Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.CN(C)CCN(C)C.[CH3:14][Si:15]([CH3:25])([CH3:24])[NH:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[C:26]1([P:32](Cl)(Cl)=[O:33])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CCCCCC.C1CCCCC1>[C:26]1([P:32]2(=[O:33])[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[CH2:17][N:16]2[Si:15]([CH3:25])([CH3:24])[CH3:14])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: C[Si](C)(C)NCc1ccccc1
Reactant: O=P(Cl)(Cl)c1ccccc1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCCCC1
Product: C[Si](C)(C)N1Cc2ccccc2P1(=O)c1ccccc1
Temperature: 26 °C
Reaction time: 16 h

Procedure:
Under a static nitrogen atmosphere at 0° C., a solution of n-butyllithium (16 g, 0.25 mol) in hexane was added to a solution of tetramethylethylenediamine (28.6 g, 0.246 mol) in 120 ml. of anhydrous cyclohexane with constant stirring. While maintaining the temperature of the reaction at 0° C., a solution of N-trimethylsilylbenzylamine (21.6 g, 0.12 mol) in 60 ml. of anhydrous cyclohexane was added to the reaction mixture to produce a suspension containing a dilithio compound. This suspension was stirred for 16 hours at 26° C. and then cooled to -76° C. using a solid carbon dioxide-acetone bath. A solution of phenylphosphonic dichloride (25 g, 0.128 mol) in 120 ml. of anhydrous cyclohexane was rapidly added to the suspension causing the temperature of the reaction to increase to -15° C. The reaction mixture was allowed to cool to -76° C., after which time the solid carbon dioxide-acetone bath was removed and the reaction mixture was stirred for 3 hours. The reaction mixture was cooled to 0° C., then quenched with the rapid addition of 24 ml. of acetic acid. After stirring the reaction mixture for 5 minutes, the cyclohexane was removed on a rotary evaporator, and the resulting residue was partitioned between methylene chloride and water. The layers were separated and the methylene chloride layer was dried over magnesium sulfate and concentrated in vacuo to yield an oil. Distillation of this oil at 180° C. and 0.3 mm yielded 1-phenyl-2-trimethylsilyl-2,3-dihydro-1H-2,1-benzazaphosphole-1-oxide.
Reaction SMILES: [C-:1]1([CH2:6][C:7]([OH:9])=[O:8])[CH:5]=[CH:4][CH:3]=[CH:2]1.[CH-:10]1[CH:14]=[CH:13][CH:12]=[CH:11]1.[Fe+2:15].S(=O)(=O)(O)O>C(O)C>[C-:1]1([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:5]=[CH:4][CH:3]=[CH:2]1.[CH-:10]1[CH:14]=[CH:13][CH:12]=[CH:11]1.[Fe+2:15]
Reactant: O=C(O)C[c-]1cccc1
Agent: [Fe+2]
Agent: O=S(=O)(O)O
Agent: c1cc[cH-]c1
Solvent: CCO
Product: CCOC(=O)C[c-]1cccc1
Temperature: 0 °C
Yield: 199 %

Procedure:
2.00 g (8.2 mmol) of ferrocenylacetic acid are dissolved in 50 ml of ethanol. 0.5 ml of concentrated sulfuric acid is added. The mixture is brought to reflux for 1 hour. After cooling, the reaction mixture is poured into 100 ml of ice-cold water. The product is extracted with 3 times 40 ml of ether. The ethereal phase is first washed with water (2 times 40 ml) and then dried over magnesium sulfate, filtered and evaporated. 2.22 g of ethyl ferrocenylacetate are obtained. The yield of the reaction is 100%.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[N:8]2[CH:9]=[CH:10][CH:11]=[C:12]([O:13][CH2:14][C:15]3[C:20]([Cl:21])=[CH:19][CH:18]=[C:17]([N:22]([C:24](=[O:27])[CH2:25][OH:26])[CH3:23])[C:16]=3[Cl:28])[C:7]2=[N:6][C:5]=1[CH3:29].[CH3:30]I.O>CN(C)C=O>[Br:3][C:4]1[N:8]2[CH:9]=[CH:10][CH:11]=[C:12]([O:13][CH2:14][C:15]3[C:20]([Cl:21])=[CH:19][CH:18]=[C:17]([N:22]([C:24](=[O:27])[CH2:25][O:26][CH3:30])[CH3:23])[C:16]=3[Cl:28])[C:7]2=[N:6][C:5]=1[CH3:29]
Reactant: Cc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)CO)c3Cl)cccn2c1Br
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCC(=O)N(C)c1ccc(Cl)c(COc2cccn3c(Br)c(C)nc23)c1Cl
Reaction time: 0.17 h
Yield: 19.4 %

