Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([OH:13])[C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6].I[CH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:13][CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[C:11]=1[O:12][CH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc(O)c(O)c(Cl)c1
Reactant: IC1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Cl)c(OC2CCCC2)c(OC2CCCC2)c1
Temperature: 70 °C
Reaction time: 46 h
Yield: 85.1 %

Procedure:
A mixture of methyl 3-chloro-4,5-dihydroxybenzoate (3) (300 mg, 1.48 mmol), iodocyclopentane (558 μL, 4.44 mmol) and potassium carbonate (614 mg, 4.44 mmol) in DMF (10 mL) was stirred at 70° C. for 46 h. The reaction mixture was cooled to room temperature and then partitioned between 1M HCl (75 mL) and EtOAc (100 mL). The phases were separated and the organic phase was washed with brine (2×75 mL) then dried over MgSO4 and filtered. The solvent was removed in vacuo and the residue was purified by silica gel chromatography (40 g, 0-100% EtOAc in isohexane) to give methyl 3-chloro-4,5-bis(cyclopentyloxy)benzoate (4) (427 mg, 1.26 mmol, 85% yield): m/z 339 [M+H]+ (ES+); 1H NMR (400 MHz, CDCl3) δ: 7.66 (1H, d), 7.45 (1H, d), 5.05-4.98 (1H, m), 4.87-4.83 (1H, m), 3.89 (3H, s), 1.95-1.55 (16H, m).
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:9])=[CH:4][C:5](N)=[N:6][CH:7]=1.S(=O)(=O)(O)[OH:11].N([O-])=O.[Na+].O>>[Br:1][C:2]1[C:3]([Cl:9])=[CH:4][C:5]([OH:11])=[N:6][CH:7]=1
Reactant: Nc1cc(Cl)c(Br)cn1
Reactant: O=S(=O)(O)O
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Oc1cc(Cl)c(Br)cn1
Reaction time: 3 h
Yield: 96 %

Procedure:
5-Bromo-4-chloropyridin-2-amine (2.01 g, 9.69 mmol) was dissolved in 75% (v/v) sulfuric acid (40.2 mL, 566 mmol) and then chilled in an ice bath. A solution of sodium nitrite (2.21 g, 32.0 mmol) in water (20.1 mL, 1116 mmol) was added drop-wise and the reaction mixture was then stirred for 3 hours. The mixture was concentrated under reduced pressure and aqueous ammonia (15 mL) was added drop-wise. The resulting white precipitate was collected via vacuum filtration and the filter cake washed with cold water (100 mL) then dried in a vacuum oven for 24 hours to give 1.94 g (95%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[NH:13][C:12]([C:14]([CH3:20])([CH3:19])[C:15](OC)=[O:16])=[N:11][C:10]=1[C:21]1[N:26]=[C:25]2[O:27][C:28]([NH:30][C@@H:31]([CH3:36])[CH2:32][CH2:33][O:34][CH3:35])=[N:29][C:24]2=[CH:23][CH:22]=1.[BH4-].[Li+].Cl>C(OCC)C.C1COCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[NH:13][C:12]([C:14]([CH3:20])([CH3:19])[CH2:15][OH:16])=[N:11][C:10]=1[C:21]1[N:26]=[C:25]2[O:27][C:28]([NH:30][C@@H:31]([CH3:36])[CH2:32][CH2:33][O:34][CH3:35])=[N:29][C:24]2=[CH:23][CH:22]=1
Reactant: COCC[C@H](C)Nc1nc2ccc(-c3nc(C(C)(C)C(=O)OC)[nH]c3-c3ccc(F)cc3F)nc2o1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COCC[C@H](C)Nc1nc2ccc(-c3nc(C(C)(C)CO)[nH]c3-c3ccc(F)cc3F)nc2o1
Temperature: 0 °C
Reaction time: 2 h
Yield: 74.2 %

