Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[C:15](I)[CH:14]=[C:13]([Cl:18])[C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1)=[O:5].[C:19]([Cu])#[N:20].CC#N>CN(C=O)C>[Cl:1][C:2]1[CH:16]=[C:15]([C:19]#[N:20])[CH:14]=[C:13]([Cl:18])[C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1)=[O:5]
Reactant: O=C(Nc1ccncc1)c1c(Cl)cc(I)cc1Cl
Reactant: N#C[Cu]
Solvent: CC#N
Solvent: CN(C)C=O
Product: N#Cc1cc(Cl)c(C(=O)Nc2ccncc2)c(Cl)c1
Temperature: 150 °C
Yield: 22.9 %

Procedure:
To the solution of 2,6-dichloro-4-iodo-N-(pyridin-4-yl)benzamide (0.15 g, 0.38 mmol) in DMF (2 mL) was added CuCN (0.17 g, 1.9 mmol). The mixture was heated at 150° C. under the irradiation of microwave for 1 hour. After the completion of the reaction, the mixture was filtered through Celite and purified by acid HPLC(YMC, 150 mm×30 mm, gradient: CH3CN/0.5% TFA, 10-50, 17 min) to afford the desired product (25.4 mg, yield: 23%). 1HNMR (DMSO-d6, 400 MHz): 611.95 (s, 1H), 8.74 (br, 2H), 8.33 (s, 2H), 7.97 (2H). LCMS (ESI) m/z: 292.1 [M+H+]
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:5]=1[O:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].S([O-])([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([CH2:12][O:11][C:5]2[CH:6]=[CH:7][C:8]([CH3:10])=[CH:9][C:4]=2[CH2:3][OH:2])=[CH:14][CH:15]=1
Reactant: COC(=O)c1cc(C)ccc1OCc1ccc(OC)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: COc1ccc(COc2ccc(C)cc2CO)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-(4-methoxybenzyloxy)-5-methylbenzoic acid methyl ester (7.32 g, 25.6 mmol) in THF (20 mL) is added LiAlH4 solution (26 mL, 1M in THF) dropwise and the mixture is stirred at RT for 1 h. The mixture is diluted with THF (80 mL) and cooled in an ice bath then saturated sodium sulfate solution (1 mL) is added dropwise. The mixture is filtered and the filtrate dried over magnesium sulfate and evaporated to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]([O:11]C)=[O:10])=[N:7][CH:8]=1.[OH-].[Na+:14]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]([O-:11])=[O:10])=[N:7][CH:8]=1.[Na+:14]
Reactant: COC(=O)c1ccc(OC)cn1
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc(C(=O)[O-])nc1
Temperature: 120 °C
Yield: 96.7 %

Procedure:
A microwave vial was charged with methyl 5-methoxypicolinate (9.700 g, 58.0 mmol, synthesized according to Tetrahedron Letters 2011, 52, 122-124) and sodium hydroxide solution (10 N; 58.0 ml, 580 mmol). The reaction mixture was stirred and heated in a CEM Voyager microwave (Large-Scale Unit) at 120° C. for 11 min (150 watts, Powermax feature on). Subsequently, the reaction mixture was allowed to stir for 10 minutes at ambient temperature. The precipitate was collected by filtration and the solid was rinsed with hexanes. The solid was dried to obtain sodium 5-methoxypicolinate (9.83 g, 56.1 mmol, 97% yield) as a light-yellow solid. MS m/z=175.9 [M+H]+. Calculated for C7H6NNaO3: 175. 1H NMR (400 MHz, MeOH) d ppm 8.23 (d, J=2.93 Hz, 1H) 8.06 (d, J=8.61 Hz, 1H) 7.39 (dd, J=8.80, 2.93 Hz, 1H) 3.91 (s, 3H)
Reaction SMILES: C([O:4][C:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=1)(=O)C.Br[C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([O:23][CH3:24])[CH:17]=1.C[O-].C([Sn+](CCCC)CCCC)CCC>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([CH:6]2[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH2:13][CH2:14][C:5]2=[O:4])=[CH:17][C:18]=1[O:23][CH3:24]
Reactant: CC(=O)OC1=Cc2ccccc2CC1
Reactant: COc1cc(Br)ccc1Cl
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[Sn+](CCCC)CCCC
Solvent: Cc1ccccc1
Product: COc1cc(C2C(=O)CCc3ccccc32)ccc1Cl
Temperature: 25 °C

