Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][C:14]([CH3:21])([CH3:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH2:22]([O:24][CH2:25][C:26](Cl)=O)[CH3:23].C(N(CC)CC)C>C(O)C>[CH2:22]([O:24][CH2:25][C:26]1[N:12]([CH2:13][C:14]([CH3:20])([CH3:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=1)[CH3:23]
Reactant: CCOCC(=O)Cl
Reactant: CCOC(=O)C(C)(C)CNc1c(N)cnc2ccccc12
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOCc1nc2cnc3ccccc3c2n1CC(C)(C)C(=O)OCC
Reaction time: 8 h
Yield: 36.9 %

Procedure:
A modification of the method described in Part C of Example 5 was used to treat ethyl 3-[(3-aminoquinolin-4-yl)amino]-2,2-dimethylpropanoate (15.5 g, 60.2 mmol, prepared in Parts A through D of Example 26) with ethoxyacetyl chloride (8.7 g, 71 mmol) followed by triethylamine (24.4 mL, 175 mmol). The reaction with ethoxyacetyl chloride was stirred overnight, and the reaction with triethylamine was heated at reflux in ethanol (125 mL) for four days. Following the work-up procedure, the crude product was purified by column chromatography on silica gel (eluting with dichloromethane:methanol in a gradient from 100:0 to 95:5) to provide 7.9 g of ethyl 3-[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-2,2-dimethylpropanoate as an oil.
Reaction SMILES: C([O:3][C:4]([C:6]1([CH2:16][C:17]#[N:18])[CH2:15][CH2:14][C:9]2([O:13][CH2:12][CH2:11][O:10]2)[CH2:8][CH2:7]1)=O)C.[H][H]>CO.C(O)(=O)C>[O:13]1[C:9]2([CH2:14][CH2:15][C:6]3([CH2:16][CH2:17][NH:18][C:4]3=[O:3])[CH2:7][CH2:8]2)[O:10][CH2:11][CH2:12]1
Reactant: CCOC(=O)C1(CC#N)CCC2(CC1)OCCO2
Reactant: [H][H]
Solvent: CC(=O)O
Solvent: CO
Product: O=C1NCCC12CCC1(CC2)OCCO1
Temperature: 25 °C
Reaction time: 18 h
Yield: 38.6 %

Procedure:
8-Cyanomethyl-1,4-dioxa-spiro[4.5]decane-8-carboxylic acid ethyl ester (525 mg) was dissolved in methanol (10 mL) and acetic acid (5 mL). Platinium(IV) oxide (235 mg) was added and an atmosphere of hydrogen was introduced. The mixture was then stirred at RT for 18 hours. The reaction was filtered over dicalite speed plus (Acros Organics) and the filtrate was concentrated in vacuo. The residue was poured into ice/water and was basified with 2M aqueous NaOH solution. The aqueous layer was extracted two times with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered and the solvent was evaporated. The residue was purified by flash chromatography (silica gel, gradient of ethyl acetate in heptane) to give the title compound as a colorless solid (169 mg). MS (ESI): 212.2 (MH+.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][C:15](O)=[O:16])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH:18]([NH:21][NH:22][C:23](=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([CH3:20])[CH3:19].C(N(CC)CC)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C>[CH:1]1[C:13]2[CH:12]([CH2:14][C:15]([N:21]([CH:18]([CH3:20])[CH3:19])[NH:22][C:23](=[O:30])[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[O:16])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)CC1c2ccccc2-c2ccccc21
Reactant: CC(C)NNC(=O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)N(NC(=O)c1ccccc1)C(=O)CC1c2ccccc2-c2ccccc21
Yield: 40.4 %

