7.5 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ ppm 191.3, 160.6, 138.6, 124.2, 120.1, 68.9, 31.3, 19.4, 14.1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=O)=[CH:5]2.[CH3:14][N:15]([CH3:31])[CH:16]1[CH2:20][CH2:19][N:18]([C:21]2[S:22][C:23]3[CH:29]=[C:28]([NH2:30])[CH:27]=[CH:26][C:24]=3[N:25]=2)[CH2:17]1>>[CH3:14][N:15]([CH3:31])[CH:16]1[CH2:20][CH2:19][N:18]([C:21]2[S:22][C:23]3[CH:29]=[C:28]([NH:30][C:11]([C:6]4[NH:7][C:8]5[C:4]([CH:5]=4)=[CH:3][C:2]([F:1])=[CH:10][CH:9]=5)=[O:13])[CH:27]=[CH:26][C:24]=3[N:25]=2)[CH2:17]1
Reactant: O=C(O)c1cc2cc(F)ccc2[nH]1
Reactant: CN(C)C1CCN(c2nc3ccc(N)cc3s2)C1
Product: CN(C)C1CCN(c2nc3ccc(NC(=O)c4cc5cc(F)ccc5[nH]4)cc3s2)C1
Yield: 17.3 %

Procedure:
Prepare according to Method B, using 5-fluoroindole-2-carboxylic acid (110 mg, 0.614 mmol) and 2-(3-dimethylamino-pyrrolidin-1-yl)-benzothiazol-6-ylamine (162 mg, 0.618 mmol) to yield the title compound (45 mg, 28%). mass spectrum (m/e): 424 [M+H], 422 [M−H].
Reaction SMILES: [F:1][C:2]([F:18])([C:14]([F:17])([F:16])[F:15])[C:3]([F:13])([F:12])[C:4]([F:11])([F:10])[CH2:5][CH2:6][CH2:7][CH2:8]O.[BrH:19].S(=O)(=O)(O)O>O>[Br:19][CH2:8][CH2:7][CH2:6][CH2:5][C:4]([F:11])([F:10])[C:3]([F:13])([F:12])[C:2]([F:18])([F:1])[C:14]([F:17])([F:16])[F:15]
Reactant: Br
Reactant: OCCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: O=S(=O)(O)O
Solvent: O
Product: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)CCCCBr
Temperature: 100 °C

Procedure:
To a mixture of 12.50 g of 4-(nonafluorobutyl)-1-butanol and 150 mL of 48 weight percent hydrobromic acid was slowly added 15 mL of concentrated sulfuric acid. The reaction mixture was heated at 100° C. for 18 hr, and then poured into 500 mL of water. The mixture was extracted with hexanes, and the combined organic phases were washed with saturated aqueous sodium bicarbonate and dried over anhydrous magnesium sulfate. Filtration and concentration afforded 12.50 g of crude 1-bromo-4-(nonafluorobutyl)butane as a light amber liquid, which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH2:6][NH2:7].[Cl:13][C:14]1[N:15]=[C:16](Cl)[C:17]2[CH:22]=[C:21]([CH3:23])[S:20][C:18]=2[N:19]=1>>[Cl:13][C:14]1[N:15]=[C:16]([NH:7][CH2:6][C:5]2[CH:8]=[CH:9][C:10]([O:11][CH3:12])=[C:3]([O:2][CH3:1])[CH:4]=2)[C:17]2[CH:22]=[C:21]([CH3:23])[S:20][C:18]=2[N:19]=1
Reactant: COc1ccc(CN)cc1OC
Reactant: Cc1cc2c(Cl)nc(Cl)nc2s1
Product: COc1ccc(CNc2nc(Cl)nc3sc(C)cc23)cc1OC

