Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][OH:7].[C:8]1(=O)[O:13][C:11](=[O:12])[CH:10]2[CH2:14][CH2:15][CH2:16][CH2:17][CH:9]12>C(O)C>[OH:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2][N:1]1[C:11](=[O:12])[CH:10]2[CH2:14][CH2:15][CH2:16][CH2:17][CH:9]2[C:8]1=[O:13]
Reactant: NCCOCCO
Reactant: O=C1OC(=O)C2CCCCC12
Solvent: CCO
Product: O=C1C2CCCCC2C(=O)N1CCOCCO
Yield: 95.6 %

Procedure:
A 500-ml, two necked flask was equipped with a magnetic stirring bar, heating mantle and condenser. The flask was charged with 51 g of 2-(aminoethoxy) ethanol (0.49 mol.) and 250 ml of ethanol. Next, 75 g of hexahydrophthalic anhydride (0.49 mol.) was slowly added to the flask. After the addition was complete the reaction was refluxed for 12 hours. The IR spectrum indicated the reaction was complete. The ethanol was removed with a rotoevaporator to yield 113 g (96%) of N-(2-hydroxyethoxyethyl)hexahydrophthalimide.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([O:17][CH2:18][C:19]([OH:21])=O)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:23][C@@H:24]([CH2:30][C:31]1[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][CH:32]=1)[C:25]([O:27][CH2:28][CH3:29])=[O:26]>>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][CH:14]([O:17][CH2:18][C:19]([NH:23][C@@H:24]([CH2:30][C:31]2[CH:32]=[CH:33][C:34]([N+:37]([O-:39])=[O:38])=[CH:35][CH:36]=2)[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[O:21])[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)COC1CCN(C(=O)OCc2ccccc2)CC1
Reactant: CCOC(=O)[C@@H](N)Cc1ccc([N+](=O)[O-])cc1
Agent: Cl
Product: CCOC(=O)[C@H](Cc1ccc([N+](=O)[O-])cc1)NC(=O)COC1CCN(C(=O)OCc2ccccc2)CC1
Yield: 76.1 %

Procedure:
In the same manner as in Example 67 (1), [N-benzyloxycarbonyl-4-piperidinyloxy]acetic acid (530 mg, 1.81 mmol) and ethyl (S)-2-amino-3-(4-nitrophenyl)propionate hydrochloride (500 mg, 1.82 mmol) were condensed to give 707 mg of ethyl (S)-2-[(N-benzyloxycarbonyl-4-piperidinyloxy)acetylamino]-3-(4-nitrophenyl)propionate as a yellow oil (76%).
Reaction SMILES: [OH-].[Na+].[C:3]([CH:7]([C:32]1[CH:37]=[CH:36][C:35]2[O:38][CH2:39][O:40][C:34]=2[CH:33]=1)[O:8][C:9]1[C:14]([CH2:15][CH2:16][CH3:17])=[CH:13][C:12]([CH2:18][N:19]2[C:27]3[C:22](=[N:23][CH:24]=[CH:25][CH:26]=3)[N:21]=[C:20]2[CH3:28])=[CH:11][C:10]=1[CH2:29][CH2:30][CH3:31])([O:5]C)=[O:4].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO.C(Cl)Cl>[C:3]([CH:7]([C:32]1[CH:37]=[CH:36][C:35]2[O:38][CH2:39][O:40][C:34]=2[CH:33]=1)[O:8][C:9]1[C:14]([CH2:15][CH2:16][CH3:17])=[CH:13][C:12]([CH2:18][N:19]2[C:27]3[C:22](=[N:23][CH:24]=[CH:25][CH:26]=3)[N:21]=[C:20]2[CH3:28])=[CH:11][C:10]=1[CH2:29][CH2:30][CH3:31])([OH:5])=[O:4]
Reactant: CCCc1cc(Cn2c(C)nc3ncccc32)cc(CCC)c1OC(C(=O)OC)c1ccc2c(c1)OCO2
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: CCCc1cc(Cn2c(C)nc3ncccc32)cc(CCC)c1OC(C(=O)O)c1ccc2c(c1)OCO2
Yield: 48.7 %