Procedure:
A solution of 9-fluoreneacetic acid (126 mg, 0.56 mmoles) and benzoic acid N′-isopropyl-hydrazide (100 mg, 0.56 mmoles) in DMF (5 mL) was treated with triethylamine (0.23 mL, 1.68 mmol), HOBT (91 mg, 0.67 mmoles) and EDCI (129 mg, 0.67 mmol) at room temperature for 72 h. The reaction mixture was partitioned between water and dichloromethane. The organic layer was washed with water and brine, then dried over sodium sulfate, filtered and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 10-30% ethyl acetate/hexanes gradient to afford the product as a solid (87 mg, 40%). LC-MS m/e 385.19 (M+H+)
Reaction SMILES: CS([O:5][CH2:6][C:7]1[C:8]([Cl:19])=[N:9][S:10][C:11]=1[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)(=O)=O.[F:20][C:21]1[CH:22]=[C:23]([CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH:24]=[C:25]([F:28])[C:26]=1O.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Cl:19][C:8]1[C:7]([CH2:6][O:5][C:26]2[C:25]([F:28])=[CH:24][C:23]([CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:22][C:21]=2[F:20])=[C:11]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[S:10][N:9]=1
Reactant: CS(=O)(=O)OCc1c(Cl)nsc1-c1ccc(Cl)cc1
Reactant: CCOC(=O)CCc1cc(F)c(O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1cc(F)c(OCc2c(Cl)nsc2-c2ccc(Cl)cc2)c(F)c1
Temperature: 30 °C
Reaction time: 8 h

Procedure:
Into a 50-mL round-bottom flask, was placed [3-chloro-5-(4-chlorophenyl)-1,2-thiazol-4-yl]methyl methanesulfonate (320 mg, 0.95 mmol, 1.00 equiv), ethyl 3-(3,5-difluoro-4-hydroxyphenyl)propanoate (230 mg, 1.00 mmol, 1.06 equiv), potassium carbonate (420 mg, 3.04 mmol, 3.21 equiv), N,N-dimethylformamide (10 mL). The resulting solution was stirred overnight at 30° C. The resulting solution was diluted with of H2O. The resulting solution was extracted with 3×10 mL of ethyl acetate and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (17/83). The collected fractions were combined and concentrated under vacuum. This resulted in 340 mg (68%) of ethyl 3-(4-[[3-chloro-5-(4-chlorophenyl)-1,2-thiazol-4-yl]methoxy]-3,5-difluorophenyl)propanoate as colorless oil. Mass spectrum (ESI, m/z): Calcd. for C21H17C12F2NO3S, 472.0 (M+H). found 472.0.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]=[C:9]([NH2:12])[CH:10]=[CH:11][C:5]2=[N:4][CH:3]=1.[C:13]1(B(O)O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.O.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>[C:13]1([C:2]2[N:7]=[C:6]3[N:8]=[C:9]([NH2:12])[CH:10]=[CH:11][C:5]3=[N:4][CH:3]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: OB(O)c1ccccc1
Reactant: Nc1ccc2ncc(Cl)nc2n1
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: CN(C)C=O
Solvent: O
Product: Nc1ccc2ncc(-c3ccccc3)nc2n1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
1.00 g of 3-chloropyrido[2,3-b]pyrazin-6-ylamine (5.54 mmol), 743 mg of phenylboronic acid (6.09 mmol), 640 mg of tetrakis(triphenylphosphine)palladium(0) (0.55 mmol) and 1.76 g of sodium carbonate (16.6 mmol) were initially charged in 100 ml of dimethylformamide/water (1:1) under nitrogen as a protective gas and stirred at 80° C. for 2 h. Once the reaction had ended, the mixture was filtered off with suction and the filtrate was poured onto 800 ml of distilled water. The aqueous phase was extracted repeatedly with ethyl acetate. The organic phase was freed of solvents under reduced pressure. The resulting solid was purified by means of column chromatography on silica gel (dichloromethane/methanol eluent). This gave a yellow solid.
Reaction SMILES: [CH:1]1([OH:5])[CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[C:8]([C:12]1[N:13]=[C:14](Cl)[C:15]2[N:20]=[N:19][N:18]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:28])[C:16]=2[N:17]=1)([CH3:11])([CH3:10])[CH3:9].C(O)=O>CN(C=O)C>[C:8]([C:12]1[N:13]=[C:14]([O:5][CH:1]2[CH2:4][CH2:3][CH2:2]2)[C:15]2[N:20]=[N:19][N:18]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:28])[C:16]=2[N:17]=1)([CH3:11])([CH3:9])[CH3:10]
Reactant: OC1CCC1
Reactant: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3Cl)c2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=CO
Product: CC(C)(C)c1nc(OC2CCC2)c2nnn(Cc3ccccc3Cl)c2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 13.4 %