Procedure:
Methyl 2-[5-(2,4-difluorophenyl)-4-[2-[[(1S)-3-methoxy-1-methyl-propyl]amino]oxazolo[5,4-b]pyridin-5-yl]-1H-imidazol-2-yl]-2-methyl-propanoate (50 g, 100.1 mmol) is dissolved in a mixture of diethyl ether (1 L) and THF (500 mL). The mixture is cooled to 0° C. and lithium borohydride (4.36 g, 200.19 mmol) is added. The reaction mixture is stirred at RT under a nitrogen atmosphere for 2 h. 1 M HCl (600 mL) is slowly added (gas evolution) and the resulting mixture is stirred for 1.5 h at RT. The layers are separated and the aqueous phase is extracted with methyl tert-butyl ether. The aqueous layer is basified (pH=8) by the addition of 2 M NaOH (200 mL) and is extracted with dichloromethane (3×400 mL). The combined organic layers are dried over Na2SO4, filtered, and concentrated under reduced pressure to a brown foam. The crude is eluted through a silica gel column (eluent: dichloromethane/3N NH3 in methanol 95:5) to obtain the desired product as a violet colored foam (35 g). The solid is suspended in a mixture of 2:1 heptane/methyl tert-butyl ether and sonicated. The suspension is stirred at RT overnight. The solid is filtered and dried under a vacuum to afford the title compound as a crystalline off-white solid (30 g, 64%). MS (m/z): 472 (M+1).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[N:12]=[C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[N:10]=[C:9]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:37])[NH:27][C:28]4[CH:36]=[CH:35][C:31]([C:32](O)=[O:33])=[CH:30][CH:29]=4)=[CH:21][CH:20]=3)[N:8]=2)[CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:71]1[CH2:76][CH2:75][NH:74][CH2:73][CH2:72]1>CN1C(=O)CCC1>[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[N:12]=[C:11]([N:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)[N:10]=[C:9]([C:19]3[CH:20]=[CH:21][C:22]([NH:25][C:26]([NH:27][C:28]4[CH:36]=[CH:35][C:31]([C:32]([N:71]5[CH2:76][CH2:75][NH:74][CH2:73][CH2:72]5)=[O:33])=[CH:30][CH:29]=4)=[O:37])=[CH:23][CH:24]=3)[N:8]=2)[CH2:3][CH2:2]1
Reactant: O=C(Nc1ccc(C(=O)O)cc1)Nc1ccc(-c2nc(N3CCOCC3)nc(N3CCOCC3)n2)cc1
Reactant: C1CNCCN1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: O=C(Nc1ccc(C(=O)N2CCNCC2)cc1)Nc1ccc(-c2nc(N3CCOCC3)nc(N3CCOCC3)n2)cc1
Yield: 30.3 %

Procedure:
To the solution of 4-(3-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)ureido)benzoic acid (50 mg; 0.099 mmol), Hunig's base (103 μL, 0.594 mmol), HBTU (188 mg, 0.495 mmol) in 2 mL of NMP was reacted according to example 68 with piperazine (34 mg, 0.396 mmol). Evaporated the solvent and purified by HPLC to give the product (17.2 mg, 30% yield); MS (ESI) m/z=573.6
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([S:30](=[O:33])(=[O:32])[NH2:31])=[CH:26][CH:25]=2)[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([Br:21])=[CH:10][CH:9]=2)=[O:4].[C:34](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:23][C:24]2[CH:25]=[CH:26][C:27]([S:30](=[O:33])(=[O:32])[NH:31][CH3:34])=[CH:28][CH:29]=2)[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[CH:12][C:11]([Br:21])=[CH:10][CH:9]=2)=[O:4]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc(S(N)(=O)=O)cc1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CNS(=O)(=O)c1ccc(Cn2c(C(=O)OC)c(-c3ccccc3)c3cc(Br)ccc3c2=O)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 30.6 %