Procedure:
A 5N sodium hydroxide solution (0.2 mL) was added to a stirred mixture of the product of Step A (27 mg, 0.0524 mmol) in methanol (2 mL). A few drops of methylene chloride were added to allow stirring then the mixture was stirred at room temperature for 2 h. The solution volume was reduced to ~10% in vacuo then 5% citric acid solution added. The mixture was extracted with ethyl acetate (3 times). The combined organic phase was washed with water, brine, dried (magnesium sulfate) and the solvent removed in vacuo. The residue was purified by flash-chromatography using silica gel (8, 10% methanol/methylene chloride) to give the titled compound (12.8 mg) as a white solid.
Reaction SMILES: Br[CH:2]([CH2:11][CH2:12][CH3:13])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9]C)=[O:8].[CH3:14][C:15]([C:17]1[CH:18]=[CH:19][C:20]([OH:24])=[CH:21][C:22]=1[OH:23])=[O:16]>C(C(C)=O)C>[C:15]([C:17]1[CH:18]=[CH:19][C:20]([O:24][CH:2]([CH2:11][CH2:12][CH3:13])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8])=[CH:21][C:22]=1[OH:23])(=[O:16])[CH3:14]
Reactant: CC(=O)c1ccc(O)cc1O
Reactant: CCCC(Br)CCCCC(=O)OC
Solvent: CCC(C)=O
Product: CCCC(CCCCC(=O)O)Oc1ccc(C(C)=O)c(O)c1

Procedure:
Following the procedure of Example 48, 1.13 g. of methyl 6-bromo-nonanoate and 1.31 g. of 2,4-dihydroxyacetophenone were reacted in 50 ml. of methyl ethyl ketone. Hydrolysis of the resulting methyl ester intermediate gave 0.3 g. of the title product, M+ =308; NMR, IR.
Reaction SMILES: [Na].[CH3:2][O-:3].[Na+].F[C:6]1[C:13]([F:14])=[CH:12][CH:11]=[C:10]([F:15])[C:7]=1[C:8]#[N:9]>CO>[F:14][C:13]1[C:6]([O:3][CH3:2])=[C:7]([C:10]([F:15])=[CH:11][CH:12]=1)[C:8]#[N:9]
Reactant: C[O-]
Reactant: N#Cc1c(F)ccc(F)c1F
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: COc1c(F)ccc(F)c1C#N
Temperature: 25 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
Methanol (600 mL) was treated portionwise with sodium (Alfa, 16.1 g, 0.702 gatoms, 1.05 equiv.). The sodium methoxide solution was cooled to room temperature and added dropwise to a solution of 2,3,6-trifluorobenzonitrile (Matrix, 105 g, 0.699 mol) in methanol (600 ml) at room temperature. After addition was complete the mixture was stirred for 1 hour at room temperature before removing the methanol under reduced pressure. The residue was partitioned between diethyl ether (500 ml) and water (500 mL). The organic layer was removed, dried over MgSO4, filtered and evaporated to give the crude product. This was purified by distillation using a 6″ vigreux column @ 20 mmHg, oil bath 160° C., head temp 120° C. to give the title compound as a white solid (108 g, 91%)
Reaction SMILES: CC(O[CH2:5][C:6]1[CH2:23][S:22][C@@H:9]2[C@H:10]([NH:13][C:14]([CH2:16][C:17]3[S:21][CH:20]=[CH:19][CH:18]=3)=[O:15])[C:11](=[O:12])[N:8]2[C:7]=1[C:24]([O-:26])=[O:25])=O.[Na+].[SH:28][C:29]1[S:33][C:32]([CH2:34][C:35]([NH2:37])=[O:36])=[N:31][N:30]=1>>[S:21]1[CH:20]=[CH:19][CH:18]=[C:17]1[CH2:16][C:14]([NH:13][CH:10]1[C:11](=[O:12])[N:8]2[C:7]([C:24]([OH:26])=[O:25])=[C:6]([CH2:5][S:28][C:29]3[S:33][C:32]([CH2:34][C:35](=[O:36])[NH2:37])=[N:31][N:30]=3)[CH2:23][S:22][C@H:9]12)=[O:15]
Reactant: CC(=O)OCC1=C(C(=O)[O-])N2C(=O)[C@@H](NC(=O)Cc3cccs3)[C@H]2SC1
Reactant: NC(=O)Cc1nnc(S)s1
Agent: [Na+]
Product: NC(=O)Cc1nnc(SCC2=C(C(=O)O)N3C(=O)C(NC(=O)Cc4cccs4)[C@H]3SC2)s1