Procedure:
A mixture of cyclobutanol (173 mg, 2.4 mmol) and NaH (4.8 mg, 0.12 mmol) in DMF (1 mL) was stirred for 30 min at room temperature. 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine (26.9 mg, 0.08 mmol) was added and the mixture was stirred at room temperature overnight. Formic acid added and the mixture was subjected to preparative HPLC purification on reversed phase eluting with a gradient formed from acetonitrile, water and formic acid. The product containing fractions were evaporated to yield 4 mg (13%) of the title compound. MS(m/e): 372.3.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[NH:5][C:6]2[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=2[N:8]=1.[C:13]1([CH3:28])[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]2[CH:27]=[CH:26][C:23]([CH2:24]Br)=[CH:22][CH:21]=2)[CH:14]=1.O>CN(C)C=O>[CH3:3][C:4]1[N:8]([CH2:24][C:23]2[CH:22]=[CH:21][C:20]([O:19][C:15]3[CH:14]=[C:13]([CH3:28])[CH:18]=[CH:17][CH:16]=3)=[CH:27][CH:26]=2)[C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[N:5]=1
Reactant: Cc1cccc(Oc2ccc(CBr)cc2)c1
Reactant: Cc1nc2ccccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cccc(Oc2ccc(Cn3c(C)nc4ccccc43)cc2)c1
Reaction time: 1 h
Yield: 71.1 %

Procedure:
To a suspension of sodium hydride (0.14 g, 3.6 mmole; 62% in oil) in anhydrous dimethylformamide (10 ml), 2-methylbenzimidazole (0.48 g, 3.6 mmole) was added while stirring, and stirring was continued at room temperature for 1 hour. The resultant mixture was cooled to 5°-10° C., and a solution of 4-(3-tolyloxy)benzyl bromide (1.00 g, 3.6 mmole) in anhydrous dimethylformamide (5 ml) was dropwise added thereto in 30 minutes, followed by stirring at room temperature overnight. After completion of the reaction, the reaction mixture was poured into water (100 ml) and extracted with toluene (30 ml) two times. The toluene layer 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 2-methyl-1-[4-(3-tolyloxy)benzyl]benzimidazole (0.84 g) as colorless liquid. nD27.0 1.6112.
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][N:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[CH:13]=2)=[N:5][C:4]([NH2:25])=[N:3]1.[O:26]1[CH:30]=[CH:29][CH:28]=[C:27]1[C:31](Cl)=[O:32]>N1C=CC=CC=1>[CH3:1][N:2]1[C:6]([NH:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][N:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[CH:13]=2)=[N:5][C:4]([NH:25][C:31]([C:27]2[O:26][CH:30]=[CH:29][CH:28]=2)=[O:32])=[N:3]1
Reactant: O=C(Cl)c1ccco1
Reactant: Cn1nc(N)nc1NCCCOc1cccc(CN2CCCCC2)c1
Solvent: c1ccncc1
Product: Cn1nc(NC(=O)c2ccco2)nc1NCCCOc1cccc(CN2CCCCC2)c1
Yield: 23.6 %

