Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN1CCCC1=O.[CH3:8][C:9]1[N:14]=[C:13]([C:15]2[CH:16]=[N:17][N:18]([CH3:23])[C:19]=2[C:20]([OH:22])=O)[C:12]([CH3:24])=[CH:11][N:10]=1.Cl.[F:26][C:27]1[C:28]([NH2:42])=[CH:29][C:30]2[N:31]([N:33]=[C:34]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[N:35]=2)[CH:32]=1.C(N(C(C)C)CC)(C)C>O>[CH3:8][C:9]1[N:14]=[C:13]([C:15]2[CH:16]=[N:17][N:18]([CH3:23])[C:19]=2[C:20]([NH:42][C:28]2[C:27]([F:26])=[CH:32][N:31]3[N:33]=[C:34]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[N:35]=[C:30]3[CH:29]=2)=[O:22])[C:12]([CH3:24])=[CH:11][N:10]=1
Reactant: Cc1ncc(C)c(-c2cnn(C)c2C(=O)O)n1
Reactant: Nc1cc2nc(-c3ccccc3)nn2cc1F
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ncc(C)c(-c2cnn(C)c2C(=O)Nc2cc3nc(-c4ccccc4)nn3cc2F)n1

Procedure:
An N-methylpyrrolidone (7.7 ml) solution of the 4-(2,5-dimethylpyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxylic acid (715 mg) obtained in (Example 3.22) <Step 2>, 6-fluoro-2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-amine hydrochloride (obtained according to the method described in International Publication No. WO2012/076430, p. 80, Example 30-h) (815 mg), 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate methanaminium (2.34 g), and diisopropylethylamine (2.69 ml) was stirred at 80° C. for 3 hours. Thereafter, water was added to the reaction solution, and the mixed solution was then extracted with ethyl acetate. Organic layers were combined, and the combined organic layer was then dried over anhydrous sodium sulfate. Subsequently, the solvent was distilled away under reduced pressure, and the obtained residue was then purified by silica gel column chromatography (NH silica gel:eluent; heptane:ethyl acetate=3:1-1:1). The obtained fraction was concentrated under reduced pressure. The obtained residue (solid) was triturated with methanol to obtain the title compound (377 mg) in the form of a colorless solid.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][Si:5]([C:8]([CH3:11])([CH3:10])[CH3:9])([CH3:7])[CH3:6].[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][NH2:21])=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[Si:5]([O:4][CH2:3][CH2:2][NH:21][CH2:20][C:17]1[CH:18]=[CH:19][C:14]([O:13][CH3:12])=[CH:15][CH:16]=1)([C:8]([CH3:11])([CH3:10])[CH3:9])([CH3:7])[CH3:6]
Reactant: COc1ccc(CN)cc1
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(CNCCO[Si](C)(C)C(C)(C)C)cc1
Temperature: 80 °C
Reaction time: 16 h
Yield: 76.5 %

Procedure:
(2-bromoethoxy)(tert-butyl)dimethylsilane (20 g, 84 mmol) was added to a solution of (4-methoxyphenyl) methanamine (11.47 g, 84 mmol) in acetonitrile (200 mL) followed by K2CO3 (57.8 g, 418 mmol), and the mixture was stirred at 80° C. for 16 h. Insoluble solids were filtered off, filtrate was concentrated and partitioned between ethyl acetate and water. Organic layer was separated, washed with brine, dried over sodium sulphate and filtered. The filtrate was concentrated in vacuo and purified by flash chromatography using 30% ethyl acetate in hexane to afford title compound (19 g, 77%) as an oil. 1H NMR (300 MHz, DMSO-d6): δ 7.22 (d, J=8.4 Hz, 2H), 6.82 (d, J=8.7 Hz, 2H), 3.77 (s, 3H), 3.62 (m, 4H), 2.56 (t, J=5.7 Hz, 2H), 2.5 (m, 1H), 0.85 (s, 9H), 0.02 (s, 6H).
Reaction SMILES: COC1[CH:10]=[C:9](OC)[CH:8]=[C:7]([O:13]C)C=1C=O.C[O:16]C1C=C(OC)C(OC)=CC=1C=O.CO[C:31]1[CH:32]=[C:33]([CH:36]=[C:37](OC)[C:38]=1OC)[CH:34]=O>>[CH:9]1([CH2:8][C:7]([OH:13])=[O:16])[C:32]2[C:33](=[CH:36][CH:37]=[CH:38][CH:31]=2)[CH:34]=[CH:10]1
Reactant: COc1cc(OC)c(C=O)c(OC)c1
Reactant: COc1cc(C=O)cc(OC)c1OC
Reactant: COc1cc(OC)c(OC)cc1C=O
Product: O=C(O)CC1C=Cc2ccccc21