Procedure:
Following the procedure of Example 1, the reaction of 3,4-dimethoxybenzylamine with 2,4-dichloro-6-methyl-thieno-[2,3-d]-pyrimidine yields 2-chloro-6-methyl-4-(3,4-dimethoxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[N:11][C:12]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([C@H:22]3[O:27][CH2:26][CH2:25][N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:23]3)=[CH:18][CH:17]=2)=[N:13][CH:14]=1)C1C=CC=CC=1.CO>C1COCC1>[OH:8][C:9]1[CH:14]=[N:13][C:12]([NH:15][C:16]2[CH:17]=[CH:18][C:19]([C@H:22]3[O:27][CH2:26][CH2:25][N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:23]3)=[CH:20][CH:21]=2)=[N:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](c2ccc(Nc3ncc(OCc4ccccc4)cn3)cc2)C1
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCO[C@H](c2ccc(Nc3ncc(O)cn3)cc2)C1
Yield: 107.3 %

Procedure:
(R)-tert-Butyl 2-(4-(5-(benzyloxy)pyrimidin-2-ylamino)phenyl)morpholine-4-carboxylate (0.36 g) was combined with MeOH (15 ml) and THF (5 ml) to give a light brown solution. The mixture was degassed by bubbling through argon for several minutes. Palladium on charcoal (41.4 mg, 10%) was added. The reaction mixture was then stirred under a balloon filled with argon overnight. The reaction mixture was then filtered through celite and concentrated in vacuo to afford (R)-tert-butyl 2-(4-(5-hydroxypyrimidin-2-ylamino)phenyl)morpholine-4-carboxylate (311 mg, quant.) as a light brown foam which was used in the next step without further purification. MS (ISP): 373.2 ([M+H]+).
Reaction SMILES: [C:1]1([C:7]2[S:8][CH:9]=[C:10]([CH:12]3[CH2:17][CH2:16][N:15](C(OCC4C5C=CC=CC=5C5C4=CC=CC=5)=O)[CH2:14][CH2:13]3)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO.N1CCCCC1>C(Cl)Cl>[C:1]1([C:7]2[S:8][CH:9]=[C:10]([CH:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[N:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)N1CCC(c2csc(-c3ccccc3)n2)CC1
Solvent: ClCCl
Solvent: CO
Solvent: C1CCNCC1
Product: c1ccc(-c2nc(C3CCNCC3)cs2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.4 %

Procedure:
To a stirred solution of (9H-fluoren-9-yl)methyl 4-(2-phenylthiazol-4-yl)piperidine-1-carboxylate (2 g, 4.29 mmol) in CH2Cl2:MeOH (15:5 mL) was added piperidine (5 mL). This reaction mixture was stirred at RT for 8 h. The reaction mixture was concentrated under reduced pressure and the crude material was chromatographed over silica gel eluting with a gradient (0-10% MeOH:CH2Cl2) to afford 2-phenyl-4-(piperidin-4-yl)thiazole (1 g, 96%) as an off white solid.
Reaction SMILES: [OH:1]O.[CH:3]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH:4]=1>C(Cl)(Cl)Cl>[CH:3]12[O:1][CH:4]1[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]2
Reactant: C1=CCCCCCC1
Reactant: OO
Solvent: ClC(Cl)Cl
Product: C1CCCC2OC2CC1
Temperature: 70 °C
Yield: 89.3 %

Procedure:
Crosslinked polystyrene-divinylbenzene beads substituted in the phenyl rings by arsono groups (Polymer II of Example 2 (B) above, containing 0.25 mmole As) was added to a two phase system of 1.7 g of 30% aqueous H2O2 (15 mmoles of H2O2) and cyclooctene (7.5 mmoles) in chloroform (7 ml). The mixture was heated in a closed thick-walled tube at 70° C. for 45 hours. Cyclooctene oxide (6.7 mmol, 89% yield) was obtained after 45 hours. The polymer was then filtered and reused with no apparent loss of activity (90% yield after 55 hours at 70° C.).
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:20][CH2:19][CH:18]([N:21]([C:33]2[CH:34]=[C:35]3[C:39](=[CH:40][CH:41]=2)[NH:38][CH:37]=[CH:36]3)[CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29](OC)=[O:30])[CH:24]=2)[CH2:17][CH2:16]1)=O)(C)(C)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(Cl)Cl>[NH:38]1[C:39]2[C:35](=[CH:34][C:33]([N:21]([CH2:22][C:23]3[CH:24]=[C:25]([CH2:29][OH:30])[CH:26]=[CH:27][CH:28]=3)[CH:18]3[CH2:19][CH2:20][NH:15][CH2:16][CH2:17]3)=[CH:41][CH:40]=2)[CH:36]=[CH:37]1
Reactant: COC(=O)c1cccc(CN(c2ccc3[nH]ccc3c2)C2CCN(C(=O)OC(C)(C)C)CC2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: OCc1cccc(CN(c2ccc3[nH]ccc3c2)C2CCNCC2)c1
Reaction time: 3 h
Yield: 8.7 %

