Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:19])[C:3](=[O:18])[C:4]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)Cl.[NH:20]1[CH:24]=[CH:23][N:22]=[CH:21]1>C(#N)C>[CH3:1][N:2]([CH3:19])[C:3](=[O:18])[C:4]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:21]1[NH:20][CH:24]=[CH:23][N:22]=1
Reactant: c1c[nH]cn1
Reactant: CN(C)C(=O)C(Cl)(c1ccccc1)c1ccccc1
Solvent: CC#N
Product: CN(C)C(=O)C(c1ccccc1)(c1ccccc1)c1ncc[nH]1

Procedure:
18.1 g diphenyl-chloroacetic acid dimethylamide (m.p. 128°C, prepared by analogy with Example 19) are heated with 15.6 g imidazole in 120 ml acetonitrile at boiling temperature for 18 hours. The solvent is distilled off in a vacuum. After the addition of 70 ml of water, the mixture is extracted with methylene chloride. After drying, the solvent is distilled off in a vacuum and the solid residue is recrystallized from methanol. The diphenyl-imidazolyl-acetic acid dimethyl amide of m.p. 202°C is thus obtained in the form of colourless crystals.
Reaction SMILES: CN(C=O)C.[C:6]([O:10][C:11]([N:13]1[CH2:25][CH2:24][C:23]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][C:15]=2[CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7].[H-].[Na+].[CH2:28](Br)[CH:29]=[CH2:30]>C(OCC)(=O)C>[C:6]([O:10][C:11]([N:13]1[CH2:25][CH2:24][C:23]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]([CH2:30][CH:29]=[CH2:28])[C:15]=2[CH2:14]1)=[O:12])([CH3:9])([CH3:7])[CH3:8]
Reactant: CC(C)(C)OC(=O)N1CCc2c([nH]c3ccccc23)C1
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CCn1c2c(c3ccccc31)CCN(C(=O)OC(C)(C)C)C2
Temperature: -60 °C
Reaction time: 1 h
Yield: 85.2 %

Procedure:
Anhydrous DMF solution (10 ml) of 2-t-butoxycarbonyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (4.40 g, 16.2 mmol) was mixed with 60% sodium hydride (700 mg, 10 mmol) and stirred at roam temperature for 1 hour. The reaction solution was cooled to −60° C., mixed with allyl bromide (2.18 g, 18 mmol) and then returned to room temperature by further stirring for 1 hour. The reaction solution was mixed with ethyl acetate (150 ml), washed with water and dried with anhydrous sodium sulfate, and then the solvent was removed by evaporation under a reduced pressure. The thus obtained residue was purified by a silica gel chromatography to obtain 4.32 g of the title compound as an oil (13.8 mmol, 87% in yield).
Reaction SMILES: [C:1]1(=O)[CH2:4][CH2:3][CH2:2]1.[C:6]([O:10][C:11]([NH:13][NH2:14])=[O:12])([CH3:9])([CH3:8])[CH3:7]>CCCCCC>[C:6]([O:10][C:11]([NH:13][N:14]=[C:1]1[CH2:4][CH2:3][CH2:2]1)=[O:12])([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)OC(=O)NN
Reactant: O=C1CCC1
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)NN=C1CCC1
Yield: 81.2 %