Procedure:
1.19 g (5.0 mmol) of 5,6-difluoro-2-methylindene-3-acetic acid methyl ester is dissolved in 10 ml of dry pyridine followed by 0.98 g (5.0 mmol) of 3,4,5-trimethoxy-benzaldehyde. The flask is placed under nitrogen, and 5.0 g (5.1 mol) of Triton B is added. The deeply colored solution is allowed to stand overnight, and then water (2 ml) is added. After standing for 15 minutes, it is poured into an excess of water. The organics are extracted with ether (2×50 ml). The aqueous phase is added to 10% HCl-ice. The orange, gummy solid that precipitates is extracted into methylene chloride and dried (MgSO4). The solvent is removed to leave an orange solid. The solid is filtered to give a crude product which is recrystallized to give 5,6-difluoro-2-methyl-1-(3,4,5-trimethoxy-benzylidene)-indene-3-acetic acid. When 2,4,6-trimethoxybenzaldehyde or 2,4,5-trimethoxybenzaldehyde is utilized in the above procedure, instead of 3,4,5-trimethoxy-benzaldehyde, the corresponding indene acetic acid is obtained. (R and R1 =H, R2 and R3 =F, R4 =H, R5, R6 and R7 =OCH3, R8 =CH3, R9 =H, R10 and R11 =double bond, m=0, n=0, M=OH)
Reaction SMILES: [F:1][C:2](I)([F:4])[F:3].[N:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>>[F:1][C:2]([C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][N:6]=1)([F:4])[F:3]
Reactant: FC(F)(F)I
Reactant: c1ccncc1
Product: FC(F)(F)c1ccccn1
Temperature: 180 °C
Yield: 19.9 %

Procedure:
In the same reaction vessel as used in Example 1, 15.82 g of pyridine and 7.83 g of trifluoromethyl iodide were mixed. The vessel was airtightly sealed and heated at 180° C. for 24 hours. After the reaction, the reactor was cooled to room temperature. Thereafter, the reaction mixture was removed from the cooled vessel and treated by following the procedure of Example 1. Consequently, there was obtained 1.17 g (19.90% of theoretical value) of trifluoromethyl pyridine. This substance was found to be a 48:41:11 mixture of α, β and γ isomers.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:25][O:26][CH2:27][C@@H:28]([O:30][C:31]1[CH:32]=[C:33]([CH:37]=[C:38]([O:40][C:41]2[CH:46]=[CH:45][C:44]([S:47]([CH3:50])(=[O:49])=[O:48])=[CH:43][CH:42]=2)[CH:39]=1)[C:34](O)=[O:35])[CH3:29].CCN(C(C)C)C(C)C.[NH2:60][C:61]1[CH:65]=[CH:64][N:63]([C:66]([O:68][C:69]([CH3:72])([CH3:71])[CH3:70])=[O:67])[N:62]=1>CN(C=O)C>[CH3:25][O:26][CH2:27][C@H:28]([CH3:29])[O:30][C:31]1[CH:32]=[C:33]([CH:37]=[C:38]([O:40][C:41]2[CH:46]=[CH:45][C:44]([S:47]([CH3:50])(=[O:49])=[O:48])=[CH:43][CH:42]=2)[CH:39]=1)[C:34]([NH:60][C:61]1[CH:65]=[CH:64][N:63]([C:66]([O:68][C:69]([CH3:72])([CH3:71])[CH3:70])=[O:67])[N:62]=1)=[O:35]
Reactant: CC(C)(C)OC(=O)n1ccc(N)n1
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(C(=O)O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(C(=O)Nc2ccn(C(=O)OC(C)(C)C)n2)c1
Reaction time: 4 h
Yield: 42.9 %