Procedure:
A solution of 1-methyl-N5 -[3-[3-(1-piperidinylmethyl)phenoxy]propyl]-1H-1,2,4-triazole-3,5-diamine (A) (1.0 g) and 2-furancarboxylic acid, chloride (0.42 g) in pyridine (25 ml) was kept at ambient temperature for 1 h. The pyridine was evaporated in vacuo and the residue was azeotropically distilled with toluene to give an oil which was partitioned between ethyl acetate and 2 M hydrochloric acid. The pH of the aqueous extract was adjusted to pH 9 and it was extracted with ethyl acetate. The organic extracts were evaporated to a gum which was chromatographed on silica using ethyl acetate: methanol (9:1) to give the title compound (0.30 g) as a glassy solid. tlc System B, Rf 0.57. Nmr (CDCl3) 1.5,brs, (1H); 2.53,m, (1H); 2.75,t+m, (2H); 3.0-3.3,m, (3H); 3.5,dd (1H); 5.31,t, (1H); 5.92,t, (2H); 6.42,q, (2H); 6.50,s, (3H); 6.59,s, (3H); 7.6,brs; (4H); 7.9,m, (2H); 8.5,m, (6H).
Reaction SMILES: [NH2:1][C:2]1[C:10]([C:11]2[S:12][C:13]3[CH:19]=[CH:18][C:17]([NH:20][C:21]([NH:23][C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[CH:25]=4)=[O:22])=[CH:16][C:14]=3[CH:15]=2)=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][N:3]=1.Cl.[NH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][C:38]([O:40][CH3:41])=[O:39].CCN=C=NCCCN(C)C>CN(C1C=CN=CC=1)C.ClCCCl.C(OCC)(=O)C>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:6]([NH:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][C:38]([O:40][CH3:41])=[O:39])=[O:7])=[CH:9][C:10]=1[C:11]1[S:12][C:13]2[CH:19]=[CH:18][C:17]([NH:20][C:21]([NH:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[CH:25]=3)=[O:22])=[CH:16][C:14]=2[CH:15]=1
Reactant: COC(=O)CCCCCN
Reactant: Cc1cccc(NC(=O)Nc2ccc3sc(-c4cc(C(=O)O)cnc4N)cc3c2)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: COC(=O)CCCCCNC(=O)c1cnc(N)c(-c2cc3cc(NC(=O)Nc4cccc(C)c4)ccc3s2)c1
Temperature: 50 °C

Procedure:
The reaction mixture of 6-amino-5-[5-({[(3-methylphenyl)amino]carbonyl}amino)-1-benzothien-2-yl]nicotinic acid (84 mg, 0.2 mmol, 1 eq), methyl 6-aminohexanoate hydrochloride (43.7 mg, 1.2 eq), DMAP (5 mg, 0.2 eq), and EDCI (46.1 mg, 1.2 eq) in anhydrous 1,2-dichloroethane (3 mL) was stirred and heated at 50° C. for 2 hours. It was then diluted with ethyl acetate, washed sequentially with aqueous NH4Cl, saturated aqueous NaHCO3, and brine, and dried with anhydrous sodium sulfate. The upper clear solution was decanted, concentrated, and the solid residue was triturated with EtOAc-Hex (3:1) yielding methyl 6-[({6-amino-5-[5-({[(3-methylphenyl)amino]carbonyl}amino)-1-benzothien-2-yl]pyridin-3-yl}carbonyl)amino]hexanoate as a white solid in amount of 83 mg.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]([C:15]1[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([CH3:22])[CH:16]=1)=[C:9]2[CH2:23][CH2:24][NH:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=1)=[O:5])[CH3:2].C(N(CC)C(C)C)(C)C.Cl[C:46]([O:48][CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)=[O:47]>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]([C:15]1[CH:16]=[C:17]([CH3:22])[CH:18]=[C:19]([CH3:21])[CH:20]=1)=[C:9]2[CH2:23][CH2:24][N:25]([C:46]([O:48][CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)=[O:47])[CH2:26][CH2:27][CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=1)=[O:5])[CH3:2]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCOC(=O)c1ccc2[nH]c(-c3cc(C)cc(C)c3)c(CCNCCCCc3ccncc3)c2c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1ccc2[nH]c(-c3cc(C)cc(C)c3)c(CCN(CCCCc3ccncc3)C(=O)OCc3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A solution of 3.19 g (6.83 mmol) of 2-(3,5-dimethylphenyl)- 3-[2-[4-(pyridin-4-yl)butylamino] ethyl]-1H-indole-5-carboxylic acid ethyl ester in 25 mL of dry methylene chloride was stirred under nitrogen and cooled to -78° C. in a dry ice-acetone bath as 2.38 mL (1.76 g, 13.7 mmol) of N,N-diisopropylethylamine was added, followed by gradual addition of 3.4 mL (4.06 g; 23.7 mmol) of benzyl chloroformate by syringe, in portions. After about 2.5 hours, the solution was removed from the cooling bath and allowed to warm to room temperature. It was then partitioned between ethyl acetate and 5% potassium bisulfate aqueous solution. The organic phase was dried over magnesium sulfate, filtered, and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (elution with a gradient of 0.5-10% methanol in methylene chloride) afforded a quantitative yield of the product as a yellow foam. 500 MHz 1H NMR was complex, owing to the existence of rotamers, but was consistent with the assigned structure. Mass spectrum (PB-NH3 /CI): m/e=604.3 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:12]([CH:15]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][O:26][CH3:27])=[CH:20][CH:19]=2)[CH2:16][CH3:17])[CH2:13][CH3:14])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][O:10][CH3:11].[CH3:28][O:29][P:30]([O:50][CH3:51])([C:32]([P:44]([O:48][CH3:49])([O:46][CH3:47])=[O:45])([O:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[CH2:33][CH2:34][CH2:35][C:36](O)=[O:37])=[O:31]>>[CH3:49][O:48][P:44]([O:46][CH3:47])([C:32]([P:30]([O:29][CH3:28])([O:50][CH3:51])=[O:31])([O:39][Si:40]([CH3:42])([CH3:41])[CH3:43])[CH2:33][CH2:34][CH2:35][C:36]([NH:1][C:2]1[CH:3]=[C:4]([CH:12]([CH:15]([C:18]2[CH:19]=[CH:20][C:21]([O:24][CH2:25][O:26][CH3:27])=[CH:22][CH:23]=2)[CH2:16][CH3:17])[CH2:13][CH3:14])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][O:10][CH3:11])=[O:37])=[O:45]
Reactant: COP(=O)(OC)C(CCCC(=O)O)(O[Si](C)(C)C)P(=O)(OC)OC
Reactant: CCC(c1ccc(OCOC)cc1)C(CC)c1ccc(OCOC)c(N)c1
Product: CCC(c1ccc(OCOC)cc1)C(CC)c1ccc(OCOC)c(NC(=O)CCCC(O[Si](C)(C)C)(P(=O)(OC)OC)P(=O)(OC)OC)c1