Procedure:
Trifluoroacetic acid (0.5 mL) was added to a solution of 4-[(1H-indol-5-yl)-(3-methoxycarbonyl-benzyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester (210 mg, 0.453 mmol) in DCM (2.0 mL). The reaction mixture was stirred for 3 hours, the solvent was then evaporated under reduced pressure and the residue was dissolved in DCM, a mixture of MeOH/NH4OH (9.5/0.5) was then added. The resulting mixture was filtered through a celite and silica pad and the filtrate was evaporated under reduced pressure. The residue was dissolved in THF (5.0 mL) and a solution of lithium aluminum hydride (1.0 M in THF, 1.81 mL, 1.81 mmol) was added under nitrogen atmosphere. The reaction mixture was stirred for 30 minutes and it was then quenched by addition of Na2SO4.10H2O. The resulting mixture was filtered and the filtrate was evaporated under reduced pressure to give 13.2 mg (9% yield) of (3-{[(1H-indol-5-yl)-piperidin-4-yl-amino]-methyl}-phenyl)-methanol, MS=336 [M+H]+.
Reaction SMILES: Cl.[CH2:2]([C:9]1([CH2:19][C:20]([C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][C:31]([C:34]4[C:38]5[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=5[O:36][C:35]=4[CH2:43][C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)=[CH:30][CH:29]=3)=[CH:24][CH:23]=2)=[O:21])C(=O)OC(C)(C)[O:11][C:10]1=[O:18])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>C1COCC1>[CH2:2]([CH:9]([CH2:19][C:20]([C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][C:31]([C:34]3[C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=4[O:36][C:35]=3[CH2:43][C:44]3[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=3)=[CH:30][CH:29]=2)=[CH:24][CH:23]=1)=[O:21])[C:10]([OH:18])=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC1(C)OC(=O)C(CC(=O)c2ccc(-c3ccc(-c4c(Cc5ccccc5)oc5ccccc45)cc3)cc2)(Cc2ccccc2)C(=O)O1
Agent: Cl
Solvent: C1CCOC1
Product: O=C(CC(Cc1ccccc1)C(=O)O)c1ccc(-c2ccc(-c3c(Cc4ccccc4)oc4ccccc34)cc2)cc1
Temperature: 25 °C
Yield: 37.5 %