Procedure:
HATU (375 mg, 1.17 mmol) was added to 3-{(1S)-2-methoxy-(1-methylethyl)oxy}-5-{[4-(methylsulfonyl)phenyl]oxy}benzoic acid (300 mg, 0.79 mmol) followed by addition of DMF (5 mL), DIPEA (0.35 mL) and tert-butyl 3-amino-1H-pyrazole-1-carboxylate (155 mg, 0.85 mmol) and the reaction was stirred under argon for 4 h. The solvent was evaporated and the residue was dissolved in saturated aqueous sodium hydrogencarbonate (30 mL) and ethyl acetate (50 mL). The organic layer was separated, washed with saturated aqueous ammonium chloride (30 mL) then dried (MgSO4), filtered and evaporated. Purification by column chromatography, eluting with 50% ethyl acetate in hexanes, afforded the title compound as a colourless oil (185 mg, 43%).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)=[CH2:2].[CH2:15]([O:17][SiH:18]([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])[CH3:16].C1(C(O)=O)CCCCC1.C([Si](C=C)(C)O[Si](C)(C)C)=C>C1(C)C=CC=CC=1>[C:9]1([C:6]2[CH:7]=[CH:8][C:3]([CH2:1][CH2:2][Si:18]([O:22][CH2:23][CH3:24])([O:19][CH2:20][CH3:21])[O:17][CH2:15][CH3:16])=[CH:4][CH:5]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: C=Cc1ccc(-c2ccccc2)cc1
Reactant: CCO[SiH](OCC)OCC
Agent: C=C[Si](C)(C=C)O[Si](C)(C)C
Solvent: Cc1ccccc1
Solvent: O=C(O)C1CCCCC1
Product: CCO[Si](CCc1ccc(-c2ccccc2)cc1)(OCC)OCC
Temperature: 50 °C
Yield: 32 %

Procedure:
361 mg Of 4-vinylbiphenyl and 394 mg of triethoxysilane were placed in a glass reaction tube and 0.0009 ml of cyclohexanoic acid was added. Then, 0.009 ml of a toluene solution of a 0-valent platinum complex of divinyltetramethyldisiloxane (platinum content: 0.0044 Wt. %) was added to this mixture. The reaction tube was sealed with Teflon tape and heated for 30 minutes in an oil bath at 50° C. When the tube contents were analyzed by GC-MS following cooling, the conversion rate of 4-vinylbiphenyl was 36% and para-phenylphenethyltriethoxysilane was produced at a yield of 32%. The yield of α-(4-biphenylyl) triethoxysilane was 3%.
Reaction SMILES: CC(C)([O-])C.[K+].[CH2:7]([SH:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Br[C:16]1[C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][CH:19]=[C:18]([C:26]([F:29])([F:28])[F:27])[N:17]=1>CN(C)C=O>[C:8]1([CH2:7][S:14][C:16]2[C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][CH:19]=[C:18]([C:26]([F:27])([F:29])[F:28])[N:17]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: COC(=O)c1ccc(C(F)(F)F)nc1Br
Reactant: SCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C(F)(F)F)nc1SCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred suspension of 6.55 g (0.0584 mol) of potassium-t-butoxide in 60 mL dry dimethylformamide under nitrogen at 0° C. was added 6.84 mL (0.0584 mol) of benzyl mercaptan in 20 mL dimethylformamide while maintaining the temperature below 15° C. A solution of 15.83 g (0.053 mol) of the product from Example 2a or 2b in 20 mL dry dimethylformamide was added dropwise maintaining the temperature at 0° C. and then stirred another 30 minutes at 0° C. The reaction was poured into ice water and extracted with ether. The combined organic layers were washed with water, brine, dried over magnesium sulfate and evaporated to afford 17.84 g (100%). 1H NMR is similar to Example 3. IR (neat) 1725, 1675, 1575, 1135, 850 cm-1.
Reaction SMILES: [OH:1][CH:2]([C:5]1[N:6]=[C:7]([C:10]([F:13])([F:12])[F:11])[S:8][CH:9]=1)[CH2:3][NH2:4].[C:14]([CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27](=O)[CH3:28])=[CH:22][CH:21]=1)([O:16][CH3:17])=[O:15].C([BH3-])#N.[Na+].Cl>CO>[C:14]([CH2:18][O:19][C:20]1[CH:21]=[CH:22][C:23]([CH2:26][CH:27]([NH:4][CH2:3][CH:2]([OH:1])[C:5]2[N:6]=[C:7]([C:10]([F:13])([F:12])[F:11])[S:8][CH:9]=2)[CH3:28])=[CH:24][CH:25]=1)([O:16][CH3:17])=[O:15]
Reactant: NCC(O)c1csc(C(F)(F)F)n1
Reactant: COC(=O)COc1ccc(CC(C)=O)cc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: COC(=O)COc1ccc(CC(C)NCC(O)c2csc(C(F)(F)F)n2)cc1
Yield: 92 %