Procedure:
Erythro 3-(3-(5,5-bis(dimethoxyphosphinoyl)-5-trimethylsilyloxybutyrylamino)-4-methoxymethoxyphenyl)-4-(4-methoxymethoxyphenyl)hexane (1.17 g, quantitative yield) was obtained in the same manner as in Example 4 except for using erythro 3-(3-amino-4-methoxymethoxyphenyl)-4-(4-methoxymethoxyphenyl)hexane (560 mg) obtained by the process described in Reference Example 4 and 5,5-bis(dimethoxyphosphinoyl)-5-trimethylsilyloxyvaleric acid (1 equivalent per equivalent of the former) obtained by the process described in Reference Example 31.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([Cl:9])=[CH:4][C:3]=1B(O)O.[NH2:13][C:14]1[C:19](Br)=[N:18][CH:17]=[C:16]([Cl:21])[N:15]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.C1C=CC=CC=1>[NH2:13][C:14]1[C:19]([C:3]2[CH:4]=[C:5]([Cl:9])[CH:6]=[C:7]([Cl:8])[C:2]=2[Cl:1])=[N:18][CH:17]=[C:16]([Cl:21])[N:15]=1
Reactant: Nc1nc(Cl)cnc1Br
Reactant: OB(O)c1cc(Cl)cc(Cl)c1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: c1ccccc1
Product: Nc1nc(Cl)cnc1-c1cc(Cl)cc(Cl)c1Cl