Procedure:
To a suspension of sodium hydride (60% in oil, 9 mg) in N,N-dimethylformamide (1 ml) was added 3-bromo-8-[2,6-dichloro-3-(N-glycoloyl-N-methylamino)benzyloxy]-2-methylimidazo[1,2-a]pyridine (100 mg). After stirring for 10 minutes, methyl iodide (36 mg) was added thereto and the mixture was stirred at ambient temperature for 1 hour. To this mixture were added methyl iodide (36 mg) and N,N-dimethylformamide (1 ml). The mixture was stirred at 60° C. for additional 2 hours. The reaction mixture was poured into water and extracted with ethyl acetate 3 times. The combined organic layers were washed with water 4 times and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by preparative thin-layer chromatography (dichloromethane: methanol=20:1, V/V) followed by crystallization from ethanol-diethyl ether to give 3-bromo-8-[3-(N-methoxyacetyl-N-methylamino)-2,6-dichlorobenzyloxy]-2-methylimidazo[1,2-a]pyridine (20 mg) as crystals.
Reaction SMILES: CON(C)[C:4]([CH:6]1[CH2:11][CH2:10][NH:9][C:8](=[O:12])[CH2:7]1)=[O:5].C[Mg+].[Br-].[CH3:17]COCC>C1COCC1>[C:4]([CH:6]1[CH2:11][CH2:10][NH:9][C:8](=[O:12])[CH2:7]1)(=[O:5])[CH3:17]
Reactant: CON(C)C(=O)C1CCNC(=O)C1
Reactant: CCOCC
Agent: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: CC(=O)C1CCNC(=O)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of N-methoxy-N-methyl-2-oxopiperidine-4-carboxamide (2.72 g, 9.79 mmol) in THF (30 ml) was immersed in an ice-bath. MeMgBr (3M) in Et2O (4.57 ml, 13.70 mmol) was added slowly and the remaining white suspension was stirred for 1 h in an ice-bath and over night at room temperature. The reaction mixture was quenched carefully with aqueous saturated NaHCO3 and extracted with DCM. The organic layers were washed with brine, combined, dried over Na2SO4, filtered and concentrated in vacuo to obtain the title compound as yellow-brown oil. The crude product was directly used in the next step.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[CH:13]=[C:12](Cl)[CH:11]=[C:10](Cl)[C:9]=2[Cl:16])=[CH:6][N:5]=[C:4]([N:17]([CH3:19])[CH3:18])[N:3]=1.[Cl:20]C1C=C(Cl)C=CC=1CC#N>>[CH3:19][N:17]([CH3:18])[C:4]1[N:3]=[C:2]([NH2:1])[C:7]([C:8]2[CH:13]=[CH:12][C:11]([Cl:20])=[CH:10][C:9]=2[Cl:16])=[CH:6][N:5]=1
Reactant: CN(C)c1ncc(-c2cc(Cl)cc(Cl)c2Cl)c(N)n1
Reactant: N#CCc1ccc(Cl)cc1Cl
Product: CN(C)c1ncc(-c2ccc(Cl)cc2Cl)c(N)n1