Procedure:
Charge an oven dried, argon flushed 3-L 3-necked round bottomed flask equipped with a mechanical stirrer and reflux condenser with 2-acetoxy-3,4-dihydronaphthalene (100.69 grams, 0.5349 moles), 4-bromo-2-methoxy-1-chlorobenzene (116.81 grams, 0.5274 moles), palladium acetate (1.19 grams, 0.0053 moles), tri (ο-tolyl)phosphine (3.24 grams, 0.0107 moles), tri-n-butyltin methoxide (172.83 grams, 0.5383 moles) and 1 L toluene. Place in an oil bath pre-heated to 100°-105° C. for 20 hours. Distill off about 750 mL toluene, cool to RT, add 500 mL 5% HCl and 250 mL ethyl acetate, stir for a few minutes, filter through a pad of celite and wash the celite pad with 5×250 mL ethyl acetate. Separate the layers, extract the aqueous layer with 1×250 mL ethyl acetate, wash the combined organic layers with saturated sodium bicarbonate solution followed by saturated salt solution, dry over magnesium sulfate and concentrate on a Buchi rotavapor. Kugelrohr treat the resulting oil (heated to about 130° C., 1 Torr) to remove the more volatile by-products to yield product. An analytical sample can be prepared by flash chromatography (5-30% ethyl acetate/hexanes) followed by recrystallization (ethyl acetate/hexanes).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(Cl)CCl.[CH2:16]([C:21]12[CH2:28][CH2:27][C:24]([C:29](O)=[O:30])([CH2:25][CH2:26]1)[CH2:23][CH2:22]2)[CH2:17][CH2:18][CH2:19][CH3:20]>CN(C1C=CN=CC=1)C.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][C:29]([C:24]23[CH2:25][CH2:26][C:21]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])([CH2:28][CH2:27]2)[CH2:22][CH2:23]3)=[O:30])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: CCCCCC12CCC(C(=O)O)(CC1)CC2
Reactant: NS(=O)(=O)c1ccc(Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CCCCCC12CCC(C(=O)NS(=O)(=O)c3ccc(Cl)cc3)(CC1)CC2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
0.42 g of 4-chlorophenylsulfonamide, 60 mg of DMAP and 0.42 g of EDC are added to a solution of 0.5 g of 4-pentyl-bicyclo[2.2.2]octane-1-carboxylic acid in 8 ml of DMF, the mixture obtained is stirred for ca. 16 h at RT and solvent from the mixture obtained is evaporated. The evaporation residue obtained is dissolved in EtAc and washed with 1 N HCl, saturated NaHCO3 solution and brine and the organic phase obtained is dried. Solvent of the organic phase obtained is evaporated and the evaporation residue obtained is subjected to chromatography. 4-Chloro-N-(4-pentyl- bicyclo[2.2.2]octane-1-carbonyl)-benzenesulfonamide is obtained in the form of a white powder;
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([OH:10])=[O:9])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[OH-].[Li+]>CN(C=O)C.C1COCC1>[CH2:7]([O:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([OH:10])=[O:9])[CH:3]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(O)c1cc(O)ccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCCCOc1ccnc(C(=O)O)c1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To 4-hydroxypyridine-2-carboxylic acid 10b (R9=hydroxy) (200 mg, 1.4 mmol) in DMF (2 mL), potassium carbonate (397 mg, 2.8 mmol) was added followed by n-bromobutane (197 mg, 1.4 mmol), warmed at 60° C. for overnight. The solvent was removed to obtain the crude ester product. The crude ester (360 mg, 1.4 mmol) was dissolved in THF (4 mL), lithium hydroxide (72 mg, 1.7 mmol) was added, and the reaction mixture stirred at room temperature for 2 hr. The residue obtained on removal of solvent was purified by silica gel chromatography using 10% MeOH in DCM to provide 4-butoxypyridine-2-carboxylic acid 15a (R9′=butyl) (100 mg, 43%). 1H NMR (300 MHz, CD3OD) δ 8.37 (d, J=6.0, 1), 7.63 (d, J=2.7, 1), 7.07 (dd, J=2.7, 6.0, 1), 4.15 (t, J=6.6, 2), 1.82 (m, 2), 1.54 (m, 2), 1.01 (t, J=7.5, 3). MS (ESNEG): 194 [M−H]−.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]2(O)[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)[CH:5]=[CH:4][CH:3]=1>OS(O)(=O)=O>[Br:1][C:2]1[N:7]=[C:6]([C:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH:9]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: CN1CCC(O)(c2cccc(Br)n2)CC1
Agent: O=S(=O)(O)O
Product: CN1CC=C(c2cccc(Br)n2)CC1
Temperature: 100 °C

