Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:14][C@H:15]([OH:20])[C:16]([F:19])([F:18])[F:17])[C:10](=[O:13])[NH:11][N:12]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[Br:27][C:28]1[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[C:30]([CH2:38]Br)[CH:29]=1.O>C(#N)C>[Br:27][C:28]1[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[C:30]([CH2:38][N:11]2[C:10](=[O:13])[N:9]([CH2:14][C@H:15]([OH:20])[C:16]([F:18])([F:19])[F:17])[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)=[N:12]2)[CH:29]=1
Reactant: COC(=O)c1ccc(Br)cc1CBr
Reactant: O=c1[nH]nc(-c2ccc(Cl)cc2)n1C[C@H](O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC#N
Product: COC(=O)c1ccc(Br)cc1Cn1nc(-c2ccc(Cl)cc2)n(C[C@H](O)C(F)(F)F)c1=O
Temperature: 25 °C

Procedure:
515 mg (1.67 mmol) of the compound from Example 5A and 818 mg (2.51 mmol) of cesium carbonate were suspended in 10 ml of acetonitrile, and 810 mg (1.84 mmol) of methyl 4-bromo-2-(bromomethyl)benzoate were added. The mixture was stirred under reflux for 3 h. After cooling to RT, 15 ml of water were added and the mixture was extracted three times with in each case 10 ml of ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified chromatographically [Method 19]. This gave 455 mg (51% of theory) of the target compound.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][S:10]([CH3:13])(=[O:12])=[O:11])=O.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:20][O:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Cl)=[CH:24][CH:23]=1>C(#N)C.C(OCC)(=O)C>[CH3:20][O:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][N:9]2[C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[CH:1]=[CH:13][S:10]2(=[O:12])=[O:11])=[CH:24][CH:23]=1
Reactant: COc1ccc(CCl)cc1
Reactant: CS(=O)(=O)Nc1ccccc1C=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COc1ccc(CN2c3ccccc3C=CS2(=O)=O)cc1
Temperature: 50 °C
Reaction time: 48 h

Procedure:
The title compound was synthesized according to the method described in WO 2008/073956 A2. To a solution of N-(2-formylphenyl)methanesulfonamide (2.0 g, 10 mmol) in anhydrous acetonitrile (45 mL) was added cesium carbonate (6.5 g, 20 mmol) and 4-methoxybenzylchloride (2.7 mL, 20 mmol). The mixture was heated to 50° C. and stirred for 48 hours, diluted with ethyl acetate, filtered through Celite, and concentrated. The crude product was purified by silica gel column chromatography (50-100% methylene chloride in hexanes) to give the product (0.9 g, 31%). 1H NMR (CDCl3, 300 MHz) δ 7.40-7.32 (m, 2H), 7.28-7.24 (m, 3H), 7.16-7.11 (m, 2H), 6.85-6.81 (m, 3H), 5.15 (s, 2H), 3.77 (s, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[N:21]([NH:22][CH:23]([CH3:25])[CH3:24])[C:20]([CH2:26][O:27][CH2:28][CH3:29])=[N:19][C:14]=3[CH:15]=[N:16][C:17]=2[CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[NH4+:31].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C(Cl)(Cl)Cl.O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[N:21]([NH:22][CH:23]([CH3:25])[CH3:24])[C:20]([CH2:26][O:27][CH2:28][CH3:29])=[N:19][C:14]=3[C:15]([NH2:31])=[N:16][C:17]=2[CH:18]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOCc1nc2cnc3cc(OCc4ccccc4)ccc3c2n1NC(C)C
Reactant: [NH4+]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [OH-]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCOCc1nc2c(N)nc3cc(OCc4ccccc4)ccc3c2n1NC(C)C
Reaction time: 3 h