Procedure:
Sodium cephalothin (1.05 g, 2.5 mmole) and 5-mercapto-1,3,4-thiadiazol-2-yl-acetamide (0.48 g, 2.75 mmole) were reacted together as described in example 1b. The reaction mixture was poured onto ice, washed with ethyl acetate, covered with ethyl acetate and acidified. The product precipitated as a pale yellow solid, this was filtered off, washed with water and ethyl acetate and dried, 0.87 g, (68.1%); t.l.c. (SiO2 ; B.A.W.; 12:3:5) Rf=0.41; νmax (95% ethanol) 276 nm (ε=12300); δ[(CD3)2SO] 3.85 (2H,s, C2 methylene), 3.95 (2H,s, --CH2CONH--), 4.19 (2H,s, --CH2CONH2), 4.41 and 4.67 (2H, AB quartet, J 14 Hz, --CH2S--), 5.22 (1H,d, J 5 Hz, C6 proton), 5.90 (1H,dd, J 5 and 8 Hz, C7 proton), 6.8-8.1 (6H,m, --CO2H, --CONH2 and thienyl protons), 8.85 (1H,d, J 8 Hz, --CONH--).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[C:12]#[N:13])=[O:2].[C:17]1([Mg]Br)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1COCC1>[OH:2][CH:1]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[C:12]#[N:13]
Reactant: N#Cc1cccc(-c2ccncc2C=O)c1
Reactant: Br[Mg]c1ccccc1
Solvent: C1CCOC1
Product: N#Cc1cccc(-c2ccncc2C(O)c2ccccc2)c1

Procedure:
To a solution of 3-(3-formyl-pyridin-4-yl)-benzonitrile (21 mg, 0.1 mmol) in THF (1 mL) at −78° C. was added 3.0 M phenylmagnesium bromide in THF (0.1 mL). The reaction mixture was quenched with ammonium chloride and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, concentrated, and the residue purified by flash chromatography to yield 3-[3-(hydroxy-phenyl-methyl)-pyridin-4-yl]-benzonitrile as a colorless oil.
Reaction SMILES: C[O-].[Na+].[SH:4][CH2:5][CH2:6][OH:7].Cl[CH2:9][C:10]#[C:11][CH2:12][C:13]#[C:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].O>CO>[CH2:6]([OH:7])[CH2:5][S:4][CH2:9][C:10]#[C:11][CH2:12][C:13]#[C:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCCC#CCC#CCCl
Reactant: OCCS
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCCCCCCCC#CCC#CCSCCO
Reaction time: 0.5 h
Yield: 61 %

Procedure:
1.06 ml of a 30% solution of sodium methoxide in methanol were added dropwise, at room temperature, to a solution of 374 μl of 2-mercaptoethanol in 5 ml of anhydrous methanol, under an inert atmosphere. The mixture was maintained under stirring for 30 min and then added to a solution of 1.2 g of 1-chloro-2,5-tetradecadiyne in 6 ml of methanol, under an inert atmosphere. The mixture was maintained under stirring for 15 hours at room temperature and then the reaction medium was poured over 100 ml of acid water (98 ml of water+2 ml concentrated H2SO4) and then extracted 3 times with ethyl ether. The combined organic phases were washed 3 times with water and then with a saturated aqueous solution of NaCl before being dried (Na2SO4), filtered and concentrated under vacuum in a rotary evaporator. The oil thus obtained crystallized on cooling. It was purified by recrystallization from a heptane/pentane mixture and then from a heptane/pentane/diisopropyl ether mixture. 3-Thia-5,8-heptadecadiyn-1-ol was thus isolated in the form of pale yellow flakes with a yield of 61%.
Reaction SMILES: C[Sn]([N:5]=[N+:6]=[N-:7])(C)C.[Cl:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][C:15]([CH2:19][O:20][C:21]3[CH:38]=[CH:37][C:24]4[O:25][CH2:26][C:27]5[CH:34]=[C:33]([C:35]#[N:36])[CH:32]=[CH:31][C:28]=5[C:29](=[O:30])[C:23]=4[CH:22]=3)=[N:16]2)=[CH:11][CH:10]=1.Cl.[OH-].[Na+]>C1(C)C(C)=CC=CC=1>[Cl:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][C:15]([CH2:19][O:20][C:21]3[CH:38]=[CH:37][C:24]4[O:25][CH2:26][C:27]5[CH:34]=[C:33]([C:35]6[NH:36][N:7]=[N:6][N:5]=6)[CH:32]=[CH:31][C:28]=5[C:29](=[O:30])[C:23]=4[CH:22]=3)=[N:16]2)=[CH:11][CH:10]=1
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Reactant: N#Cc1ccc2c(c1)COc1ccc(OCc3ccc4ccc(Cl)cc4n3)cc1C2=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1C
Product: O=C1c2ccc(-c3nnn[nH]3)cc2COc2ccc(OCc3ccc4ccc(Cl)cc4n3)cc21
Yield: 106.1 %