Procedure:
To a 150 mL flask containing 6-bromo-1′-methyl-2′,3′,5′,6′-tetrahydro-1′H-[2,4′]bipyridinyl-4′-ol (5 g, 18.5 mmol) was added conc. H2SO4 (50 mL). Heated to 100° C. for 18 h. Cooled and poured onto ice carefully. Neutralized with 5 N NaOH and extracted with EtOAc. Washed with brine, dried (MgSO4) and concentrated in vacuo. Diluted residue with EtOAc and filtered. Concentrated filtrate in vacuo to give 6-bromo-1′-methyl-1′,2′,3′,6′-tetrahydro-[2,4′]bipyridinyl as an orange oil. MS m/z: 254.2 (M+H). Calc'd for C11H13BrN2 253.14.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:20])[N:8]([CH2:12][CH2:13][N:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[CH2:9][CH2:10][CH2:11][C:5]=2[NH:4][C:3]=1[CH:21]=O.[F:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][S:31]([C:34]2[CH:35]=[C:36]3[C:40](=[CH:41][CH:42]=2)[NH:39][C:38](=[O:43])[CH2:37]3)(=[O:33])=[O:32])=[CH:26][CH:25]=1.N1CCCCC1>C(O)C>[F:23][C:24]1[CH:25]=[CH:26][C:27]([CH2:30][S:31]([C:34]2[CH:35]=[C:36]3[C:40](=[CH:41][CH:42]=2)[NH:39][C:38](=[O:43])/[C:37]/3=[CH:21]\[C:3]2[NH:4][C:5]3[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][N:14]4[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]4)[C:7](=[O:20])[C:6]=3[C:2]=2[CH3:1])(=[O:33])=[O:32])=[CH:28][CH:29]=1
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCCCC1)CCC2
Reactant: O=C1Cc2cc(S(=O)(=O)Cc3ccc(F)cc3)ccc2N1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4ccc(F)cc4)cc32)[nH]c2c1C(=O)N(CCN1CCCCC1)CCC2
Temperature: 25 °C
Yield: 74.8 %

Procedure:
3-Methyl-4-oxo-5-(2-piperidin-1-yl-ethyl)-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 32d (57.6 mg, 0.21 mmol) and 5-(4-fluoro-phenylmethanesulfonyl)-1,3-dihydro-indol-2-one 65a (57.6 mg, 0.19 mmol) were dissolved in 2 ml of ethanol, and added with 42 μl of piperidine to the solution at room temperature. Upon completion of the addition, the reaction mixture was heated to reflux for 3 hours. After thin lay chromatography showed the disappearance of starting materials, the reaction mixture was naturally cooled to room temperature, and filtered. The filter cake was washed with anhydrous ethanol (3 ml×2) and dried to obtain the title compound (Z)-2-((5-(4-fluorobenzyl sulfonyl)-2-oxoindolin-3-ylidene)methyl)-3-methyl-5-(2-(piperidin-1-yl)ethyl)-5,6,7,8-tetrahydropyrrolo[3,2-c]azepin-4(1H)-one 67 (84 mg, yield 76%) as an orange solid.
Reaction SMILES: [C:1]1([C:7]2[S:8][C:9]([C:18]([O:20]C)=O)=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:22][OH:23].[OH-].[K+]>CO.C1COCC1>[OH:23][NH:22][C:18]([C:9]1[S:8][C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[N:11][C:10]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:20]
Reactant: COC(=O)c1sc(-c2ccccc2)nc1-c1ccccc1
Reactant: NO
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(NO)c1sc(-c2ccccc2)nc1-c1ccccc1
Temperature: 0 °C
Reaction time: 18 h
Yield: 71.9 %