Procedure:
A mixture of 6-bromo-2-(4-sulfamoylbenzyl)-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester (264 mg), potassium carbonate (152 mg), methyl iodide (34 μl) and dimethylformamide (DMF) (5 ml) was stirred at room temperature for 5 hrs. The solvent was evaporated under reduced pressure, and the residue was extracted with ethyl acetate. The extract was washed with saturated brine, dried over sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by preparative HPLC to give the title compound (83 mg, 31%).
Reaction SMILES: C[O:2][C:3](=[O:41])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]([C:29]2[CH:34]=[CH:33][C:32]([CH:35]3[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]3)=[CH:31][CH:30]=2)[C:12]([NH:14][C:15]2[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[C:17]([C:25]([F:28])([F:27])[F:26])[CH:16]=2)=[O:13])=[CH:6][CH:5]=1.[OH-].[Na+]>C(O)C>[F:22][C:21]([F:23])([F:24])[C:19]1[CH:20]=[C:15]([NH:14][C:12](=[O:13])[N:11]([CH2:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:41])=[O:2])=[CH:5][CH:6]=2)[C:29]2[CH:30]=[CH:31][C:32]([CH:35]3[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40]3)=[CH:33][CH:34]=2)[CH:16]=[C:17]([C:25]([F:27])([F:28])[F:26])[CH:18]=1
Reactant: COC(=O)c1ccc(CN(C(=O)Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ccc(C3CCCCC3)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc(CN(C(=O)Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ccc(C3CCCCC3)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4-[3-(3,5-Bis(trifluoromethyl)phenyl)-1-(4-cyclohexylphenyl)ureidomethyl]benzoic acid methyl ester (4.2 g, 7.36 mmol) was suspended in ethanol (80 mL) and added sodium hydroxide (4 N, 11 mL) and stirred at room temperature for 16 hours. The reaction mixture was concentrated to dryness in vacuo, and the residue was added water (50 mL) and acidified with hydrochloric acid (4 N, 12 mL). The aqueous phase was extracted twice with ethyl acetate (75 mL and 25 mL) and the combined organic phases were washed with water (3×15 mL), dried (magnesium sulphate) and concentrated in vacuo to afford 4-[3-(3,5-bis(trifluoromethyl)phenyl)-1-(4-cyclohexylphenyl)ureidomethyl]benzoic acid.
Reaction SMILES: Br[C:2]1[C:3]([F:9])=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[C:10]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])(=[O:13])[CH:11]=[CH2:12].C(N(CC)CC)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[NH2:5][C:4]1[C:3]([F:9])=[C:2](/[CH:12]=[CH:11]/[C:10]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH:8]=[CH:7][CH:6]=1
Reactant: Nc1cccc(Br)c1F
Reactant: C=CC(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)/C=C/c1cccc(N)c1F
Temperature: 145 °C
Reaction time: 8 h

Procedure:
400 mg (2.10 mmol) of 3-bromo-2-fluoroaniline, 809.42 mg (6.32 mmol) of tert-butyl acrylate and 1.47 ml (10.53 mmol) of triethylamine were initially charged in 2.4 ml of DMF. The reaction vessel was evacuated three times and in each case vented with argon. 47.26 mg (0.21 mmol) of palladium(II) acetate and 128.14 mg (0.42 mmol) of tri-2-tolylphosphine were then added, and the reaction vessel was evacuated two more times and again vented with argon. The mixture was stirred at 145° C. overnight. The reaction mixture was then cooled, added to saturated ammonium chloride solution and extracted three times with ethyl acetate. The combined organic phases were dried over magnesium sulfate and concentrated. The crude product was purified by preparative RP-HPLC (mobile phase: acetonitrile/water gradient). This gave 210 mg (42% of theory) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:25]2[CH2:26][CH2:27][N:28]([CH3:31])[CH2:29][CH:30]=2)[CH:6]=[C:7]2[C:11]=1[C:10](=[O:12])[N:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=1)[CH2:8]2.[H][H]>CO.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:25]2[CH2:26][CH2:27][N:28]([CH3:31])[CH2:29][CH2:30]2)[CH:6]=[C:7]2[C:11]=1[C:10](=[O:12])[N:9]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([O:20][C:21]([F:22])([F:23])[F:24])=[CH:18][CH:19]=1)[CH2:8]2
Reactant: COc1cc(C2=CCN(C)CC2)cc2c1C(=O)N(Cc1ccc(OC(F)(F)F)cc1)C2
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COc1cc(C2CCN(C)CC2)cc2c1C(=O)N(Cc1ccc(OC(F)(F)F)cc1)C2
Reaction time: 18 h
Yield: 41.4 %

Procedure:
7-Methoxy-5-(1-methyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindol-1-one (17 mg, 0.040 mmol) was stirred in methanol for 20 minutes under argon before a small scoop of palladium on carbon was added and the reaction atmosphere was changed to hydrogen. The reaction was allowed to stir for 18 hours under hydrogen. The reaction was filtered and the solvent was removed under reduced pressure to yield 7.2 mg (42%) of a yellow oil. 1H NMR (300 MHz, CDCl3): δ 7.35 (d, 2H), 7.16 (d, 2H), 6.74 (d, 2H), 4.74 (s, 2H), 4.20 (s, 2H), 3.98 (s, 3H), 3.50 (s, 2H), 2.98-3.01 (m, 2H), 2.53-2.60 (m, 1H), 2.04-2.11 (m, 2H), 1.75-1.87 (m, 5H).
Reaction SMILES: [C:1]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][C:15]1[CH:16]=[N:17][CH:18]=[C:19](Br)[CH:20]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH:22]#[C:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>C(Cl)Cl.CCN(CC)CC.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I>[C:1]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][C:15]1[CH:16]=[N:17][CH:18]=[C:19]([C:22]#[C:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH:20]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: C#CCCCCCC
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1COc1cncc(Br)c1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCC#Cc1cncc(OC[C@@H]2CCCN2C(=O)OC(C)(C)C)c1
Temperature: 25 °C
Yield: 78.5 %