Procedure:
This compound was prepared in an analogous manner to the compound of Example 10 from 2,4-dichlorophenylacetonitrile (Aldrich), mp. 151° C.
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].[Li]CCCC.C[O:14][C:15](=O)[C:16]1[CH:21]=[CH:20][C:19]([F:22])=[C:18]([CH3:23])[CH:17]=1.Cl>C1COCC1.CCCCCC.O1CCOCC1>[CH3:4][O:3][P:2]([CH2:1][C:15]([C:16]1[CH:21]=[CH:20][C:19]([F:22])=[C:18]([CH3:23])[CH:17]=1)=[O:14])(=[O:7])[O:5][CH3:6]
Reactant: COP(C)(=O)OC
Reactant: COC(=O)c1ccc(F)c(C)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: C1COCCO1
Product: COP(=O)(CC(=O)c1ccc(F)c(C)c1)OC
Reaction time: 0.75 h

Procedure:
To a mixture of 19.2 g (155 mmol) dimethyl methylphosphonate in 150 mL THF at −70° C. was added 97 mL (155 mmol) 1.6M n-BuLi in hexane. The mixture was stirred for 45 min and a solution of 11.8 g (70 mmol) 4-fluoro-3-methyl-benzoic acid methyl ester in 15 mL THF was added. After 15 min at −70° C. the mixture was allowed to warm to 0° C. and neutralized with 4N HCl in dioxane. The mixture was diluted with 500 mL THF to obtain [2-(4-fluoro-3-methyl-phenyl)-2-oxo-ethyl]-phosphonic acid dimethyl ester. 6 mmol [2-(4-fluoro-3-methyl-phenyl)-2-oxo-ethyl]-phosphonic acid dimethyl ester in THF was stirred together with 0.5 g (4.6 mmol) pyrimidine-5-carboxaldehyde and 1.65 g Cs2CO3 for 16 h at room temperature. The mixture was diluted with NH4Cl aq. and ethyl acetate. The organic layer was separated, dried with MgSO4 and evaporated to dryness. The residue was used crude in the consecutive step.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([N:9]2[CH2:14][CH2:13][CH:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][CH2:10]2)[S:6][C:7]=1[CH3:8].[O:20]=[CH:21][C:22]1[CH:30]=[CH:29][C:27]([OH:28])=[C:24]([O:25][CH3:26])[CH:23]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH:21]([C:22]1[CH:30]=[CH:29][C:27]([O:28][CH2:2][C:3]2[N:4]=[C:5]([N:9]3[CH2:14][CH2:13][CH:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][CH2:10]3)[S:6][C:7]=2[CH3:8])=[C:24]([O:25][CH3:26])[CH:23]=1)=[O:20]
Reactant: CCOC(=O)C1CCN(c2nc(CCl)c(C)s2)CC1
Reactant: COc1cc(C=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCN(c2nc(COc3ccc(C=O)cc3OC)c(C)s2)CC1
Temperature: 90 °C
Reaction time: 2 h
Yield: 83.1 %

Procedure:
A mixture of ethyl 1-(4-chloromethyl-5-methyl-1,3-thiazol-2-yl)piperidine-4-carboxylate (1.48 g), vanillin (0.75 g), anhydrous potassium carbonate (0.68 g) and N,N-dimethylformamide (50 mL) was stirred at 90° C. for 2 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:3, v/v) to give ethyl 1-{4-[(4-formyl-2-methoxyphenoxy)methyl]-5-methyl-1,3-thiazol-2-yl}piperidine-4-carboxylate as colorless crystals (1.70 g, yield 83%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 97-98° C.
Reaction SMILES: OC(C(F)(F)F)=O.C([N:15]1[CH2:24][CH2:23][C:22]2[C:17](=[N:18][C:19]([NH:40][C@@H:41]([CH3:45])[CH2:42][O:43][CH3:44])=[C:20]([N:25]3[CH2:30][CH2:29][CH:28]([O:31][C:32]4[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:33]=4[F:39])[CH2:27][CH2:26]3)[N:21]=2)[CH2:16]1)C1C=CC=CC=1>C1COCC1.[OH-].[OH-].[Pd+2]>[F:39][C:33]1[CH:34]=[C:35]([F:38])[CH:36]=[CH:37][C:32]=1[O:31][CH:28]1[CH2:27][CH2:26][N:25]([C:20]2[N:21]=[C:22]3[CH2:23][CH2:24][NH:15][CH2:16][C:17]3=[N:18][C:19]=2[NH:40][C@@H:41]([CH3:45])[CH2:42][O:43][CH3:44])[CH2:30][CH2:29]1
Reactant: COC[C@H](C)Nc1nc2c(nc1N1CCC(Oc3ccc(F)cc3F)CC1)CCN(Cc1ccccc1)C2
Agent: [Pd+2]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: COC[C@H](C)Nc1nc2c(nc1N1CCC(Oc3ccc(F)cc3F)CC1)CCNC2
Reaction time: 1 h