Procedure:
Prepared by analogy to Example 13 by reaction of 2-hydroxy-2-(2-trifluoromethyl-thiazol-4-yl)ethanamine with 1-(4-carbomethoxymethoxyphenyl)propan-2-one and sodium cyanoborohydride in methanol (reaction time: 5 hours) followed by purification on a silica gel column using methylene chloride/methanol=20:1. This results in a 50:50 diastereomer mixture of the base. This is recrystallised from a mixture of ether/ethyl acetate=65:10. The mother liquor resulting from this is mixed with ethereal hydrochloric acid, and the mixture is evaporated to dryness. The residue resulting from this is recrystallised from a mixture of ether/ethyl acetate/methanol=100:60:1. The mother liquor obtained after the crystals have been removed by filtration is evaporated to dryness, and the base is liberated by shaking with alkali and methylene chloride and purified on a silica gel column using methylene chloride/methanol=20:1 as eluant. This results in diastereomer B as an oil approximately 92-94% pure.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=S)[CH2:10][N:9]=[C:8]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:7]=2[CH:20]=1.[C:23]1(=[O:38])[N:27]([CH2:28][C:29](=[O:32])[CH2:30][NH2:31])[C:26](=[O:33])[C:25]2=[CH:34][CH:35]=[CH:36][CH:37]=[C:24]12>C(O)C>[F:1][C:2]([F:22])([F:21])[C:3]1[CH:4]=[CH:5][C:6]2[N:12]=[C:11]([NH:31][CH2:30][C:29]([CH2:28][N:27]3[C:23](=[O:38])[C:24]4=[CH:37][CH:36]=[CH:35][CH:34]=[C:25]4[C:26]3=[O:33])=[O:32])[CH2:10][N:9]=[C:8]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:7]=2[CH:20]=1
Reactant: FC(F)(F)c1ccc2c(c1)C(c1ccccc1)=NCC(=S)N2
Reactant: NCC(=O)CN1C(=O)c2ccccc2C1=O
Solvent: CCO
Product: O=C(CNC1=Nc2ccc(C(F)(F)F)cc2C(c2ccccc2)=NC1)CN1C(=O)c2ccccc2C1=O