Procedure:
A 100 mL round-bottomed flask was charged with methyl 2,4-diphenylthiazole-5-carboxylate 73 (420 mg, 1.422 mmol) in MeOH (2.844 ml) and THF (2.84 ml) and the solution was cooled down to 0° C. Then a 50% aqueous solution of hydroxylamine (4697 mg, 71.1 mmol) and 4M potassium hydroxide solution (0.427 ml, 1.706 mmol) were added and the reaction mixture was allowed to warm up to rt while stirring for 18 h. The reaction mixture was partitioned between EtOAc and water. The aqueous layer was extracted with fresh EtOAc and the combined organic layers were washed with 1M HCl, sat NaHCO3, and brine, dried over MgSO4, filtered and concentrated. The resulting solid was triturated (Et2O) to afford the title compound 74 (0.303 g, 72% yield). 1H NMR: (DMSO-d6) d(ppm) 1H, 11.29 (s, 1H), 9.44 (s, 1H), 8.03 (dd, J=6.3, 2.7 Hz, 2H), 7.84 (d, J=7.0 Hz, 2H), 7.56-7.55 (m, 3H), 7.50-7.43 (m, 3H). LRMS (ESI): (calc.) 296.34 (found) 297.1 (MH)+
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[NH2:9][C:10]1[C:15]([C:16]#[N:17])=[CH:14][N:13]=[C:12](Cl)[N:11]=1>>[NH2:9][C:10]1[C:15]([C:16]#[N:17])=[CH:14][N:13]=[C:12]([NH:5][C:4]2[CH:6]=[CH:7][CH:8]=[C:2]([Cl:1])[CH:3]=2)[N:11]=1
Reactant: N#Cc1cnc(Cl)nc1N
Reactant: Nc1cccc(Cl)c1
Product: N#Cc1cnc(Nc2cccc(Cl)c2)nc1N
Yield: 87.5 %

Procedure:
3-Chloroaniline (277 mg, 2.2 mmol) was treated with 4-amino-2-chloro-5-cyanopyrimidine (0.3 g, 2.0 mmol) by the procedure described in Example 1 to give the title compound (430 mg, 90%). NMR: 7.00 (d, 1H), 7.28 (dd, 1H), 7.55 (s, 2H), 7.70 (d, 1H), 7.89 (s, 1H), 8.38 (s, 1H), 9.81 (s, 1H); m/z 246 (MH)+.
Reaction SMILES: C(O)(=O)CC(CC(O)=O)(C(O)=O)O.[F:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][C:19]1[C:24]3([CH2:32][CH2:31][C:30]([CH2:43][C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)([NH:33]CC4C=CC(OC)=CC=4)[CH2:29][CH2:28]3)[O:25][CH2:26][CH2:27][C:18]2=1>O1CCCC1.CO.[Pd]>[CH2:43]([C:30]1([NH2:33])[CH2:31][CH2:32][C:24]2([C:19]3[NH:20][C:21]4[C:17]([C:18]=3[CH2:27][CH2:26][O:25]2)=[CH:16][C:15]([F:14])=[CH:23][CH:22]=4)[CH2:28][CH2:29]1)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: COc1ccc(CNC2(Cc3ccccc3)CCC3(CC2)OCCc2c3[nH]c3ccc(F)cc23)cc1
Agent: [Pd]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CO
Solvent: C1CCOC1
Product: NC1(Cc2ccccc2)CCC2(CC1)OCCc1c2[nH]c2ccc(F)cc12