Procedure:
To a solution of 3-(1-BOC-2-(S)-pyrrolidinylmethoxy)-5-bromopyridine (300 mg, 0.84 mmol) in CH2Cl2 (10 mL) and NEt3 (0.4 mL) was added bis(triphenylphosphine)palladium (II) chloride (20 mg, 0.028 mmol), copper (1) iodide (2 mg) and 1-octyne (0.25 mL. 1.7 mmol). The reaction mixture was stirred and refluxed under N2 atmosphere for two days and then cooled to room temperature. After washing with aqueous 10% NaOH (1X), the organic layer was dried (MgSO4), concentrated and chromatographed (silica gel; hexane/EtOAc, 10: 1 to 10:2) to afford an oil (255 mg, 79%): 1H NMR (CDCl3, 300 MHz) δ0.88 (t, 3H, J=2.5 Hz), 1.20-1.38 (m, 4H), 1.42 (d, 4H, J=2.5 Hz), 1.44 (s, 9H), 1.90 (m, 1H), 2.00 (m, 1H), 2.40 (t, 2H, J=7.0 Hz), 3.12 (q, 4H, J=7.5 Hz), 3.32-3.44 (m, 2H), 3.90 (br, 1H), 4.08-4.20 (m, 2H), 7.10 (s, 1H), 8.08-8.30 (m, 2H); MS (CI/NH3) m/z 387 (M+H)+.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:12]=[CH:11][C:7]2[O:8][CH2:9][O:10][C:6]=2[CH:5]=1.NC(N)=[S:15].[OH-].[Na+]>C(O)C.O>[O:8]1[C:7]2[CH:11]=[CH:12][C:4]([CH2:3][CH2:2][SH:15])=[CH:5][C:6]=2[O:10][CH2:9]1
Reactant: NC(N)=S
Reactant: BrCCc1ccc2c(c1)OCO2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: SCCc1ccc2c(c1)OCO2
Yield: 95.5 %

Procedure:
750 g of 5-(2-bromoethyl)-1,3-benzodioxole was dissolved in 1 l of ethanol. 312 g of thiourea was added to the solution and the mixture was heated under reflux on a boiling water bath for 2 h. The reaction mixture was cooled and a solution of 300 g of sodium hydroxide in 1 l of water was added thereto. The resulting mixture was heated under reflux on a boiling water bath for 45 min. After cooling, 3 l of water was added thereto. After extraction with 5 l of ethyl acetate, the extract was washed with dilute hydrochloric acid and then with water until the washing became almost neutral. After drying over anhydrous sodium sulfate followed by distillation of the solvent at 40° C., about 570 g of a faint yellow oil was obtained. This product was purified according to column chromatography (hexane/benzene=2:1) with about 3 kg of silica gel to obtain 310 g of the intended compound in the form of a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[O:9])=[CH:6][N:5]=[C:4]([NH:19][CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[N:3]=1.[Cl:26][CH2:27][CH2:28][CH2:29][S:30](Cl)(=[O:32])=[O:31].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[O:9])=[CH:6][N:5]=[C:4]([NH:19][CH:20]2[CH2:21][CH2:22][N:23]([S:30]([CH2:29][CH2:28][CH2:27][Cl:26])(=[O:32])=[O:31])[CH2:24][CH2:25]2)[N:3]=1
Reactant: O=S(=O)(Cl)CCCCl
Reactant: COc1ccc(F)cc1C(=O)c1cnc(NC2CCNCC2)nc1N
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(F)cc1C(=O)c1cnc(NC2CCN(S(=O)(=O)CCCCl)CC2)nc1N
Temperature: 5 °C
Reaction time: 1 h
Yield: 82 %