Procedure:
1.03 g of trimethyltin azide was added to 1.07 g of 2-(7-chloroquinolin-2-yl)methoxy-8-cyano-11-oxo-6,11-dihydrodibenz[b,e]oxepine obtained by the same method as in Reference example 34 suspended in 30 ml of xylene and the mixture was refluxed under heating for 13 hours. 1 ml of conc. hydrochloric acid was added to the reaction mixture, the mixture was adjusted to about pH 4 with a 1N-sodium hydroxide aqueous solution and crystals precipitated were collected by filtration. The crystals were dissolved in a chloroform-methanol mixed solution and the organic layer was washed with a saturated saline solution and then dried over anhydrous sodium sulfate. The residue obtained by removing the solvent was applied to silica gel column chromatography to obtain 1.25 g of the title compound.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:26])[NH:20][C:21]([CH3:25])=[CH:22][C:23]=2[CH3:24])=[O:15])[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=1.[N:27]1[CH:32]=[CH:31][CH:30]=[C:29](B(O)O)[CH:28]=1.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CS(C)=O>[CH3:24][C:23]1[CH:22]=[C:21]([CH3:25])[NH:20][C:19](=[O:26])[C:18]=1[CH2:17][NH:16][C:14]([C:4]1[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=[C:2]([C:29]2[CH:28]=[N:27][CH:32]=[CH:31][CH:30]=2)[CH:3]=1)=[O:15]
Reactant: OB(O)c1cccnc1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Cl)nc3c2cnn3C(C)C)c(=O)[nH]1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3cccnc3)nc3c2cnn3C(C)C)c(=O)[nH]1
Yield: 42.4 %

Procedure:
To a 5-mL microwave vial were added 6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (70 mg, 0.187 mmol), 3-pyridinylboronic acid (29.9 mg, 0.243 mmol), DMSO (1.5 mL) and sodium carbonate (0.281 mL, 0.562 mmol), and the mixture was degassed with nitrogen for 10 min. Next was added bis(triphenylphosphine)palladium(II) chloride (10.51 mg, 0.015 mmol) and the vial was sealed. The reaction mixture was irradiated (microwave) at 140° C. overnight. The reaction mixture was filtered and the residue was washed with DMSO. The crude product in DMSO was purified using reverse-phase HPLC. The TFA salt of the product was neutralized using saturated NaHCO3, filtered, washed with water and dried under high vacuum to give 33 mg (42%) of product. LCMS E-S (M+H)=417.2 1H NMR (400 MHz, DMSO-d6) δ ppm 1.56 (d, J=6.4 Hz, 6 H), 2.13 (s, 3 H), 2.23 (s, 3 H), 4.42 (d, J=4.29 Hz, 2 H), 5.26-5.43 (m, 1 H), 5.91 (s, 1 H), 7.62 (dd, J=7.3, 5.0 Hz, 1 H), 8.26 (s, 1 H), 8.43 (s, 1 H), 8.64 (d, J=7.8 Hz, 1 H), 8.70-8.79 (m, 1 H), 8.96 (br. s., 1 H), 9.46 (br. s., 1 H), 11.59 (br. s., 1 H).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([C:13]3[CH:14]=[N:15][CH:16]=[CH:17][C:18]=3[CH3:19])[C:9]2=[O:12])=[CH:4][CH:3]=1.[CH:20]1([C:23](Cl)=[O:24])[CH2:22][CH2:21]1>C1COCC1>[CH3:19][C:18]1[CH:17]=[CH:16][N:15]=[CH:14][C:13]=1[N:8]1[CH2:7][CH2:6][C:5]2[C:10](=[CH:11][C:2]([NH:1][C:23]([CH:20]3[CH2:22][CH2:21]3)=[O:24])=[CH:3][CH:4]=2)[C:9]1=[O:12]
Reactant: O=C(Cl)C1CC1
Reactant: Cc1ccncc1N1CCc2ccc(N)cc2C1=O
Solvent: C1CCOC1
Product: Cc1ccncc1N1CCc2ccc(NC(=O)C3CC3)cc2C1=O
Yield: 14.1 %