Procedure:
A solution of the free base of 6′-fluoro-4′,9′-dihydro-N-(4-methoxybenzyl)-4-benzyl-spiro[cyclohexane-1,1′(3′H)-pyrano[3,4-b]indol]-4-amine citrate (200 mg, 0.4 mmol) in tetrahydrofuran (20 ml) and methanol (20 ml) was mixed with 10% palladium on activated carbon (40 mg) and hydrogenated for 7 h under 3 bar and at 40° C. Then the reaction mixture was filtered through a pleated filter, the filter residue was washed with methanol and the filtrate was concentrated to small volume under vacuum. The crude product (186 mg) was purified by flash chromatography (20 g, 21×2 cm) with methanol. Yield: 136 mg (64%), beige-coloured solid. Melting point 198-205° C. (decomposition).
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[CH:9][C:10]([NH:12][C:13](=[O:17])[C:14]([OH:16])=O)=[CH:11][C:5]=2[O:4][CH2:3]1.[CH2:18]([O:25][CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(OCC)C>[CH2:18]([O:25][CH:26]1[CH2:31][CH2:30][N:29]([C:14](=[O:16])[C:13]([NH:12][C:10]2[CH:9]=[CH:8][C:6]3[NH:7][C:2](=[O:1])[CH2:3][O:4][C:5]=3[CH:11]=2)=[O:17])[CH2:28][CH2:27]1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: c1ccc(COC2CCNCC2)cc1
Reactant: O=C1COc2cc(NC(=O)C(=O)O)ccc2N1
Solvent: CCOCC
Product: O=C1COc2cc(NC(=O)C(=O)N3CCC(OCc4ccccc4)CC3)ccc2N1

Procedure:
The title compound is prepared from N-(3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-7-yl)-oxalamic acid and 4-benzyloxy-piperidine [Tetrahedron Lett., 36 3465. (1995)] according to the method described in Example 1c. Melting Point: 143-146° C. (diethylether)
Reaction SMILES: [NH2:1][C:2]1[CH:36]=[CH:35][CH:34]=[CH:33][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][CH:12]([O:15][C:16]2[N:20]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[C:19]3[CH:29]=[CH:30][CH:31]=[CH:32][C:18]=3[N:17]=2)[CH2:11][CH2:10]1)=[O:5].[C:37]([OH:42])(=[O:41])[C:38]([OH:40])=[O:39].[CH3:43][C:44](=O)[CH3:45]>>[C:37]([OH:42])(=[O:41])[C:38]([OH:40])=[O:39].[F:28][C:25]1[CH:26]=[CH:27][C:22]([CH2:21][N:20]2[C:19]3[CH:29]=[CH:30][CH:31]=[CH:32][C:18]=3[N:17]=[C:16]2[O:15][CH:12]2[CH2:13][CH2:14][N:9]([CH2:8][CH2:7][N:6]3[C:4](=[O:5])[C:3]4[C:2](=[CH:36][CH:35]=[CH:34][CH:33]=4)[NH:1][C:44]3([CH3:45])[CH3:43])[CH2:10][CH2:11]2)=[CH:23][CH:24]=1
Reactant: CC(C)=O
Reactant: Nc1ccccc1C(=O)NCCN1CCC(Oc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Agent: O=C(O)C(=O)O
Product: CC1(C)Nc2ccccc2C(=O)N1CCN1CCC(Oc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Reaction time: 1 h
Yield: 77 %

Procedure:
A mixture of 5 parts of 2-amino-N-[2-[4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]oxy]-1-piperidinyl]ethyl]-benzamide, 80 parts of 2-propanone and 1.9 parts of ethanedioic acid was stirred for 1 hour at reflux temperature. After cooling, the product was filtered off and dried, yielding 4.8 parts (77%) of 3-[2-[4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]oxy]-1-piperidinyl]ethyl]-2,3-dihydro-2,2-dimethyl-4(1H)-quinazolinone ethanedioate (1:1); mp. 166.5° C. (485).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([O:13]C)=[O:12])=[CH:8][CH:9]=2)[CH:4]=[N:3]1.[Li+].[OH-].OS([O-])(=O)=O.[K+]>CO.O.O>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([OH:13])=[O:12])=[CH:8][CH:9]=2)[CH:4]=[N:3]1
Reactant: COC(=O)c1ccc2c(cnn2C)c1
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [Li+]
Solvent: O
Solvent: CO
Product: Cn1ncc2cc(C(=O)O)ccc21
Temperature: 40 °C
Yield: 71 %