Procedure:
A solution of N-(7-benzyloxy-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)isopropylamine (6.63 g, 17.0 mmol) in 90 mL of CHCl3 was treated with MPCBA (6.29 g, 25.5 mmol, 70%). After 3 h, HPLC and LC/MS indicated complete conversion to the intermediate 5-N-oxide. The reaction mixture was then treated with concentrated ammonium hydroxide solution (30 mL, 30%). The biphasic reaction mixture was stirred vigorously while p-toluenesulfonyl chloride (3.40 g, 17.9 mmol) was added. After 45 min, LC/MS indicated complete conversion to the 4-amine. The reaction mixture was diluted with 30 mL of water and 45 mL of CHCl3 and separated. The organic portion was washed with 10% Na2CO3 solution (50 mL) and water (50 mL). The combined aqueous portions were then back-extracted with CHCl3 (25 mL). The combined organic portions were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated to yield a tan solid. The solid was purified by chromatography (SiO2, 96:4 CHCl3:MeOH) to give 5.90 g of 7-benzyloxy-2-ethoxymethyl-N1-isopropyl-1H-imidazo[4,5-c]quinoline-1,4-diamine as a light tan solid.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.C(N(CC)CC)C.[CH2:18]([O:20][C:21]1[CH:35]=[CH:34][C:24]([O:25][C:26]2[CH:33]=[CH:32][C:29]([CH2:30]Cl)=[CH:28][CH:27]=2)=[CH:23][CH:22]=1)[CH3:19]>C1(C)C=CC=CC=1>[CH2:18]([O:20][C:21]1[CH:35]=[CH:34][C:24]([O:25][C:26]2[CH:33]=[CH:32][C:29]([CH2:30][N:3]3[C:4]4[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=4[N:6]=[C:2]3[CH3:1])=[CH:28][CH:27]=2)=[CH:23][CH:22]=1)[CH3:19]
Reactant: Cc1nc2ccccc2[nH]1
Reactant: CCOc1ccc(Oc2ccc(CCl)cc2)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOc1ccc(Oc2ccc(Cn3c(C)nc4ccccc43)cc2)cc1
Temperature: 25 °C
Yield: 88.1 %

Procedure:
A mixture of toluene (20 ml), 2-methylbenzimidazole (0.55 g, 4.2 mmole), triethylamine (0.42 g, 4.2 mmole) and 4-(4-ethoxyphenoxy)benzyl chloride (1.00 g, 3.8 mmole) was heated under reflux for 5 hours and then cooled to room temperature. The resultant mixture was washed with water, dried over anhydrous sodium sulfate and distilled under reduced pressure to remove toluene. The residue was purified by silica gel column chromatography to give 1-[4-(4-ethoxyphenoxy)benzyl]-2-methylbenzimidazole (1.20 g) as colorless liquid. nD26.0 1.5984.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[N:4][CH:3]=1.[CH3:12][Mg]Br.C(OCC)C.Cl>C1COCC1.Cl[Ni]1(Cl)[P](C2C=CC=CC=2)(C2C=CC=CC=2)CCC[P]1(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:12][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[N:4][CH:3]=1
Reactant: Brc1cncc2ccccc12
Reactant: C[Mg]Br
Agent: Cl[Ni]1(Cl)[P](c2ccccc2)(c2ccccc2)CCC[P]1(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1cncc2ccccc12
Reaction time: 18 h
Yield: 78 %

Procedure:
To a solution of 4-bromoisoquinoline (1 g, 4.81 mmol) in THF (20 ml) was added [1,3-Bis(diphenylphosphino)propane]nickel(II)chloride (0.026 g, 0.048 mmol) followed by methyl magnesium bromide in diethyl ether (1.923 ml, 5.77 mmol) at room temperature. The reaction mass was stirred at the same temperature for 18 h. The reaction mixture was acidified with 1N HCl and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to get crude compound. The crude compound was purified by silica gel chromatography (5% ethyl acetate in pet ether) to get desired compound (0.6 g, 78%) as an oil. 1H NMR (400 MHz, DMSO-d6): δ ppm 9.15(s, 1H), 8.37 (s, 1H), 8.13-8.11 (d, J=8 Hz 1H), 8.05-8.03 (d, J=8 Hz, 1H), 7.83 (t, J=8 Hz, 1H), 7.71 (t, J=8 Hz, 1H) 2.59 (s, 3H); GC-MS: MS m/z 143 (M+).
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][C:5]2[NH:6][C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[CH2:9][CH2:10][C:4]=2[CH:3]=1.[C:17]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])(=[O:20])[CH:18]=[CH2:19].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:22]([O:21][C:17](=[O:20])[CH:18]=[CH:19][C:2]1[CH:16]=[CH:15][C:5]2[NH:6][C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[CH2:9][CH2:10][C:4]=2[CH:3]=1)([CH3:25])([CH3:24])[CH3:23]
Reactant: C=CC(=O)OC(C)(C)C
Reactant: Brc1ccc2c(c1)CCc1ccccc1N2
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)C=Cc1ccc2c(c1)CCc1ccccc1N2
Temperature: 100 °C
Yield: 33.6 %