Procedure:
Using analogous reaction conditions as described in Example 24, 7-amino-2-(4-methyl-pyridin-3-yl)-3,4-dihydro-2H-isoquinolin-1-one (I-25a: 100 mg, 0.3533 mmol) in THF (5 mL) was reacted with cyclopropanecarbonyl chloride (35.5 mL, 0.3886 mmol) and TEA (74.4 mL, 0.5299 mmol) to afford the crude product. Purification by column chromatography on silica gel (80% ethylacetate in hexane), followed by preparative HPLC afforded 16 mg of the product (14% yield).
Reaction SMILES: C([O:5][C:6](=[O:39])[CH:7]=[C:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:19][CH:18]=[C:17]([C:20]3[CH2:21][N:22]([CH3:38])[CH:23]=[C:24]4[C:33]=3[NH:32][N:31]=[C:30]3[C:26]5[C:27](=[CH:34][C:35]([F:37])=[CH:36][C:25]4=5)[CH:28]=[CH:29]3)[CH2:16][CH2:15]2)[CH2:10][CH2:9]1)(C)(C)C.ClCCl.FC(F)(F)C(O)=O>>[F:37][C:35]1[CH:34]=[C:27]2[CH:28]=[CH:29][C:30]3=[N:31][NH:32][C:33]4[C:24](=[CH:23][N:22]([CH3:38])[CH2:21][C:20]=4[C:17]4[CH2:18][CH2:19][N:14]([CH:11]5[CH2:10][CH2:9][C:8](=[CH:7][C:6]([OH:39])=[O:5])[CH2:13][CH2:12]5)[CH2:15][CH:16]=4)[C:25](=[C:26]23)[CH:36]=1
Reactant: CN1C=C2C(=C(C3=CCN(C4CCC(=CC(=O)OC(C)(C)C)CC4)CC3)C1)NN=C1C=Cc3cc(F)cc2c31
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1C=C2C(=C(C3=CCN(C4CCC(=CC(=O)O)CC4)CC3)C1)NN=C1C=Cc3cc(F)cc2c31