Procedure:
The reaction mixture of cyclobutanone (15 g, 214 mmol) and hydrazinecarboxylic acid tert-butyl ester (28.3 g, 214 mmol) in hexane (225 mL) was heated to reflux for 2 hours. After cooling down, a precipitate formed and the solid was filtered under vacuum. Isopropanol (10 mL) and hexane (100 mL) were added to the solid and the mixture was put on the rotary evaporator under vacuum until a slurry was generated. After filtration, the solid was washed with hexane twice and dried in vacuo to afford N′-cyclobutylidene-hydrazinecarboxylic acid tert-butyl ester (32 g, 81%) as white solid which was used without further purification.
Reaction SMILES: [C:1](Cl)(Cl)=[S:2].[CH3:5][NH:6][C:7]1[C:8]([NH2:16])=[CH:9][C:10]([N+:13]([O-:15])=[O:14])=[CH:11][CH:12]=1.CCN(CC)CC>C1COCC1>[CH3:5][N:6]1[C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:8]=2[NH:16][C:1]1=[S:2]
Reactant: CNc1ccc([N+](=O)[O-])cc1N
Reactant: S=C(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cn1c(=S)[nH]c2cc([N+](=O)[O-])ccc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of thiophosgene (2.3 ml, 30 mmol) in THF (300 ml) was added dropwise to a solution containing N1-Methyl-4-nitro-benzene-1,2-diamine (5.01 g, 30 mmol) and Et3N (9.2 ml, 66 mmol) in THF (300 ml) at 0° C. over 90 min. After stirring at 0° C. for another 1 hr, the mixture was allowed to warm to room temperature. The mixture was then concentrated to about 100 ml, water (200 ml) was added, the mix was stirred for 20 min, the product was collected by filtration and washed with small amount of cold CH2Cl2, after drying left 5.16 g as a mustard yellow solid: LC/MS (m/e) at 210.0 [M+H]+, Rt at 1.49 min.
Reaction SMILES: C([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[C:22]3[O:21][CH2:20][CH2:19][C:18]=3[CH:17]=[C:16](Br)[CH:15]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1>CCO.Cl.[Pd]>[O:21]1[C:22]2[C:14]([CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)=[CH:15][CH:16]=[CH:17][C:18]=2[CH2:19][CH2:20]1
Reactant: Brc1cc2c(c(C3=CCN(Cc4ccccc4)CC3)c1)OCC2
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: c1cc2c(c(C3CCNCC3)c1)OCC2
Temperature: 50 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
To a solution of 1-benzyl-4-(5-bromo-2,3-dihydro-benzofuran-7-yl)-1,2,3,6-tetrahydro-pyridine in EtOH and 4N HCl was added 40 wt % of 10% Pd/C catalyst. The reaction flask was charged with H2 (3.5 bar) and then stirred overnight at 50° C. The reaction mixture was filtered over Celite under argon. The solvents were evaporated and the product was partitioned between CH2Cl2 and aq. K2CO3. The organic phase was dried over Na2SO4 and evaporated to give the title compound in 81% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[C:9]2[C:4]=1[C:5](=O)[N:6]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)[CH:7]=[N:8]2.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:33])=CC=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[C:9]2[C:4]=1[C:5](=[S:33])[N:6]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)[CH:7]=[N:8]2
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COc1ccc(-n2cnc3cc(OC)cc(OC)c3c2=O)cc1
Solvent: Cc1ccccc1
Product: COc1ccc(-n2cnc3cc(OC)cc(OC)c3c2=S)cc1
Yield: 72.1 %

Procedure:
The mixture of 5,7-dimethoxy-3-(4-methoxyphenyl)-quinazoline-4-one (240 mg, 0.76 mmol), as prepared in Example 18 or 19, and Lawesson's reagent (310 mg, 0.76 mmol) in toluene (4 mL) was refluxed overnight. The mixture was evaporated to dryness. EtOAc was added and the mixture was washed with water, brine and dried over MgSO4. Evaporation gave a crude solid. Purification was performed by flash chromatography on silica gel, loaded with dichloromethane and eluted with 45% ethyl acetate in hexane. The pure fraction was combined and evaporated to give a yellow foam (180 mg, 72%).
Reaction SMILES: [I:1][C:2]1[N:3]=[CH:4][N:5]([CH2:8][O:9][CH2:10][CH2:11][Si:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1I.C([Li])CCC.CN([CH:24]=[O:25])C.[NH4+].[Cl-]>C1COCC1>[I:1][C:2]1[N:3]=[C:4]([CH:24]=[O:25])[N:5]([CH2:8][O:9][CH2:10][CH2:11][Si:12]([CH3:15])([CH3:14])[CH3:13])[CH:6]=1
Reactant: C[Si](C)(C)CCOCn1cnc(I)c1I
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1cc(I)nc1C=O
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 75 %