Procedure:
A solution of 2,3,5-trichlorobenzeneboronic acid (1.62 g, 7.18×10−3 mole) in absolute ethanol (2.05 ml) was added slowly to a mixture of 2-amino-3-bromo-6-chloropyrazine (1 g, 5.1×10−3 mole) and tetrakis(triphenylphospine)palladium(0) (0.334 g,2.89×1−4 mole) in benzene (10.20 ml)/2M aqueous sodium carbonate (5.50 ml). The mixture was refluxed for 17 hrs. The cooled reaction mixture was evaporated in vacuo and then extracted with chloroform (50 ml). The chloroform layer was washed with water (2×30 ml), dried over anhydrous magnesium sulphate, filtered and the filtrate evaporated down in vacuo. The residue was triturated with 40-60° C. petroleum ether, filtered and dried in vacuo. Yield 0.205 g (14%), M.p. 211-214° C.
Reaction SMILES: N[C:2]1[CH:15]=[CH:14][C:5]2[N:6]=[C:7]([CH2:9][CH2:10][CH2:11][C:12]#[N:13])[S:8][C:4]=2[CH:3]=1.N(OCCC(C)C)=O.[I:24]CI>O1CCCC1.[Cu]I>[I:24][C:2]1[CH:15]=[CH:14][C:5]2[N:6]=[C:7]([CH2:9][CH2:10][CH2:11][C:12]#[N:13])[S:8][C:4]=2[CH:3]=1
Reactant: N#CCCCc1nc2ccc(N)cc2s1
Reactant: ICI
Agent: [Cu]I
Agent: CC(C)CCON=O
Solvent: C1CCOC1
Product: N#CCCCc1nc2ccc(I)cc2s1

Procedure:
1.1 g of 4-(6-amino-1,3-benzothiazol-2-yl)butane nitrile synthesized according to a method described in JP-A 5–194440, 2 mL isoamyl nitrite, 0.96 g of copper (I) iodide and 2 mL diiodomethane were heated in tetrahydrofuran at 80° C. for 1 hour. After the solvent was removed, the residue was purified by NH silica gel column to give 888 mg of the title compound as colorless crystals.
Reaction SMILES: [F:1][C:2]1[C:14]([F:15])=[C:13]([F:16])[C:12]([F:17])=[C:11]([F:18])[C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1.[N+]([NH:22][C:23](N)=[O:24])([O-])=O.O>C(O)C>[NH2:22][C:23]([N:8]1[CH2:9][CH2:10][CH:5]([O:4][C:3]2[C:11]([F:18])=[C:12]([F:17])[C:13]([F:16])=[C:14]([F:15])[C:2]=2[F:1])[CH2:6][CH2:7]1)=[O:24]
Reactant: Fc1c(F)c(F)c(OC2CCNCC2)c(F)c1F
Reactant: NC(=O)N[N+](=O)[O-]
Solvent: CCO
Solvent: O
Product: NC(=O)N1CCC(Oc2c(F)c(F)c(F)c(F)c2F)CC1
Temperature: 65 °C
Reaction time: 5 h
Yield: 73.4 %

Procedure:
A solution of 4.0 g of 4-(2,3,4,5,6-pentafluorophenoxy)piperidine in 100 ml of 95% ethanol was treated with 1.73 g of nitrourea and then stirred at 65° C. for five hours. After cooling to room temperature, the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water followed by a saturated sodium chloride solution and dried over anhydrous magnesium sulfate. Filtration, followed by evaporation of the solvents afforded a residue which was purified by means of high pressure liquid chromatography (silica gel; elution with 5% methanol/dichloromethane). The resultant solid was recrystallized from hot isopropanol to yield 3.41 g (73.3%) of 1-aminocarbonyl-4-(2,3,4,5,6-pentafluorophenoxy)piperidine, m.p. 170°-172° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[C:4]([CH3:9])[N:3]=1.[NH2:10][NH2:11]>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([NH:10][NH2:11])[N:5]=[C:4]([CH3:9])[N:3]=1
Reactant: NN
Reactant: Cc1nc(Cl)cc(Cl)n1
Solvent: C1CCOC1
Product: Cc1nc(Cl)cc(NN)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 4,6-dichloro-2-methylpyrimidine (1.63 g, 10.0 mmol) in THF (25 mL) at room temperature under argon was added H2NNH2 (0.64 g, 20.0 mmol). The reaction mixture was stirred at room temperature under argon overnight. Analysis by HPLC/MS indicated that the reaction was complete. The solvent was evaporated, and the residue was coevaporated with toluene (2×5 mL) then THF (5 mL), and then dried under vacuum. The crude title compound was used directly in the next step. HPLC/MS: retention time=0.77 min.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([Cl:22])[CH:5]=[C:6]2[C:14]=1[NH:13][C:12]1[CH:11]=[N:10][CH:9]=[C:8]([NH:15][C:16](=[O:21])[C:17]([F:20])([F:19])[F:18])[C:7]2=1.C[C:24]1[N:32]=[CH:31][CH:30]=[CH:29][C:25]=1[C:26](O)=[O:27].CCN=C=NCCCN(C)C>N1C=CC=CC=1>[Cl:22][C:4]1[CH:5]=[C:6]2[C:14](=[C:2]([NH:1][C:26](=[O:27])[C:25]3[CH:29]=[CH:30][CH:31]=[N:32][CH:24]=3)[CH:3]=1)[NH:13][C:12]1[CH:11]=[N:10][CH:9]=[C:8]([NH:15][C:16](=[O:21])[C:17]([F:20])([F:19])[F:18])[C:7]2=1
Reactant: Cc1ncccc1C(=O)O
Reactant: Nc1cc(Cl)cc2c1[nH]c1cncc(NC(=O)C(F)(F)F)c12
Agent: CCN=C=NCCCN(C)C
Solvent: c1ccncc1
Product: O=C(Nc1cc(Cl)cc2c1[nH]c1cncc(NC(=O)C(F)(F)F)c12)c1cccnc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 32 %