Procedure:
A mixture of Example 175B (90 mg, 0.119 mmol) in 1:1 dichloromethane/trifluoroacetic acid (0.6 mL) was stirred at room temperature for 3 hours. The reaction mixture was concentrated in vacuo to provide the title compound as bis-trifluroacetic acid salt. 1H NMR (400 MHz, Pyridine-d5) δ 1.68-2.43 (m, 8H), 2.99 (s, 3H), 3.18-3.61 (m, 4H), 4.05 (d, J=3.7 Hz, 2H), 4.32-4.47 (m, 3H), 5.93-6.15 (m, 2H), 7.15-7.32 (m, 2H), 7.44 (d, J=5.2 Hz, 1H), 7.88 (dd, J=10.4, 3.0 Hz, 1H), 8.63 (d, J=5.2 Hz, 1H), 12.82 (s, 1H). MS (ESI+) m/z 473.1 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH2:8][OH:9])[CH:5]=[CH:4][N:3]=1.[Si:10](Cl)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11].N1C=CN=C1>CN(C)C=O.C(OCC)(=O)C>[NH2:1][C:2]1[N:7]=[C:6]([CH2:8][O:9][Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11])[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Nc1nccc(CO)n1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OCc1ccnc(N)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
2-Amino-4-hydroxymethylpyrimidine (750 mg, 6.0 mmol, Reference Compound No. 4-1) and tert-butyldimethylsilyl chloride (990 mg, 6.6 mmol) were suspended in anhydrous N,N-dimethylformamide (8.0 mL), then imidazole (0.90 g, 13 mmol) was added thereto and the mixture was stirred for 1 hour at room temperature. The reaction mixture was diluted with ethyl acetate (50 mL), washed twice with saturated aqueous sodium hydrogencarbonate solution (50 mL), and then washed with brine (50 mL), and dried over anhydrous magnesium sulfate. Then the solvent was evaporated under reduced pressure, the precipitated solid was filtered off with 50% ethyl acetate-n-hexane solution, and dried under reduced pressure to give 1.2 g of the title Reference Compound as a white solid (Yield: 84%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:6]2[N:7]([CH3:26])[C:8](=[O:25])[N:9]([CH2:10][C@H:11]3[CH2:16][CH2:15][C@H:14]([C:17]([N:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)=[O:18])[CH2:13][CH2:12]3)[C:5]=2[CH:4]=1.C(N(CC)CC)C.[C:36](Cl)(=[O:38])[CH3:37]>C(Cl)Cl>[C:36]([N:22]1[CH2:21][CH2:20][N:19]([C:17]([C@H:14]2[CH2:15][CH2:16][C@H:11]([CH2:10][N:9]3[C:5]4[CH:4]=[C:3]([O:2][CH3:1])[CH:28]=[CH:27][C:6]=4[N:7]([CH3:26])[C:8]3=[O:25])[CH2:12][CH2:13]2)=[O:18])[CH2:24][CH2:23]1)(=[O:38])[CH3:37]
Reactant: COc1ccc2c(c1)n(C[C@H]1CC[C@H](C(=O)N3CCNCC3)CC1)c(=O)n2C
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc2c(c1)n(C[C@H]1CC[C@H](C(=O)N3CCN(C(C)=O)CC3)CC1)c(=O)n2C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-Methoxy-1-methyl-3-[trans-4-(piperazine-1-carbonyl)-cyclohexylmethyl]-1,3-dihydro-benzoimidazol-2-one (85 mg, 0.22 mmol) was dissolved in anhydrous DCM (4 ml). Triethyl amine (0.12 ml, 0.66 mmol) and acetyl chloride (0.02 ml, 0.26 mmol) were added and the mixture was stirred at room temperature overnight. The solution was washed with saturated NaHCO3 the organic phase was concentrated and the crude product purified on silica column using EtOAc as eluent to give the titled compound (60 mg, 64%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[C:20](=[O:27])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Br[CH2:29][CH2:30][CH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[C:20](=[O:27])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:29][CH2:30][CH:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)=[CH:4][CH:3]=1
Reactant: O=C1OC2(CCN(C(=O)c3c[nH]c4cc(Cl)ccc34)CC2)c2ccccc21
Reactant: BrCCC1CCOCC1
Product: O=C1OC2(CCN(C(=O)c3cn(CCC4CCOCC4)c4cc(Cl)ccc34)CC2)c2ccccc21

Procedure:
Following the general procedure III as described above, the alkylation of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one (prepared according to example 16) with 4-(2-bromo-ethyl)-tetrahydro-pyran (described in US 2004220214) gave the title compound. ES-MS m/e (%): 493.2 (M+H+).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH:9]=2)=[CH:4][CH:3]=1.BrCCCN1[C:31](=[O:32])[C:30]2=[CH:33][CH:34]=[CH:35][CH:36]=[C:29]2C1=O>>[CH2:31]([O:32][C:16]([NH:15][CH2:14][CH2:10][CH2:9][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:21])[CH3:20])[CH:9]=2)=[CH:6][CH:7]=1)=[O:17])[C:30]1[CH:29]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CC(C)(C)OC(=O)NCc1cccc(-c2ccc(O)cc2)c1
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Product: CC(C)(C)OC(=O)NCc1cccc(-c2ccc(OCCCNC(=O)OCc3ccccc3)cc2)c1