Procedure:
In the manner given in example 12, 7-trifluoromethyl-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepine-2-thione is heated with (3-phthalimidoacetonyl)amine, ethylene ketal in ethanol to give 7-trifluoromethyl-5-phenyl-2-[(3-phthalimidoacetonyl)amino]-3H-1,4-benzodiazepine, ethylene ketal.
Reaction SMILES: Cl.[CH2:2]([NH:4][C:5]1[N:10]=[C:9]([NH:11][C:12]2[C:13]3[CH2:24][NH:23][C:22]([CH3:26])([CH3:25])[C:14]=3[N:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[N:16]=2)[C:8]([F:27])=[CH:7][N:6]=1)[CH3:3].CCN(C(C)C)C(C)C.[Cl:37][C:38](Cl)([O:40]C(=O)OC(Cl)(Cl)Cl)Cl>O1CCOCC1.C(Cl)Cl>[Cl:37][C:38]([N:23]1[CH2:24][C:13]2[C:12]([NH:11][C:9]3[C:8]([F:27])=[CH:7][N:6]=[C:5]([NH:4][CH2:2][CH3:3])[N:10]=3)=[N:16][N:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:14]=2[C:22]1([CH3:25])[CH3:26])=[O:40]
Reactant: CCNc1ncc(F)c(Nc2nn(C(=O)OCC)c3c2CNC3(C)C)n1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCNc1ncc(F)c(Nc2nn(C(=O)OCC)c3c2CN(C(=O)Cl)C3(C)C)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of B1(iv) (4.43 g, 9.6 mmol) in dioxane (25 mL) was added HCl (20 mL, 4M in dioxane). The reaction was stirred at room temperature for 2 h then concentrated. To a solution of the HCl salt of ethyl 3-{[2-(ethylamino)-5-fluoropyrimidin-4-yl]amino}-6,6-dimethyl-5,6-dihydropyrrolo[3,4-c]pyrazole-1(4H)-carboxylate (1.27 g, 2.7 mmol) in CH2Cl2 (40 mL) was added DIPEA (1.57 g, 12.1). The reaction was cooled to −78° C. and triphosgene (0.48 g, 0.6 mmol) was added in a solution of CH2Cl2 (10 mL) with an addition funnel over 15 min. The reaction was quenched at −78° C. with water then warmed to room temperature. The mixture was made to pH 8-9 with NaHCO3 and extracted with CH2Cl2 (2×15 mL). The combined extracts were washed with brine (15 mL) then dried, filtered and concentrated. The crude material was purified by silica gel column chromatography using 0-3% 7N NH3/MeOH in CH2Cl2 to give the desired compound B1(v) as a white foam (489 mg, 36%). 1H NMR (300 MHz, DMSO-d6) δ ppm 1.07 (t, J=7.2 Hz, 3H), 1.33 (t, J=7.2 Hz, 3H), 1.78-1.84 (m, 6H), 3.12-3.28 (m, 2H), 4.42 (q, J=7.2 Hz, 2H), 4.78 (s, 2H), 6.69-6.97 (m, 1H), 7.77-8.08 (m, 1H), 10.41 (s, 1H). Mass spectrum: Calcd for C17H22ClFN7O3 (M+H): 426. Found 426.
Reaction SMILES: [C:1]([BH3-])#[N:2].[Na+].N[C:6]1[CH:7]=[C:8]([OH:13])[CH:9]=[CH:10][C:11]=1[F:12].C=O.[C:16](O)(=O)C>C(#N)C.O>[CH3:16][N:2]([CH3:1])[C:6]1[CH:7]=[C:8]([OH:13])[CH:9]=[CH:10][C:11]=1[F:12]
Reactant: Nc1cc(O)ccc1F
Reactant: CC(=O)O
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CN(C)c1cc(O)ccc1F
Reaction time: 2 h
Yield: 91 %