Procedure:
N-(8-amino-6-chloro-9H-β-carbolin-4-yl)-2,2,2-trifluoro-acetamide (90 mg, 0.274 mmol, 1 equiv.) and 2-methylnicotinic acid (40 mg, 0.329 mmol, 1.2 equiv.) were dissolved in 1.5 ml of anhydrous pyridine under N2. EDCI (84 mg, 0.438 mmol, 1.6 equiv.) was added in one portion and the reaction mixture was stirred at room temperature 2 hours. The reaction was quenched and treated following the preceding protocol to obtain 38 mg (32%) of N-[6-chloro-4-(2,2,2-trifluoro-acetylamino)-9H-β-carbolin-8-yl]-nicotinamide. 1H-NMR (300 MHz, DMSO-d6): δ 11.89 (br, 1H), 10.73 (s, 1), 9.28 (s, 1), 8.97 (s, 1), 8.84 (d, 1), 8.43 (d, 1), 8.37 (s, 1), 7.85 (s, 1), 7.76 (s, 1), 7.67 (m, 1). Formic acid standard conditions. DAD RT=1.94 min. M+H=434.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:33]=[CH:34][CH:35]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH2:15][O:16][CH2:17][CH2:18]Cl)=[CH:12][CH:13]=2)[C:8]([S:20]([C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=[CH:25][CH:24]=2)(=[O:22])=[O:21])=[N:7]1.[CH3:36][NH:37][CH3:38]>CS(C)=O.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:33]=[CH:34][CH:35]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH2:15][O:16][CH2:17][CH2:18][N:37]([CH3:38])[CH3:36])=[CH:12][CH:13]=2)[C:8]([S:20]([C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=[CH:25][CH:24]=2)(=[O:21])=[O:22])=[N:7]1
Reactant: CNC
Reactant: O=S(=O)(c1cccc2ccccc12)c1nn(Cc2cccc(Cl)c2)c2ccc(COCCCl)cc12
Solvent: CS(C)=O
Solvent: O
Product: CN(C)CCOCc1ccc2c(c1)c(S(=O)(=O)c1cccc3ccccc13)nn2Cc1cccc(Cl)c1
Temperature: 100 °C
Reaction time: 4 h
Yield: 93.7 %

Procedure:
A mixture of 1-(3-chlorobenzyl)-5-(2-chloroethoxymethy)-3-(1-naphthylsulfony)-1H-indazole (0.08 g, 0.16 mmoles) and dimethylamine (0.28 ml, 0.56 mmoles) in DMSO (1 mL) was stirred under nitrogen at 100° C. for 4 hours. Mixture was cooled to room temperature, diluted with water, extracted with EtOAc, washed with water (2×), brine (1×), dried over Na2SO4, and concentrated under vacuum. Compound was purified by flash chromatography using as eluent 5% CH3OH/EtOAc to afford the title compound (0.08 g, 0.15 mmoles).