Procedure:
The title compound was prepared in a similar manner to that described in Reference Example 31 using tert-butyl N-(4′-hydroxybiphenyl-3-ylmethyl)carbamate instead of tert-butyl N-(3′-hydroxybiphenyl-4-ylmethyl)carbamate and N-(3-bromopropyl)phthalimide instead of N-(4-bromobutyl)-phthalimide.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:29])[C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=4)[CH:14]=[CH:15][CH:16]=3)=[N:6][N:5]2[CH:30]=1.C(N(CC)CC)C.[CH:38]1([C:42](Cl)=[O:43])[CH2:41][CH2:40][CH2:39]1.[Cl-].[NH4+]>O1CCCC1>[CH:38]1([C:42]([NH:1][C:2]2[N:3]=[C:4]3[CH:9]=[CH:8][C:7]([O:10][C:11]4[CH:12]=[C:13]([NH:17][C:18](=[O:29])[C:19]5[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=5)[CH:14]=[CH:15][CH:16]=4)=[N:6][N:5]3[CH:30]=2)=[O:43])[CH2:41][CH2:40][CH2:39]1
Reactant: Nc1cn2nc(Oc3cccc(NC(=O)c4cccc(C(F)(F)F)c4)c3)ccc2n1
Reactant: O=C(Cl)C1CCC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1cccc(Oc2ccc3nc(NC(=O)C4CCC4)cn3n2)c1)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 54.6 %

Procedure:
To a solution of N-{3-[(2-aminoimidazo[1,2-b]pyridazin-6-yl)oxy]phenyl}-3-(trifluoromethyl)benzamide (150 mg, 0.362 mmol) in tetrahydrofuran (5 mL) were added dropwise triethylamine (75 μL, 0.544 mmol) and cyclobutanecarbonyl chloride (50 μL, 0.435 mmol), and the mixture was stirred at room temperature for 16 hr. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and filtrated. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=50/50→100/0) to give the title compound (98 mg, 54%) as a white powder.
Reaction SMILES: CN(C)C=O.[C:6]1(=[O:26])[N:10]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][C:18]=3[Cl:20])[NH:13][N:12]=2)[C:9](=[O:21])[C:8]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:7]12.Br.Br[CH2:29][CH2:30][CH2:31][N:32]([CH2:35][CH3:36])[CH2:33][CH3:34].C(=O)([O-])[O-].[K+].[K+]>O>[CH2:33]([N:32]([CH2:35][CH3:36])[CH2:31][CH2:30][CH2:29][N:13]1[C:14]2[C:19](=[C:18]([Cl:20])[CH:17]=[CH:16][CH:15]=2)[C:11]([N:10]2[C:9](=[O:21])[C:8]3=[CH:22][CH:23]=[CH:24][CH:25]=[C:7]3[C:6]2=[O:26])=[N:12]1)[CH3:34]
Reactant: CCN(CC)CCCBr
Reactant: O=C1c2ccccc2C(=O)N1c1n[nH]c2cccc(Cl)c12
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN(CC)CCCn1nc(N2C(=O)c3ccccc3C2=O)c2c(Cl)cccc21
Temperature: 80 °C
Reaction time: 12 h
Yield: 59 %

Procedure:
To 60 ml of anhydrous N,N-dimethylformamide were added 4.54 g of 3-phthalimido-4-chloroindazole obtained in the same method as described in Example 1, 4.83 g of 3-bromopropyldiethylamine hydrobromide and 6.3 g of anhydrous potassium carbonate, and the mixture was stirred for 12 hours at 80° C. After cooling, the mixture was added with 80 ml of water and extracted with diethyl ether. The diethyl ether layer was extracted three times with 2N hydrochloric acid, and the hydrochloric acid layer was washed with diethyl ether. After the pH of the layer was adjusted to 14 with potassium carbonate, the layer was extracted with chloroform. The chloroform layer was dried over anhydrous sodium sulfate and chloroform was removed under reduced pressure to give 3.70 g of 1-(3-diethylaminopropyl)-3-phthalimido-4-chloroindazole having the following analytical values in a yield of 59%.