Procedure:
Sodium cyanoborohydride (0.81 g, 12.7 mmol) is added to a solution of 3-amino-4-fluorophenol (0.66 g, 4.6 mmol), formaldehyde (37% solution, 2.0 g, 24.6 mmol) and acetic acid (0.5 mL) in 20 mL acetonitrile. The reaction is stirred for 2 hour and then poured into 100 mL water. The product is then extracted into diethyl ether (50 mL×3) and the combined organic fractions are washed with brine (40 mL), and dried over anhydrous sodium sulfate. The resulting solution is concentrated in vacuo, and the residue is chromatographed on silica gel using CHCl3:ethyl acetate as eluant (99:1 to 90:10 gradient) to yield 0.72 g (91%) of Compound 22 as a brown solid. 1H-NMR (CDCl3) 6.85 (dd, 1H); 6.40 (m, 1H); 6.27 (m, 1H); 2.84 (s, 6H). 1H-NMR (CDCl3) 133.25 (t, J=9.5 Hz).
Reaction SMILES: N1C2N(C3C=CC=CC=3N=2)C=CC=1C1C=CC(NC[CH2:13][CH2:14][F:15])=CC=1.[N:25]1[C:26]2[N:27]([C:38]3[CH:44]=[CH:43][CH:42]=[CH:41][C:39]=3[N:40]=2)[CH:28]=[CH:29][C:30]=1[C:31]1[CH:37]=[CH:36][C:34]([NH2:35])=[CH:33][CH:32]=1.CC1C=CC(S([O:55][CH2:56][CH2:57][O:58][CH2:59][CH2:60]OCCO)(=O)=O)=CC=1>>[N:25]1[C:26]2[N:27]([C:38]3[CH:44]=[CH:43][CH:42]=[CH:41][C:39]=3[N:40]=2)[CH:28]=[CH:29][C:30]=1[C:31]1[CH:32]=[CH:33][C:34]([NH:35][CH2:60][CH2:59][O:58][CH2:57][CH2:56][O:55][CH2:13][CH2:14][F:15])=[CH:36][CH:37]=1
Reactant: Cc1ccc(S(=O)(=O)OCCOCCOCCO)cc1
Reactant: FCCCNc1ccc(-c2ccn3c(n2)nc2ccccc23)cc1
Reactant: Nc1ccc(-c2ccn3c(n2)nc2ccccc23)cc1
Product: FCCOCCOCCNc1ccc(-c2ccn3c(n2)nc2ccccc23)cc1

Procedure:
4-(benzo[4,5]imidazo[1,2-a]pyrimidin-2-yl)-N-(2-(2-(2-fluoroethoxy)ethoxy)ethyl)aniline was prepared using the procedure for 4-(Benzo[4,5]imidazo[1,2-a]pyrimidin-2-yl)-N-(3-fluoropropyl)aniline from 4-(benzo[4,5]imidazo[1,2-a]pyrimidin-2-yl)aniline (10 mg, 0.038 mmol) and 2-(2-(2-hydroxyethoxy)ethoxy)ethyl 4-methylbenzenesulfonate (23 mg, 0.075 mmol). The product T557 was obtained as a yellow solid (1.2 mg, 5.1%). 1H NMR (400 MHz, CDCl3): δ 9.31 (d, J=7.6 Hz, 1H), 8.25 (m, 2H), 8.02 (d, J=7.2 Hz, 1H), 7.78-7.75 (m, 1H), 7.72 (m, 1H), 7.61 (m, 1H), 6.80 (d, J=9.2 Hz, 2H), 4.56 (m, 1H), 4.45 (m, 1H), 3.75 (m, 1H), 3.71 (t, J=5.2 Hz, 2H), 3.69-3.65 (m, H), 3.47-3.43 (m, H); MS (ESI): 395 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:18])=[C:6]([C:8](=[O:17])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)[CH:7]=1.[C:19](OC(=O)CC)(=O)[CH2:20][CH3:21].Cl>C(N(CC)CC)C>[CH2:20]([C:21]1[O:18][C:5]2[C:6]([C:8](=[O:17])[C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1)=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH3:19]
Reactant: O=C(Cc1cccc(F)c1)c1cc(F)ccc1O
Reactant: CCC(=O)OC(=O)CC
Agent: Cl
Solvent: CCN(CC)CC
Product: CCc1oc2ccc(F)cc2c(=O)c1-c1cccc(F)c1
Temperature: 25 °C
Yield: 52.1 %