Procedure:
A mixture of 2-bromo-10,11-Dihydro-5H-dibenzo[b,f]azepin (4.11 g, 15 mmol, prepared as described in Tetrahedron (1992), 48, 4779) tert-butyl acrylate (2.91 g, 22.5 mmol), palladium acetate (40 mg, 0.2 mmol), tri-o-tolylphosphine (183 mg, 0.6 mmol) and triethylamine (20 ml) in an screw cap ampoule was heated at 100° C. for 20 h. The cooled reaction mixture was diluted with ethyl acetate (50 ml), washed with water (3×20 ml), dried (MgSO4), filtered and evaporated in vacuo. The residue (3.9 g) was purified by column chromatography on silicagel (600 ml) using a mixture of ethyl acetate and heptane (1:6) as eluent which afforded 1.62 g (34%) of 3-(10,11-dihydro-5H-dibenzo[b,f]azepin-2-yl)acrylic acid tert-butyl ester as a solid.
Reaction SMILES: [CH3:1][N:2]1[C:7]2=[N:8][O:9][CH:10]=[C:6]2[C:5](=[O:11])[NH:4][C:3]1=[O:12].C(=O)([O-])[O-].[K+].[K+].[CH2:19](I)[CH3:20]>CN(C)C=O>[CH2:19]([N:4]1[C:5](=[O:11])[C:6]2=[CH:10][O:9][N:8]=[C:7]2[N:2]([CH3:1])[C:3]1=[O:12])[CH3:20]
Reactant: CCI
Reactant: Cn1c(=O)[nH]c(=O)c2conc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCn1c(=O)c2conc2n(C)c1=O

Procedure:
In 50 ml of dimethylformamide is dissolved 2 g of the 7-methyl-5H,7H-isoxazolo[3,4-d]pyrimidine-4,6-dione obtained in Example 19, followed by addition of 1.6 g of potassium carbonate and 2 ml of ethyl iodide. Then, the reaction and after-treatment are carried out in the same manner as Example 23 to obtain 0.9 g of the captioned compound as colorless crystals. melting point: 87°-88° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].Br[CH2:11][C:12](=[O:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[O:14]=[C:12]([CH3:13])[CH2:11][O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6]
Reactant: CC(=O)CBr
Reactant: O=Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)COc1cccc(C=O)c1
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 3.05 g of 3-hydroxybenzaldehyde, 2.3 ml of bromoacetone and 30 ml of dimethylformamide was added 4.15 g of potassium carbonate, and this was heated and stirred at 70° C. for 30 minutes. After cooled to room temperature, insolubles were filtered and the filtrate was concentrated under reduced pressure. Water was added to the resulting residue, and then extracted with ethyl acetate. The organic layer washed successively with water and an aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The resulting residue was subjected to silica gel column chromatography to obtain 0.76 g of oily 3-(2-oxo-propoxy)benzaldehyde [Compound No. (o)].
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[CH:7][C:8](I)=[CH:9][CH:10]=3)[C:5]3([CH2:20][O:19][C:18]([NH2:21])=[N:17]3)[C:4]=2[CH:3]=1.[N:22]1[CH:27]=[CH:26][CH:25]=[C:24](B(O)O)[CH:23]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.COCCOC>[N:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:2]2[CH:15]=[CH:14][C:13]3[O:12][C:11]4[C:6](=[CH:7][C:8]([C:24]5[CH:23]=[N:22][CH:27]=[CH:26][CH:25]=5)=[CH:9][CH:10]=4)[C:5]4([CH2:20][O:19][C:18]([NH2:21])=[N:17]4)[C:4]=3[CH:3]=2)[CH:23]=1
Reactant: NC1=NC2(CO1)c1cc(Br)ccc1Oc1ccc(I)cc12
Reactant: OB(O)c1cccnc1
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: COCCOC
Product: NC1=NC2(CO1)c1cc(-c3cccnc3)ccc1Oc1ccc(-c3cccnc3)cc12
Temperature: 95 °C
Reaction time: 16 h