Procedure:
2 N Hydrochloric acid (1 mL) was added to a stirred solution of 5-benzyl-5-(2-[4′-(2-benzylbenzofuran-3-yl)-biphen-4-yl]-2-oxoethyl)-2,2-dimethyl-[1,3]dioxane-4,6-dione (200 mg) in THF (5 mL), and the resultant solution was heated at 70° C. for 6 h and then cooled to room temperature and concentrated in vacuo. The resulting solid was redissolved in DMSO (5 mL), and heated to 150° C. for 3 h before being cooled to room temperature, and diluted with water (20 mL), and extracted with ethyl acetate (3×20 mL). The combined extract was washed with water (2×10 mL), sat'd aq NaCl (3×10 mL), dried over anhyd MgSO4, filtered and concentrated in vacuo. Purification by trituration and filtration from MeOH afforded the title compound as a pale yellow solid (65 mg).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]2[C:13]3[N:14]=[C:15]([CH3:28])[N:16]=[C:17]([N:18]4[CH2:23][CH2:22][CH:21]([CH2:24][C:25]([OH:27])=[O:26])[CH2:20][CH2:19]4)[C:12]=3[S:11][C:10]=2[CH3:29])=[C:4]([CH3:30])[CH:3]=1.I[CH2:32][CH3:33].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C.CCOC(C)=O>[CH2:32]([O:26][C:25](=[O:27])[CH2:24][CH:21]1[CH2:20][CH2:19][N:18]([C:17]2[C:12]3[S:11][C:10]([CH3:29])=[C:9]([C:5]4[C:6]([CH3:8])=[CH:7][C:2]([Br:1])=[CH:3][C:4]=4[CH3:30])[C:13]=3[N:14]=[C:15]([CH3:28])[N:16]=2)[CH2:23][CH2:22]1)[CH3:33]
Reactant: CCI
Reactant: Cc1nc(N2CCC(CC(=O)O)CC2)c2sc(C)c(-c3c(C)cc(Br)cc3C)c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CC1CCN(c2nc(C)nc3c(-c4c(C)cc(Br)cc4C)c(C)sc23)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 69.4 %

Procedure:
A mixture of {1-[7-(4-bromo-2,6-dimethyl-phenyl)-2,6-dimethyl-thieno[3,2-d]pyrimidin-4-yl]-piperidin-4-yl}-acetic acid (30 mg), iodoethane (97 mg) and K2CO3 (17 mg) in DMF (1 mL) was stirred at room temperature for 16 hours. To the reaction mixture were added H2O and EtOAc and separated. The organic layer washed brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by a silica gel column chromatography (silica gel: Wako Gel (C200), eluent: Hexane/EtOAc=4:1) to obtain the title compound (22 mg) as a white crystal.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:16]([F:25])([F:24])[C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[N:3]=1.[CH3:26][C:27]1[NH:31][N:30]=[C:29]([NH2:32])[CH:28]=1.CCN(C(C)C)C(C)C>CN(C=O)C.O>[F:25][C:16]([F:24])([C:17]1[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=1)[C:4]1[N:3]=[C:2]([NH:32][C:29]2[CH:28]=[C:27]([CH3:26])[NH:31][N:30]=2)[C:11]2[C:6](=[CH:7][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:10]=2)[N:5]=1
Reactant: COC(=O)c1ccc2c(Cl)nc(C(F)(F)c3ccc(F)cc3)nc2c1
Reactant: Cc1cc(N)n[nH]1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COC(=O)c1ccc2c(Nc3cc(C)[nH]n3)nc(C(F)(F)c3ccc(F)cc3)nc2c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 101.4 %

Procedure:
A mixture of methyl 4-chloro-2-(difluoro(4-fluorophenyl)methyl)quinazoline-7-carboxylate (1 g, 2.7 mmol), 5-methyl-1H-pyrazol-3-amine (0.32 g, 3.27 mmol), DIEA (0.62 mL, 3.5 mmol), and KI (0.5 g, 3 mmol) in DMF (20 mL) was stirred at rt for 20 h. The mixture was diluted with H2O and stirred for 1 h, and then the precipitated solid was collected by filtration, washed with H2O, and dried to afford methyl 2-(difluoro(4-fluorophenyl)methyl)-4-(5-methyl-1H-pyrazol-3-ylamino)quinazoline-7-carboxylate (1.17 g, 100%). 1H NMR (300 MHz, DMSO-d6) δ 2.24 (s, 3H), 3.97 (s, 3H), 6.31 (s, 1H), 7.15-7.50 (m, 2H), 7.62-7.90 (m, 2H), 7.99-8.13 (m, 1H), 8.20-8.55 (m, 1H), 8.69-9.04 (m, 1H), 10.96 (s, 1H), 12.28 (s, 1H); LC-MS (ESI) m/z 428 (M+H)+.