Procedure:
Intermediate 73 (3.00 g, 12.08 mmoles) was taken in a RB flask and to this triethylamine (25 ml) and propionic anhydride (4.92 g, 37.82 mmoles) were added and the mixture was refluxed for 24 h. After cooling to RT, the reaction mixture was acidified by the addition of 1N HCl solution, extracted with ethyl acetate, washed with sodium bicarbonate solution, dried with sodium sulphate and concentrated. The crude product was purified by column chromatography with ethyl acetate:petroleum ether to afford the title compound as off-yellow solid (1.80 g, 52% yield). 1H-NMR (δ ppm, DMSO-d6, 400 MHz): δ 7.80 (m, 1H), 7.76 (m, 2H), 7.51 (dd, J=8.0, 6.4 Hz), 7.22 (m, 1H), 7.18 (m, 2H), 2.56 (q, J=7.6 Hz, 2H), 1.20 (t, J=7.6 Hz, 3H).
Reaction SMILES: [C:1]1([N:7]2[C:11]([CH3:12])=[C:10]([C:13]([OH:15])=O)[CH:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:16][C:17]1[CH:18]=[CH:19][C:20]([N:25]2[CH2:30][CH2:29][CH:28]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)[CH2:27][CH2:26]2)=[C:21]([CH:24]=1)[C:22]#[N:23]>>[C:22]([C:21]1[CH:24]=[C:17]([NH:16][C:13]([C:10]2[CH:9]=[N:8][N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:11]=2[CH3:12])=[O:15])[CH:18]=[CH:19][C:20]=1[N:25]1[CH2:30][CH2:29][CH:28]([N:31]2[CH2:32][CH2:33][O:34][CH2:35][CH2:36]2)[CH2:27][CH2:26]1)#[N:23]
Reactant: N#Cc1cc(N)ccc1N1CCC(N2CCOCC2)CC1
Reactant: Cc1c(C(=O)O)cnn1-c1ccccc1
Product: Cc1c(C(=O)Nc2ccc(N3CCC(N4CCOCC4)CC3)c(C#N)c2)cnn1-c1ccccc1
Yield: 20.3 %

Procedure:
By the reaction and treatment in the same manner as in Example 64 using 1-phenyl-5-methylpyrazole-4-carboxylic acid (0.6 g) and 5-amino-2-(4-morpholinopiperidin-1-yl)benzonitrile (0.6 g), the title compound (0.2 g) was obtained, melting point: 223° C.
Reaction SMILES: [CH2:1]([N:7]([CH:21]([CH2:26]OS(C1C=CC(C)=CC=1)(=O)=O)[CH2:22][CH2:23][CH2:24][CH3:25])[S:8]([C:11]1[C:12]2[CH:13]=[CH:14][N:15]=[CH:16][C:17]=2[CH:18]=[CH:19][CH:20]=1)(=[O:10])=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[NH3:38]>C(O)C>[NH2:38][CH2:26][CH:21]([N:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[S:8]([C:11]1[C:12]2[CH:13]=[CH:14][N:15]=[CH:16][C:17]=2[CH:18]=[CH:19][CH:20]=1)(=[O:9])=[O:10])[CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCN(C(CCCC)COS(=O)(=O)c1ccc(C)cc1)S(=O)(=O)c1cccc2cnccc12
Reactant: N
Solvent: CCO
Product: CCCCCCN(C(CN)CCCC)S(=O)(=O)c1cccc2cnccc12
Temperature: 100 °C