Procedure:
Resealable tube was charged with 2′-bromo-7′-iodo-5H-spiro[oxazole-4,9′-xanthen]-2-amine (100 mg, 0.219 mmol), pyridin-3-ylboronic acid (81 mg, 0.656 mmol), Pd(PPh3)4 (50.6 mg, 0.044 mmol). DME (1 ml) and sodium carbonate (0.328 ml, 0.656 mmol) were added and the reaction mixture was capped with argon, sealed, and stirred at 95° C. for 16 hrs. The mixture was partitioned between DCM and water. The aqueous layer was removed and the organic layer was washed with brine, filtered and concentrated in vacuo. The crude residue was purified by flash chromatography on silica gel (12 g column, 15-100% DCM/MeOH/NH4OH in DCM) to give material with impurity followed by second FC on silica (12 g column, 50-85% DCM/MeOH/NH4OH) to give 2′,7′-di(pyridin-3-yl)-5H-spiro[oxazole-4,9′-xanthen]-2-amine.
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.[N:34]1([CH:40]2[CH2:45][CH2:44][N:43]([C:46]3[CH:52]=[CH:51][C:49]([NH2:50])=[C:48]([O:53][CH2:54][CH2:55][CH3:56])[CH:47]=3)[CH2:42][CH2:41]2)[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1.N>CC(O)C.Cl.CO>[N:34]1([CH:40]2[CH2:45][CH2:44][N:43]([C:46]3[CH:52]=[CH:51][C:49]([NH:50][C:2]4[N:7]=[C:6]([C:8]5[N:12]6[CH:13]=[CH:14][CH:15]=[CH:16][C:11]6=[N:10][C:9]=5[C:17]5[CH:18]=[C:19]([CH:31]=[CH:32][CH:33]=5)[C:20]([NH:22][C:23]5[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=5[F:30])=[O:21])[CH:5]=[CH:4][N:3]=4)=[C:48]([O:53][CH2:54][CH2:55][CH3:56])[CH:47]=3)[CH2:42][CH2:41]2)[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1
Reactant: O=C(Nc1c(F)cccc1F)c1cccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)c1
Reactant: CCCOc1cc(N2CCC(N3CCCCC3)CC2)ccc1N
Agent: Cl
Agent: N
Solvent: CO
Solvent: CC(C)O
Product: CCCOc1cc(N2CCC(N3CCCCC3)CC2)ccc1Nc1nccc(-c2c(-c3cccc(C(=O)Nc4c(F)cccc4F)c3)nc3ccccn23)n1
Temperature: 165 °C
Yield: 57.2 %