Procedure:
A solution of [4-amino-2-(piperidin-4-ylamino)-pyrimidin-5-yl]-(5-fluoro-2-methoxy-phenyl)-methanone (290 mg, 0.72 mmol, Example 59 and 3-chloropropanesulfonyl chloride (165 mg, 0.93 mmol, Aldrich) was treated with diisopropylethyl amine (102 mg, 102 mmol, Aldrich) in methylene chloride (200 mL). This was stirred for 1 hour at 5° C. The reaction was washed with 5% aqueous sodium bicarbonate, dried (MgSO4), and the solvent concentrated in vacuum. This solid was dissolved in tetrahydrofuran, filtered through celite, reduced in volume and triturated with ether to give 300 mg (82%) of [4-amino-2-[1-(3-chloro-propane-1-sulfonyl)-piperidin-4-ylamino]-pyrimidin-5-yl]-(5-fluoro-2-methoxy-phenyl)-methanone as a white solid. HRMS, observed: 486.1375; Calcd for (M+H)+: 486.1373
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:12][C:11](=[CH:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:10][CH:11]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:12]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)C=C1CC(NC(=O)OC(C)(C)C)C1
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)CC1CC(NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 97.2 %

Procedure:
10% Pd/C (360 mg) was added to a solution of ethyl 2-(3-(tert-butoxycarbonylamino)cyclobutylidene)acetate (1.2 g, 4.8 mmol) in MeOH (10 mL) at 23° C. The reaction mixture was stirred under a H2 balloon at rt for 1.5 hrs. The mixture was filtered and concentrated. The residue was purified by silica gel column (10% EtOAc/petroleum ether) to afford ethyl 2-(3-(tert-butoxycarbonylamino)cyclobutyl)-acetate (1.2 g, 96%). ESI-MS (EI+, m/z): 258 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[CH:17][C:6]2[CH2:7][C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14]Cl)[CH2:10][CH2:11][C:5]=2[CH:4]=1.[NH2:21][C:22]1[C:27]([Br:28])=[CH:26][C:25]([O:29][CH2:30][CH2:31][CH2:32][NH:33][CH3:34])=[CH:24][C:23]=1[Br:35]>C(N(CC)CC)C>[CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[CH:17][C:6]2[CH2:7][C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14][N:33]([CH3:34])[CH2:32][CH2:31][CH2:30][O:29][C:25]3[CH:24]=[C:23]([Br:35])[C:22]([NH2:21])=[C:27]([Br:28])[CH:26]=3)[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: CNCCCOc1cc(Br)c(N)c(Br)c1
Reactant: COc1cc2c(cc1OC)CC(=O)N(CCCCl)CC2
Solvent: CCN(CC)CC
Product: COc1cc2c(cc1OC)CC(=O)N(CCCN(C)CCCOc1cc(Br)c(N)c(Br)c1)CC2

Procedure:
The title compound is prepared from [3-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-1-chloropropane, N-[3-(4-amino-3,5-dibromo-phenyloxy)-propyl]-methylamine and triethylamine analogously to Example 6.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:40]=[CH:41][C:42]=1[N+:43]([O-])=O)[O:5][CH2:6][CH2:7][CH2:8][CH2:9][Si:10]([CH3:39])([CH3:38])[O:11][Si:12]([CH3:37])([CH3:36])[O:13][Si:14]([CH3:35])([CH3:34])[O:15][Si:16]([CH2:19][CH2:20][CH2:21][CH2:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([N+:30]([O-])=O)=[C:26]([CH3:33])[CH:25]=1)([CH3:18])[CH3:17].[H][H]>>[NH2:43][C:42]1[CH:41]=[CH:40][C:4]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][Si:10]([CH3:39])([CH3:38])[O:11][Si:12]([CH3:36])([CH3:37])[O:13][Si:14]([CH3:35])([CH3:34])[O:15][Si:16]([CH2:19][CH2:20][CH2:21][CH2:22][O:23][C:24]2[CH:29]=[CH:28][C:27]([NH2:30])=[C:26]([CH3:33])[CH:25]=2)([CH3:17])[CH3:18])=[CH:3][C:2]=1[CH3:1]
Reactant: Cc1cc(OCCCC[Si](C)(C)O[Si](C)(C)O[Si](C)(C)O[Si](C)(C)CCCCOc2ccc([N+](=O)[O-])c(C)c2)ccc1[N+](=O)[O-]
Reactant: [H][H]
Product: Cc1cc(OCCCC[Si](C)(C)O[Si](C)(C)O[Si](C)(C)O[Si](C)(C)CCCCOc2ccc(N)c(C)c2)ccc1N
Yield: 99.4 %