Procedure:
To 2.37 g of the thus obtained N-hexyl-N-(1-p-toluenesulfonyloxymethylpentyl)-5-isoquinolinesulfonamide was added 40 ml of an ethanol solution containing 4 g of ammonia, and the mixture was heated in a pressure vessel at 100° C. for 13 hours. Then, the solvent was removed under reduced pressure to obtain a residue. The residue thus obtained was subjected to purification by silica gel column chromatography (Wacogel C-200, solvent: a 5% methanol solution in chloroform) to obtain 0.70 g of N-(1-aminomethylpentyl)-N-hexyl-5-isoquinolinesulfonamide [Compound (19)]. Compound (19) was analyzed to give the following data.
Reaction SMILES: [NH:1]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C@@H:2]([C:15](O)=[O:16])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([CH:13]=[O:14])[CH:5]=1.Cl.[NH2:26][CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30]>CN(C=O)C>[NH:1]([C:18]([O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:19])[C@@H:2]([C:15]([NH:26][CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])=[O:16])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([CH:13]=[O:14])[CH:5]=1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1cn(C=O)c2ccccc12)C(=O)O
Reactant: COC(=O)CCN
Agent: Cl
Solvent: CN(C)C=O
Product: COC(=O)CCNC(=O)[C@@H](Cc1cn(C=O)c2ccccc12)NC(=O)OC(C)(C)C
Yield: 69.8 %

Procedure:
Boc-D-Trp(CHO)-OH (10.0 g), HCl.H-βAla-OMe (4.41 g) HOBt (4.47 g), WSCD (5.14 g) and DMF (100 ml) were reacted in a similar manner to that of Preparation 1-1) to give Boc-D-Trp(CHO)-βAla-OMe (8.77 g).
Reaction SMILES: C([O:3][C:4](=[O:40])[CH:5](Br)[CH:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[NH:15][C:16]3[N:17]([CH2:32][CH:33]4[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]4)[C:18](=[O:31])[N:19]([CH2:24][CH:25]4[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]4)[C:20](=[O:23])[C:21]=3[N:22]=2)=[CH:10][CH:9]=1)Br)C.CC(C)([O-])C.[K+].C>C(O)(C)(C)C.O>[CH:25]1([CH2:24][N:19]2[C:20](=[O:23])[C:21]3[N:22]=[C:14]([C:11]4[CH:10]=[CH:9][C:8]([C:6]#[C:5][C:4]([OH:40])=[O:3])=[CH:13][CH:12]=4)[NH:15][C:16]=3[N:17]([CH2:32][CH:33]3[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]3)[C:18]2=[O:31])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]1
Reactant: CCOC(=O)C(Br)C(Br)c1ccc(-c2nc3c(=O)n(CC4CCCCC4)c(=O)n(CC4CCCCC4)c3[nH]2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: O
Product: O=C(O)C#Cc1ccc(-c2nc3c(=O)n(CC4CCCCC4)c(=O)n(CC4CCCCC4)c3[nH]2)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 81.4 %

Procedure:
2.8 g (4.1 mmol) 3-[4-[1,3-bis(cyclohexylmethyl)-1,2,3,6-tetrahydro-2,6-dioxo-9H-purin-8-yl]phenyl}-2,3-dibromo-propionic acid ethyl ester (part a of this example) was added to 56 mL of 1M potassium t-butoxide in t-butanol (Aldrich) at room temperature. The mixture was stirred at room temperature for 2.5 hours, then 0.10 mL water was added. The solution was stirred for an additional hour then 1 g charcoal was added in 250 mL water. The mixture was stirred for 30 minutes then filtered. The filtrate was acidified with conc. hydrochloric acid (pH=1), then the resulting suspension was stirred for 15 minutes, filtered then washed with 3×50 mL water. The solid was dried under reduced pressure to give 1.63 g (81%) of title compound; 1H-NMR (DMSO-d6)δ: 8.15 (d, J=8.0 Hz, phenyl CH, 2H), 7.73 (d, J=8.0 Hz, phenyl CH, 2H), 3.87 (d, J=6.6 Hz, CH2N, 2H), 3.74 (d, J=6.8 Hz, CH2N, 2H), 1.88 (br s, c-hexyl CH, 1H), 1.4-1.8 (m, c-hexyl CH, CH2, 11H), 0.8-1.2 (m, c-hexyl CH2, 10 H); MS (ES−): 487 (M-1), 443 (M-1-CO2).