Procedure:
A solution of (S)-6-benzyl-2-(4-(2,4-difluorophenoxyl)piperidin-1-yl)-N-(1-methoxypropan-2-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine TFA salt (127.7 mg, 0.200 mmol) in THF (2.00 mL) at room temperature was treated with Pd(OH)2 (20 wt %, 42.2 mg, 0.060 mmol). Hydrogen gas (balloon) was bubbled through the reaction mixture for 5 min. The vent needle was removed and the reaction mixture was stirred under hydrogen atmosphere for 1 h. The reaction mixture was opened to air and was filtered through a pad of Celite™, eluting with EtOAc and MeOH. The filtrate was concentrated under reduced pressure to give (S)-2-(4-(2,4-difluorophenoxyl)piperidin-1-yl)-N-(1-methoxypropan-2-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine, as a TFA salt, as a yellow oil, which was carried forward without additional purification. ESI-MS m/z [M+H]+434.5.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][N:12]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]OS(C)(=O)=O)[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[CH3:23])=[O:14])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[C-:35]#[N:36].[Na+].CS(C)=O>O>[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][N:12]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:35]#[N:36])[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[CH3:23])=[O:14])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: [C-]#N
Reactant: CCCCc1ccc(CN(CCCCCCOS(C)(=O)=O)C(=O)Nc2ccc(Cl)cc2C)cc1
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCCCc1ccc(CN(CCCCCCC#N)C(=O)Nc2ccc(Cl)cc2C)cc1
Yield: 86.8 %

Procedure:
A mixture of 2.0 g of 1-[(4-butylphenyl)methyl]-3-(4-chloro-2-methylphenyl)-1[6-[(methylsulfonyl)oxy]hexyl]urea, 0.5 g of sodium cyanide, and 3.0 ml of dimethyl sulfoxide was heated at an oil bath temperature of 60°-70° C. for 16 hours. The mixture was poured into water and extracted with dichloromethane. The procedure of Example 518 was continued and gave 1.5 g (88% yield) of the desired product as a brown oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11](OS(C)(=O)=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:19]([C:23]1[CH:28]=[C:27]([SH:29])[CH:26]=[C:25]([C:30]([CH3:33])([CH3:32])[CH3:31])[C:24]=1[OH:34])([CH3:22])([CH3:21])[CH3:20].[H-].[Na+]>CN(C=O)C.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([S:29][C:27]2[CH:26]=[C:25]([C:30]([CH3:31])([CH3:32])[CH3:33])[C:24]([OH:34])=[C:23]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:28]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Sc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)CC1
Temperature: 60 °C
Reaction time: 20 h
Yield: 54.6 %