Procedure:
To a solution of methyl 1-methyl-1H-indazole-5-carboxylate (107 mg, 0.56 mmol) in methanol/water (V:V 1:1, 4 mL) was added LiOH (48 mg). The solution was heated at 40° C. for 3 hours before cooling to room temperature. The mixture was diluted with water and acidified to pH 3.5-4 with KHSO4. Solids precipitated and were isolated by filtration and dried under vacuum to afford the title compound as a yellow solid (70 mg, 71%).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:4]=1[C:20]1[O:21][CH:22]=[CH:23][N:24]=1.[N:25]1([C:31]2[CH:39]=[CH:38][C:34]([C:35](O)=[O:36])=[CH:33][N:32]=2)[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>>[N:25]1([C:31]2[CH:39]=[CH:38][C:34]([C:35]([NH:1][CH2:2][C:3]3[C:12](=[O:13])[C:11]4[C:6](=[N:7][CH:8]=[CH:9][CH:10]=4)[N:5]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[C:4]=3[C:20]3[O:21][CH:22]=[CH:23][N:24]=3)=[O:36])=[CH:33][N:32]=2)[CH2:26][CH2:27][O:28][CH2:29][CH2:30]1
Reactant: O=C(O)c1ccc(N2CCOCC2)nc1
Reactant: NCc1c(-c2ncco2)n(-c2ccccc2)c2ncccc2c1=O
Product: O=C(NCc1c(-c2ncco2)n(-c2ccccc2)c2ncccc2c1=O)c1ccc(N2CCOCC2)nc1

Procedure:
6-Morpholin-4-yl-N-(2-oxazol-2-yl-4-oxo-1-phenyl-1,4-dihydro-[1,8]naphthyridin-3-yl-methyl)-nicotinamide was prepared starting from intermediate B and 6-morpholin-4-yl-nicotinic acid. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.65-8.67 (m, 2H) 8.48 (d, J=2.90 Hz, 1H) 8.05-8.15 (m, 1H) 7.98 (d, J=0.75 Hz, 1H) 7.85 (dd, J=8.70, 2.90 Hz, 1H) 7.55 (dd, J=8.20, 4.40 Hz, 1H) 7.23-7.45 (m, 5H) 7.18 (d, J=0.75 Hz, 1H) 6.79 (d, J=8.30 Hz, 1H) 4.25 (d, J=4.20 Hz, 2H) 3.62-3.73 (m, 4H) 3.47-3.57 (m, 4H).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[S:5][CH:6]=[C:7]([C:9](OCC)=[O:10])[N:8]=1.CC(C[AlH]CC(C)C)C.C(O)(=O)C.C(C(C(C([O-])=O)O)O)([O-])=O.[K+].[Na+]>ClCCl>[CH3:1][O:2][CH2:3][C:4]1[S:5][CH:6]=[C:7]([CH:9]=[O:10])[N:8]=1
Reactant: CCOC(=O)c1csc(COC)n1
Agent: CC(C)C[AlH]CC(C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COCc1nc(C=O)cs1
Temperature: -78 °C
Reaction time: 2 h
Yield: 99.9 %

Procedure:
A solution containing the product from Example 6C (7.4 g, 36.8 mmol) in dichloromethane (40 mL) was treated with DIBAL (73.6 mL, 1 M in dichloromethane) dropwise at −78° C. over 2 hours, stirred at −78° C. for 2 hours, treated with acetic acid (10 mL) at −78° C. and warmed to 25° C. A 10% solution of aqueous sodium potassium tartrate was added and the mixture was stirred vigorously for 1 hour. The reaction mixture was partitioned between chloroform and water. The organic phase was washed with brine, dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel eluting with 0-100% ethyl acetate/dichloromethane to give the title compound (5.78 g, 71% yield).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:8]([S:10]SCC)[CH3:9]>[O-]C1C=CC=CC=1.[Zr+4].[O-]C1C=CC=CC=1.[O-]C1C=CC=CC=1.[O-]C1C=CC=CC=1>[CH2:8]([S:10][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[OH:7])[CH3:9]
Reactant: Oc1ccccc1
Reactant: CCSSCC
Agent: [Zr+4]
Agent: [O-]c1ccccc1
Product: CCSc1ccccc1O
Temperature: 195 °C
Yield: 37.7 %