Procedure:
In a 5 mL microwave vial with septum cap, 3-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-benzamide (Intermediate Example 1) (0.200 g, 0.433 mmol), 4-(1,4′-bipiperidin-1′-yl)-2-(propyloxy)aniline (0.137 g, 0.433 mmol) were taken up in iPrOH (3 mL) and concentrated HCl (3 drops) was added. The vial was sealed and heated in the microwave at 165° C. for 30 min. The reaction was cooled to rt, neutralized with 7N ammonia in MeOH, adsorbed onto silica gel, and flash chromatographed. Product was then triturated with diethyl ether to give the title compound (0.184 g, 58%). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.20 (s, 1H), 9.18-9.41 (m, 1H), 8.24-8.47 (m, 2H), 8.18 (d, J=4.9 Hz, 1H), 8.02 (d, J=7.5 Hz, 1H), 7.77 (d, J=7.5 Hz, 1H), 7.69 (d, J=9.0 Hz, 1H), 7.57 (t, J=7.6 Hz, 1H), 7.26-7.48 (m, 3H), 7.17 (t, J=8.1 Hz, 2H), 6.83-7.01 (m, 1H), 6.63 (br. s., 1H), 6.43 (d, J=5.1 Hz, 2H), 3.91 (t, J=6.0 Hz, 2H), 3.69 (d, J=11.4 Hz, 2H), 2.60 (t, J=11.6 Hz, 2H), 2.36-2.52 (m, 4H), 2.22-2.36 (m, 1H), 1.75 (d, J=11.0 Hz, 2H), 1.14-1.66 (m, 10H), 0.66-0.88 (m, 3H). MS (M+H) 743.
Reaction SMILES: [CH:1]1([N:7]([CH2:21][CH2:22][C:23]2[CH:28]=CC=CC=2)[C:8](=[O:20])[NH:9][C:10]2[S:11][C:12]([S:15][CH2:16][C:17](O)=O)=[CH:13][N:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N)CCC.C1(=O)CCCCC1.C([O:43][C:44](=[O:47])CC)C>>[CH2:21]([N:7]([CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)[C:8](=[O:20])[NH:9][C:10]1[S:11][C:12]([S:15][CH2:16][CH2:17][C:44]([OH:47])=[O:43])=[CH:13][N:14]=1)[CH2:22][CH2:23][CH3:28]
Reactant: CCOC(=O)CC
Reactant: O=C(O)CSc1cnc(NC(=O)N(CCc2ccccc2)C2CCCCC2)s1
Solvent: CCCCN
Solvent: O=C1CCCCC1
Product: CCCCN(C(=O)Nc1ncc(SCCC(=O)O)s1)C1CCCCC1

Procedure:
Prepared as described for the synthesis of [2-(3-cyclohexyl-3-phenethyl-ureido)-thiazol-5-ylsulfanyl]-acetic acid, from n-butylamine, cyclohexanone and 2-amino-thiazol-5-ylsulfanyl)propionic acid ethyl ester.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]([CH3:12])[N:9]=[C:10]([CH3:11])[C:5]2=[CH:4][C:3]=1[CH:13]=[O:14].[CH:15]1([CH2:20][NH:21][CH2:22][CH3:23])[CH2:19][CH2:18][CH2:17][CH2:16]1>>[CH:15]1([CH2:20][N:21]([CH2:22][CH3:23])[C:2]2[N:7]=[C:6]3[N:8]([CH3:12])[N:9]=[C:10]([CH3:11])[C:5]3=[CH:4][C:3]=2[CH:13]=[O:14])[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: Cc1nn(C)c2nc(Cl)c(C=O)cc12
Reactant: CCNCC1CCCC1
Product: CCN(CC1CCCC1)c1nc2c(cc1C=O)c(C)nn2C
Temperature: 100 °C
Reaction time: 8 h
Yield: 178.3 %

Procedure:
6-Chloro-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridine-5-carbaldehyde (3.90 g, 18.6 mmol) and N-(cyclopentylmethyl)-N-ethylamine (11.70 g, 92.0 mmol) synthesized by the method described in International Patent Publication WO2006/073973 were mixed, and the mixture was stirred at 100° C. for 8 hours in an argon atmosphere. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1→5:1) to obtain 6-[(cyclopentylmethyl)(ethyl)amino]-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridine 5-carbaldehyde (9.96 g, 99%) as yellow oil.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([NH2:17])[CH:15]=3)[CH:10]=[N:9]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[O:18]([C:25]1[CH:30]=[CH:29][C:28]([CH2:31][C:32](O)=[O:33])=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[O:18]([C:25]1[CH:26]=[CH:27][C:28]([CH2:31][C:32]([NH:17][C:14]2[CH:15]=[C:16]3[C:11]([CH:10]=[N:9][N:8]3[CH2:7][CH2:6][N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:12][CH:13]=2)=[O:33])=[CH:29][CH:30]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Nc1ccc2cnn(CCN3CCCC3)c2c1
Reactant: O=C(O)Cc1ccc(Oc2ccccc2)cc1
Product: O=C(Cc1ccc(Oc2ccccc2)cc1)Nc1ccc2cnn(CCN3CCCC3)c2c1