Procedure:
To 4-methanesulfonyloxy-piperidine-1-carboxylic acid tert-butyl ester (Ex. 3a, 22 g) and 2,6-di-tert-butyl-4-mercapto-phenol (16.58 g) in 300 mL of DMF was added sodium hydride (3.8 g, 60% in oil). The mixture was stirred at 60° C. for 20 h and then poured onto ice and quenched with 1 N HCl. The gooey solid obtained via filtration was dissolved in Ethyl acetate, dried over Na2SO4, and concentrated. The crude product was dissolved in a minimal amount of diethyl ether and triturated with hexanes to give 4-(3,5-di-tert-butyl-4-hydroxy-phenylsulfanyl)-piperidine-1-carboxylic acid tert-butyl ester as an off-white solid (16 g), mp 151-152° C. 1H-NMR (400 MHz, CDCl3): δ 7.28 (s, 2H), 5.28 (s, 1H), 3.98 (s, 2H), 3.03-2.96 (m, 1H), 2.87 (t, 2H, J=10.4 Hz), 1.91-1.87 (m, 2H), 1.54-1.48 (m, 2H), 1.44 (s, 9H), 1.43 (s, 18H). HRMS (ESI) Calcd. for C24H39NO3S: 421.2651 (M+). Found: 421.2656. Anal. Calcd. for C24H39NO3S, C, 68.37; H, 9.32; N, 3.32; S, 7.60. Found: C, 68.20; H, 9.42; N, 3.23; S, 7.77.
Reaction SMILES: [Br:1][C:2]1[C:6]2[N:7]=[C:8]([Cl:12])[N:9]=[C:10](Cl)[C:5]=2[S:4][CH:3]=1.[CH2:13]([NH2:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>O1CCCC1>[CH2:13]([NH:20][C:10]1[C:5]2[S:4][CH:3]=[C:2]([Br:1])[C:6]=2[N:7]=[C:8]([Cl:12])[N:9]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NCc1ccccc1
Reactant: Clc1nc(Cl)c2scc(Br)c2n1
Solvent: O
Solvent: C1CCOC1
Product: Clc1nc(NCc2ccccc2)c2scc(Br)c2n1
Temperature: 60 °C
Reaction time: 2 h
Yield: 92.4 %

Procedure:
7-Bromo-2,4-dichlorothieno[3,2-d]pyrimidine (500 mg, 1.77 mmol) was dissolved in anhydrous tetrahydrofuran (8 mL) and stirred at 60° C. for 2 hours after adding benzylamine (0.58 mL, 5.32 mmol). The reaction mixture was cooled to room temperature and added to water (30 mL). Thus prepared solid was filtered and dried with nitrogen gas. The resultant target compound (580 mg, 92% yield) was used in the following reaction without purification.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:11][C:12]1[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:19].[CH2:20]([NH:22][CH2:23][CH3:24])[CH3:21]>CO>[Cl:19][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]([Cl:18])[C:12]=1[CH2:11][N:6]1[CH:5]=[N:4][C:3]2[C:7]1=[N:8][CH:9]=[N:10][C:2]=2[N:22]([CH2:23][CH3:24])[CH2:20][CH3:21]
Reactant: CCNCC
Reactant: Clc1cccc(Cl)c1Cn1cnc2c(Cl)ncnc21
Solvent: CO
Product: CCN(CC)c1ncnc2c1ncn2Cc1c(Cl)cccc1Cl
Yield: 60.4 %

Procedure:
6-Chloro-9-(2,6-dichlorobenzyl)purine (314 mg), 365 mg of diethylamine and 25 ml of methanol were treated in the same manner as Example 2, whereby 212 mg (yield 61%) of 9-(2,6-dichlorobenzyl)-6-diethylaminopurine was obtained as needles melting at 140°-141° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:16][C:17](=[O:27])[CH2:18][CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:4][CH:3]=1.[F:28][C:29]1[CH:30]=[CH:31][C:32]([O:38][CH3:39])=[C:33](B(O)O)[CH:34]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CCO.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>[CH2:14]([O:13][C:11](=[O:12])[CH2:10][C@H:9]([NH:16][C:17](=[O:27])[CH2:18][CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:8][C:5]1[CH:6]=[CH:7][C:2]([C:31]2[CH:30]=[C:29]([F:28])[CH:34]=[CH:33][C:32]=2[O:38][CH3:39])=[CH:3][CH:4]=1)[CH3:15]
Reactant: COc1ccc(F)cc1B(O)O
Reactant: CCOC(=O)C[C@@H](Cc1ccc(Br)cc1)NC(=O)CCC(=O)OC(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOC(=O)C[C@@H](Cc1ccc(-c2cc(F)ccc2OC)cc1)NC(=O)CCC(=O)OC(C)(C)C
Temperature: 95 °C
Reaction time: 18 h