Procedure:
Zirconium phenoxide (4.0 g, 0.0086 moles) was added to phenol (8.9 g, 0.095 moles) and ethyl disulfide (10.5 g, 0.086 moles). The mixture was heated under nitrogen for 6.5 hours during which the temperature slowly increased to 195° C. Ethyl mercaptan was removed continuously by distillation. The mixture was distilled at 0.4 mm mercury to a maximum head temperature of 102° C. yielding 12.2 g of distillate. Gas chromatographic (GC) analysis indicated the distillate contained 5.0 g of ortho-(ethylthio)phenol (38% yield).
Reaction SMILES: C(OC(=O)C)C.[ClH:7].C(OC(=O)[NH:14][CH2:15][CH2:16][C:17]1[CH:34]=[CH:33][C:20]2[N:21]([CH2:31][CH3:32])[C:22](=[O:30])[C:23]([CH3:29])([CH3:28])[C:24](=[O:27])[N:25]([CH3:26])[C:19]=2[CH:18]=1)(C)(C)C>C(OCC)(=O)C>[ClH:7].[NH2:14][CH2:15][CH2:16][C:17]1[CH:34]=[CH:33][C:20]2[N:21]([CH2:31][CH3:32])[C:22](=[O:30])[C:23]([CH3:28])([CH3:29])[C:24](=[O:27])[N:25]([CH3:26])[C:19]=2[CH:18]=1
Reactant: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(CCNC(=O)OC(C)(C)C)ccc21
Agent: Cl
Solvent: CCOC(C)=O
Product: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(CCN)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 4N-hydrogen chloride ethyl acetate solution(6 ml) was added to an ethyl acetate solution (20 ml) of [2-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-yl)ethyl]carbamic acid tert-butyl ester(0.38 g), and the mixture was stirred at room temperature overnight. The reaction mixture was condensed under reduced pressure to give the title compound(0.26 g) as a pale orange amorphous solid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]Cl.[Mg].[Cl:9][CH2:10][Si:11](Cl)(Cl)[C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1>>[Cl:9][CH2:10][Si:11]1([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Fc1ccc([Si](Cl)(Cl)CCl)cc1
Reactant: ClCCCCCCl
Agent: [Mg]
Product: Fc1ccc([Si]2(CCl)CCCCC2)cc1
Yield: 48.1 %

Procedure:
In the same apparatus and procedures as Example 1-i) were reacted 6.2 g of 1,5-dichloropentane (0.044 mol) and 2.8 g of magnesium species (0.11 mol), and then followed by coupling with 5.6 g (0.03 mol) of (chloromethyl)dichloro (4-fluorophenyl)silane prepared from the above procedure i) to give 3.5 g of 1-(chloromethyl)-1-(4-fluorophenyl)-1-silacyclohexane (74° C./0.2 mmHg).
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4](=[O:14])[NH:5][C:6](=[O:13])[N:7]([CH2:10][CH2:11][CH3:12])[C:8]=1[NH2:9].C[O:16][C:17]([C:19]12[CH2:26][CH2:25][C:22]([C:27](O)=O)([CH2:23][CH2:24]1)[CH2:21][CH2:20]2)=[O:18].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC.O.[OH-].[Na+].Cl>CN(C=O)C>[O:13]=[C:6]1[N:7]([CH2:10][CH2:11][CH3:12])[C:8]2[N:9]=[C:27]([C:22]34[CH2:25][CH2:26][C:19]([C:17]([OH:18])=[O:16])([CH2:20][CH2:21]3)[CH2:24][CH2:23]4)[NH:2][C:3]=2[C:4](=[O:14])[NH:5]1
Reactant: CCCn1c(N)c(N)c(=O)[nH]c1=O
Reactant: COC(=O)C12CCC(C(=O)O)(CC1)CC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CCCn1c(=O)[nH]c(=O)c2[nH]c(C34CCC(C(=O)O)(CC3)CC4)nc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.1 %

Procedure:
5,6-Diamino-1-propyl-1H-pyrimidine-2,4-dione hydrochloride salt (570 mg) was dissolved in 20 mL of DMF along with bicyclo[2.2.2]octane-1,4-dicarboxylic acid monomethyl ester (520 mg, 2.45 mmol). HATU (980 mg, 1.05 eq) was added, followed by Et3N (1.40 mL, 4.05 eq). The resulting reaction mixture was stirred at rt overnight. The following morning, the reaction mixture was filtered to remove some of the precipitate. The filtrate was concentrated under reduced pressure. The resulting residue was dissolved in 10 mL of H2O containing 10 eq of NaOH (980 mg). The reaction mixture was stirred under reflux for 2 h. It was then cooled to rt and acidified to pH2 with concentrated HCl. The resulting precipitate was collected by filtration and dried to afford 680 mg of the acid derivative.