Procedure:
According to the procedure for Example 49, 1-(2-pyrrolidin-1-yl-ethyl)-1H-indazol-6-ylamine and (4-phenoxy-phenyl)-acetic acid were processed to provide the title compound. 1H NMR (500 MHz, DMSO-D6) δ ppm 1.82 (m, 2 H), 1.98 (m, 2 H), 3.03 (m, 2 H), 3.52 (m, 2 H), 3.69 (m, 4 H), 4.67 (t, J=6.24 Hz, 2 H), 6.99 (m, 4 H), 7.13 (m, 2 H), 7.38 (m, 4 H), 7.72 (m, 1 H), 8.08 (m, 1 H), 8.29 (s, 1 H), 10.42 (s, 1 H); MS (DCI/NH3) m/z 441 (M+H)+.
Reaction SMILES: Cl[Si]1(Cl)CCC1.Cl[Si:8]1([CH3:12])[CH2:11][CH2:10][CH2:9]1.[C:13]([O:16]C(=O)C)(=[O:15])[CH3:14]>CO>[C:13]([O:16][Si:8]1([CH3:12])[CH2:11][CH2:10][CH2:9]1)(=[O:15])[CH3:14]
Reactant: C[Si]1(Cl)CCC1
Reactant: CC(=O)OC(C)=O
Agent: Cl[Si]1(Cl)CCC1
Solvent: CO
Product: CC(=O)O[Si]1(C)CCC1

Procedure:
Several silacyclobutane monomers are known. For example, see U.S. Pat. No. 3,046,291 to Leo H. Sommer, and U.S. Pat. No. 3,687,995 to David Jonas et al. Sommer prepared his silacyclobutanes by reacting ClCH2CHRCH2SiR'Cl2 with magnesium. Jonas et al. teach organosilicon compounds having the general formula ##STR4## where R represents an atom or radical selected from the group consisting of hydrogen atom and alkyl radicals having less than 7 carbon atoms and R' represents alkoxy radicals having less than 5 carbon atoms or a radical of the formula --NR"2, in which each R" is a hydrogen atom or an alkyl radical. In U.S. Pat. No. 3,694,427, issued Sept. 26, 1972, Jonas et al. teach that R' can also be acyloxy radical. As an example, the reaction of 1,1-dichlorosilacyclobutane with methylorthoformate gave 1,1-dimethoxysilacyclobutane ##STR5## in 78% yield. Further, the same compound was prepared in only 59% yield by reaction of 1,1-dichlorosilacyclobutane and methanol (Bush, R. Ph.D. Thesis, Univ. of California at Davis, 1975; Diss. Abstr. Int. B 1976, 36, 5034). Similarly, the reaction of 1-chloro-1-methyl-silacyclobutane and acetic anhydride gave 1-acetoxy-1-methyl-silacyclobutane ##STR6## in 48% yield (Nametkin, N. S.; Vdovin, V. M.; Grinberg, P. L. Dokl. Akad. Nauk SSSR, 1964, 155, 849 [320]) Silacyclobutane silazanes have been prepared by metathesis reaction with formation of alkali metal salt or condensation reaction with formation of HCl (Nametkin, N. S.; Vdovin, V. M.; Babich, E. D.; Oppengeim, V. D. Khim. Geterotsikl. Soedin., 1965, 455) and British Patent No. 1,328,514 to Bush et al. These reactions generally give less than quantitative yields and require additional processing steps in comparison to the invention process. The invention process also provides novel compounds. See also Nametkin, N. S.; Vdovin, J. M.; Babich, E. D. Khim. Geterotsikl. Soedin., 1967, 148. Transsilylation of silazanes is taught and transsilylation of 1-chloro-1-methylsilacyclobutane with disilazanes is shown.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:20](=[O:21])[C:11]2=[CH:12][NH:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=3[C:10]2=[N:9]1.Br[C:23]1[CH:28]=[CH:27][C:26]([CH2:29][C:30]2[NH:31][C:32]3[C:33](F)=CC=C(F)[C:37]=3[C:38]3C=2C(=O)N(C2C=CC=CC=2F)N=3)=[C:25](F)[CH:24]=1.C1(B(O)O)C=CC=CC=1.C(N1C=C(B2OC(C)(C)C(C)(C)O2)C=N1)C(C)C>>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:20](=[O:21])[C:11]2=[CH:12][N:13]([CH2:33][C:32]3[CH:37]=[CH:38][C:29]([C:26]4[CH:25]=[CH:24][CH:23]=[CH:28][CH:27]=4)=[CH:30][N:31]=3)[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=3[C:10]2=[N:9]1
Reactant: O=c1c2c(Cc3ccc(Br)cc3F)[nH]c3c(F)ccc(F)c3c-2nn1-c1ccccc1F
Reactant: Cc1ccccc1-n1nc2c3ccccc3[nH]cc-2c1=O
Agent: CC(C)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: OB(O)c1ccccc1
Product: Cc1ccccc1-n1nc2c3ccccc3n(Cc3ccc(-c4ccccc4)cn3)cc-2c1=O