Procedure:
To a solution of (R)-tert-butyl 4-(1-(4-bromophenyl)-4-ethoxy-4-oxobutan-2-ylamino)-4-oxobutanoate, intermediate 13, (100 mg, 0.23 mmol) and 5-fluoro-2-methoxyphenylboronic acid (57.6 mg, 0.34 mmol) in toluene (1 mL) and EtOH (0.1 mL) is added Pd(PPh3)4 (26.1 mg, 0.023 mmol) and Na2CO3 (47.9 mg, 0.45 mmol). After stirring at 95° C. under nitrogen for 18 hours, the solution is cooled to ambient temperature and then quenched with aqueous 1 M HCl. The crude is diluted with ethyl acetate, the organic layer is washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure % The obtained residue is purified by flash column chromatography on silica gel (eluent: heptane/EtOAc=100:0 to 30:70) to give (R)-tert-butyl 4-(4-ethoxy-1-(5′-fluoro-2′-methoxybiphenyl-4-yl)-4-oxobutan-2-ylamino)-4-oxobutanoate (65 mg). HPLC retention time=1.44 minutes (condition B); MS (m+1)=488.3; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.32 (t, J=7.1 Hz, 3 H) 1.48 (s, 9 H) 2.41-2.48 (m, 2 H) 2.51-2.63 (m, 4 H) 2.90 (dd, J=13.6, 6 Hz, 1 H) 3.02 (dd, J=13.6, 6 Hz, 1 H) 3.81 (s, 3 H) 4.14-4.29 (m, 2 H) 4.49-4.63 (m, 1 H) 6.44 (d, J=8.6 Hz, 1 H) 6.89-6.97 (m, 1 H) 6.98-7.05 (m, 1 H) 7.05-7.11 (m, 1 H) 7.27 (d, J=8.1 Hz, 2 H) 7.49 (d, J=8.1 Hz, 2 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[C:9]([O:11]C)=[O:10])=[C:4]([F:18])[CH:3]=1.CO.[OH-].[Na+].Cl>C1COCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:13]2[CH2:14][CH2:15][CH2:16][CH2:17]2)[C:9]([OH:11])=[O:10])=[C:4]([F:18])[CH:3]=1
Reactant: COC(=O)C(c1ccc(Cl)cc1F)C1CCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)C(c1ccc(Cl)cc1F)C1CCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
7.55 g (27.9 mmol) of methyl (4-chloro-2-fluorophenyl)(cyclopentyl)acetate were dissolved in 32 ml each of THF, methanol and water, and 11.15 g (287.9 mmol) of sodium hydroxide were added with ice cooling. The reaction mixture was stirred at RT overnight and then diluted with water and adjusted to pH 2 with 1 N hydrochloric acid. The aqueous phase was extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulphate and concentrated under reduced pressure. The solid that remained was triturated with water, filtered off with suction and dried thoroughly under reduced pressure. This gave 6.96 g of the target compound (97.2% of theory).
Reaction SMILES: [Si]([O:18][C:19]1[CH:27]=[C:26]2[C:22]([C:23]([Cl:35])=[N:24][N:25]2[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[CH:21][CH:20]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-].C1COCC1.C(OCC)(=O)C>C1COCC1>[Cl:35][C:23]1[C:22]2[C:26](=[CH:27][C:19]([OH:18])=[CH:20][CH:21]=2)[N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[N:24]=1
Reactant: CC(C)(C)OC(=O)n1nc(Cl)c2ccc(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)n1nc(Cl)c2ccc(O)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.2 %