Procedure:
2.62 g of the above 2e (3.76 mmol) and 10 mL of a 10 wt % Pd/C ethyl acetate solution (0.0230 g) were mixed, and stirred for 2 days in a hydrogen atmosphere at room temperature. The solution was filtrated by Celite and then concentrated to obtain a colorless oily material of 1,7-bis[4-(4-amino-3-methylphenoxy)butyl]-1,1,3,3,5,5,7,7-octamethyltetrasiloxane (3e) (2.38 g, 99% of yield) represented by the following formula. Various measurements were carried out with regard to the obtained (3e), and results are shown below.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][CH:13]([N:16]3[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]3)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1>C(Cl)Cl.FC(F)(F)C(O)=O>[F:30][C:2]([F:1])([F:29])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][CH:13]([N:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C2CCN(c3ccc(OC(F)(F)F)cc3)CC2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: FC(F)(F)Oc1ccc(N2CCC(N3CCNCC3)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.3 %

Procedure:
Tert-butyl 4-[1-(4-trifluoromethoxyphenyl)-piperidin-4-yl]piperazine-1-carboxylate (1 g, 2.33 mmol) was dissolved in methylene chloride (10 ml), to which trifluoroacetic acid (10 ml) was added while cooling in an ice-bath, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was washed with a 25% sodium hydroxide aqueous solution (40 ml) and brine (10 ml), and dried over sodium sulfate. After filtration, the filtrate was concentrated to afford 1-[1-(4-trifluoromethoxyphenyl)piperidin-4-yl]piperazine (770 mg, quantitative) as a yellow amorphous form.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]1[CH2:20][C:19](=[O:21])[N:18]([N:22]([CH3:35])[CH:23]3[CH2:28][CH2:27][N:26]([C:29]4[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=4)[CH2:25][CH2:24]3)[CH:17]([C:36](O)=[O:37])[CH2:16]1)(=[O:14])=[O:13])[CH:6]=[CH:5]2.Cl.[CH2:40]([S:42][CH2:43][CH2:44][NH2:45])[CH3:41]>>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]1[CH2:20][C:19](=[O:21])[N:18]([N:22]([CH3:35])[CH:23]3[CH2:28][CH2:27][N:26]([C:29]4[CH:30]=[CH:31][N:32]=[CH:33][CH:34]=4)[CH2:25][CH2:24]3)[CH:17]([C:36]([NH:45][CH2:44][CH2:43][S:42][CH2:40][CH3:41])=[O:37])[CH2:16]1)(=[O:13])=[O:14])[CH:6]=[CH:5]2
Reactant: CCSCCN
Reactant: CN(C1CCN(c2ccncc2)CC1)N1C(=O)CN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1C(=O)O
Agent: Cl
Product: CCSCCNC(=O)C1CN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC(=O)N1N(C)C1CCN(c2ccncc2)CC1
Yield: 145.5 %

Procedure:
Similarly to Example 120 and using 4-[(6-chloro-2-naphthyl)sulfonyl)-1-[methyl[1-(4-pyridinyl)-4-piperidinyl]amino]-6-oxo-2-piperazinecarboxylic acid (0.18 g) obtained in Example 110 and 2-(ethylthio)ethylamine hydrochloride (0.065 g), the title compound (0.16 g) was obtained as a pale yellow powder.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([O:15]CC2C=CC=CC=2)[CH:12]=[CH:11][C:10]=1[CH:23]1[CH2:26][N:25]([C:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:28])[CH2:24]1)C1C=CC=CC=1>CO.[Pd]>[OH:8][C:9]1[CH:14]=[C:13]([OH:15])[CH:12]=[CH:11][C:10]=1[CH:23]1[CH2:24][N:25]([C:27]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)=[O:28])[CH2:26]1
Reactant: O=C(c1ccccc1)N1CC(c2ccc(OCc3ccccc3)cc2OCc2ccccc2)C1
Agent: [Pd]
Solvent: CO
Product: O=C(c1ccccc1)N1CC(c2ccc(O)cc2O)C1
Reaction time: 18 h

Procedure:
In a 10 ml round-bottomed flask, 0.2 g of [3-(2,4-bis(benzyloxy)phenyl)azetidin-1-yl]phenylmethanone is dissolved in 6 ml of methanol in the presence of 0.1 g of palladium-on-charcoal at 10%. The reaction mixture is stirred for 18 hours under a hydrogen atmosphere. The reaction mixture is filtered and the residue is then chromatographed on silica gel (1/1 heptane/ethyl acetate).