Procedure:
Using the procedure described in Example 95, substituting 5-[5-bromopyridin-2-yl)methyl]-2-(2-methylphenyl)-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one for 5-[(4-bromo-2-fluorophenyl)methyl-6,9-difluoro-2-(2-fluorophenyl)-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one, and, substituting phenylboronic acid for 1-iso-butyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole, the titled compound was obtained: 1H-NMR (400 MHz, CD3OD) δ 9.03 (1H, s), 8.77 (1H, s), 8.36-8.33 (1H, m), 8.10-8.07 (1H, m), 7.85 (1H, d, J=8.8 Hz), 7.68-7.37 (12H, m), 5.93 (2H, s), 2.29 (3H, s), ppm; low resolution mass spectrometry (ES+) m/z 442.9 [(M+H)+; calculated for C29H22N4O: 443.2].
Reaction SMILES: [NH2:1]/[C:2](/[C:9]([F:12])([F:11])[F:10])=[CH:3]\[C:4]([O:6]CC)=O.[H-].[Na+].[F:15][C:16]1[C:21]([F:22])=[C:20]([F:23])[CH:19]=[CH:18][C:17]=1[NH:24][C:25](=O)[O:26]CC>CN(C)C=O>[F:15][C:16]1[C:21]([F:22])=[C:20]([F:23])[CH:19]=[CH:18][C:17]=1[N:24]1[C:4](=[O:6])[CH:3]=[C:2]([C:9]([F:10])([F:11])[F:12])[NH:1][C:25]1=[O:26]
Reactant: CCOC(=O)Nc1ccc(F)c(F)c1F
Reactant: CCOC(=O)/C=C(\N)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1cc(C(F)(F)F)[nH]c(=O)n1-c1ccc(F)c(F)c1F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 16.2 %

Procedure:
1.28 g of ethyl 3-amino-4,4,4-trifluorocrotonate was added to a 10 ml dimethylformamide solution of 0.33 g of sodium hydride (purity: 55%) under ice cooling and stirred at room temperature for 15 minutes, followed by addition of 1.31 g of ethyl 2,3,4-trifluorophenylcarbamate and was stirred at 90° C. for 4 hours. Then dimethylformamide was distilled away under reduced pressure and the residue was dissolved in 100 ml of water. This aqueous solution was washed with diethyl ether, then added to a mixed solution of 50 g of ice and 20 ml of concentrated hydrochloric acid and extracted with ethyl acetate. The obtained organic layer was washed with water and dried, and then the solvent was distilled away under reduced pressure to obtain 0.3 g of the objective compound.