Procedure:
Tert-butyl 6-(tert-butyldiphenylsilyloxy)-3-chloroindazole-1-carboxylate (17.415 g) which can be prepared according to the method described in Reference example 38, etc. was dissolved in dehydrated THF (150 mL), added with 1 mol/L-TBAF-THF solution (42 mL; manufactured by Tokyo Chemical Industry, Co., Ltd.), and stirred overnight at room temperature. The reaction solution was added with ethyl acetate and the organic layer was washed once with brine, once with water, and once with brine and dried over anhydrous sodium sulfate. After the solvent was evaporated under reduced pressure, the resulting residue was added with n-hexane (150 mL) and the suspension was subjected to ultrasonication treatment. The precipitate was filtered to obtain the title compound (6.3815 g).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@H:26]3[CH2:31][CH2:30][C@@H:29]([N:32]4[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]4)[CH2:28][CH2:27]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]4[S:19]C5CCCC=5[N:22]=4)=[CH:13][CH:12]=3)[C:3]=12.[C:39]([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)(=O)[CH2:40][CH:41]([CH3:43])[CH3:42]>>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@H:26]3[CH2:31][CH2:30][C@@H:29]([N:32]4[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]4)[CH2:28][CH2:27]3)[N:9]=[C:10]([C:11]3[CH:12]=[CH:13][C:14]([NH:17][C:18]4[S:19][C:40]([CH:41]([CH3:43])[CH3:42])=[C:39]([C:45]5[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=5)[N:22]=4)=[CH:15][CH:16]=3)[C:3]=12
Reactant: CC(C)CC(=O)c1ccccc1
Reactant: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(Nc5nc6c(s5)CCC6)cc4)c4c(N)ncnc43)CC2)CC1
Product: CC(C)c1sc(Nc2ccc(-c3nn([C@H]4CC[C@@H](N5CCN(C)CC5)CC4)c4ncnc(N)c34)cc2)nc1-c1ccccc1

Procedure:
The procedure described for cis-N2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl)-5,6-dihydro-4H-cyclopenta[d][1,3]thiazol-2-amine was used to convert isovalerophenone (0.484 g, 2.98 mmol) to the title compound. Purification of the product by preparative HPLC (25 to 100% acetonitrile in 0.1 M aqueous ammonium acetate over 20 min at 21 mL/min using an 8μ Hypersil HS C18, 250×21 mm column, Rt 9.5-11.7 min) afforded cis-N2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl)-5-isopropyl-4-phenyl-1,3-thiazol-2-amine as a pink powder (0.060 g, 0.099 mmol); RP-HPLC (25 to 100% acetonitrile in 0.1 M aqueous ammonium acetate over 10 min at 1 mL/min using a 5μ Hypersil HS C18, 250×4.6 mm column) Rt 9.82 min;
Reaction SMILES: FC1C(CC2C=CC(F)=CC=2)=CC=C(OC)C=1OC1C=C(N)C=CC=1.[F:26][C:27]1[C:32]([O:33][C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([N+:40]([O-:42])=[O:41])[CH:35]=2)=[C:31]([O:43]C)[CH:30]=[CH:29][C:28]=1[CH2:45][C:46]1[CH:51]=[CH:50][C:49]([F:52])=[CH:48][CH:47]=1>CCO.[Ni]>[F:26][C:27]1[C:32]([O:33][C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([N+:40]([O-:42])=[O:41])[CH:35]=2)=[C:31]([OH:43])[CH:30]=[CH:29][C:28]=1[CH2:45][C:46]1[CH:51]=[CH:50][C:49]([F:52])=[CH:48][CH:47]=1
Reactant: COc1ccc(Cc2ccc(F)cc2)c(F)c1Oc1cccc([N+](=O)[O-])c1
Agent: [Ni]
Agent: COc1ccc(Cc2ccc(F)cc2)c(F)c1Oc1cccc(N)c1
Solvent: CCO
Product: O=[N+]([O-])c1cccc(Oc2c(O)ccc(Cc3ccc(F)cc3)c2F)c1
Reaction time: 2 h
Yield: 85 %

Procedure:
3-[2-Fluoro-3-(4-fluoro-benzyl)-6-methoxy-phenoxy]-phenylamine P-02. To a 200 mL pressure-resistant vial which contained a mixture of 2-fluoro-1-(4-fluoro-benzyl)-4-methoxy-3-(3-nitro-phenoxy)-benzene P-01 (180 mg, 0.5 mmole) in EtOH (10 mL) was added Ranny Ni (150 mg, excess) at rt. The reaction mixture was flashed 3 times with H2 and then shacked under H2 (40 psi) atmosphere for 2 h. After the catalyst was filtered out, the solvent was removed in vacuo to give 140 mg (85% yield) of desired product P-02.