Procedure:
A solution of 4,5-diiodo-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole (8.86 g, 19.68 mmol) in anhydrous THF (110 ml) under argon was cooled to −78° C. and was treated dropwise with n-butyllithium (13.5 ml, 21.65 mmol, 1.6M in hexane). After 10 minutes stirring at −78°° C. and 30 minutes at 45° C., the reaction mixture was cooled to −78° C. and treated at once with DMF (10 ml). The mixture was allowed to warm to room temperature and saturated NH4Cl (150 ml) was added. The aqueous layer was extracted 2 times with AcOEt. The combined extracts were dried over Na2SO4, filtered and the solvent was removed in vacuo. The residue was chromatographed (silica, elution with hexane/AcOEt=98:2) to provide the title compound (5.18 g, 75%) as a light yellow oil. MS: m/e=352.1 (M+).
Reaction SMILES: [CH3:1][PH:2][CH2:3][C:4]([OH:6])=O.Cl.C[O:9][C:10](=[O:30])[C@H:11]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=2)=[CH:18][CH:17]=1)[N:12]([I:14])[I:13]>>[CH3:1][PH:2][CH2:3][C:4]([C@@:11]([C:10]([OH:30])=[O:9])([CH2:15][C:16]1[CH:17]=[CH:18][C:19]([O:22][C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=2)=[CH:20][CH:21]=1)[N:12]([I:13])[I:14])=[O:6]
Reactant: CPCC(=O)O
Reactant: COC(=O)[C@H](Cc1ccc(Oc2ccc(O)cc2)cc1)N(I)I
Agent: Cl
Product: CPCC(=O)[C@](Cc1ccc(Oc2ccc(O)cc2)cc1)(C(=O)O)N(I)I

Procedure:
The compound was prepared analogously to the procedure described in examples (2) and (3). Methylphosphinoacetic acid was used in place of methylphosphinopropionic acid and diiodothyronine methyl ester hydrochloride was used in place of triiodothyronine methyl ester hydrochloride. The final product was purified by inverse phase column chromatography on silica gel RP 18 using 75% strength methanol as eluent. The unary substance of the main fraction, differing in the TLC from the starting materials, was identified by mass spectrometry as the title compound.
Reaction SMILES: [C:1]1([CH2:6][C@H:7]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[C:8](=[O:12])[C:9]([CH3:11])=[CH2:10])[CH2:5][CH2:4][CH2:3][CH:2]=1.[OH2:21]>CN(C=O)C>[C:1]1([CH2:6][C@H:7]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[C:8]([C@@:9]2([CH3:11])[CH2:10][O:21]2)=[O:12])[CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: C=C(C)C(=O)[C@H](CC1=CCCC1)NC(=O)OC(C)(C)C
Reactant: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](CC1=CCCC1)C(=O)[C@@]1(C)CO1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 53 %

Procedure:
A solution of (S)-tert-butyl (1-(cyclopent-1-en-1-yl)-4-methyl-3-oxopent-4-en-2-yl)carbamate (10.0 g, 35.6 mmol) in DMF (180 mL) was cooled to −20° C. and bleach (54.0 mL, 71.2 mmol, 10%) was added dropwise under nitrogen. The reaction mixture was warmed to 0° C. and stirred for 1.5 h. Water (200 mL) was added and the mixture was extracted with EtOAc (200 mL×2). The organic phases were combined, washed with brine (200 mL×2), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by flash column chromatography on silica gel to afford tert-butyl ((S)-3-(cyclopent-1-en-1-yl)-1-((R)-2-methyloxiran-2-yl)-1-oxopropan-2-yl)carbamate as viscous oil (5.6 g, 53% yield). 1H NMR (300 MHz, CDCl3): δ 4.62 (s, 1H), 4.91 (d, J=7.5 Hz, 1H), 4.44-4.37 (m, 1H), 3.29 (d, J=4.8 Hz, 1H), 2.89 (d, J=4.8 Hz, 1H), 2.56-2.52 (m, 1H), 2.29-2.26 (m, 5H), 1.92-1.82 (m, 2H), 1.51 (s, 3H), 1.41 (s, 9H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[CH:17][C:18]=2[O:20][CH3:21])[C:13]([C:24](O)=[O:25])=[CH:12][N:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:27][NH:28][CH:29]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH3:30]>>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[CH:17][C:18]=2[O:20][CH3:21])[C:13]([C:24](=[O:25])[N:28]([CH3:27])[CH:29]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH3:30])=[CH:12][N:11]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cc(OC)c2c(CNC(=O)OC(C)(C)C)ncc(C(=O)O)c2c1
Reactant: CNC(C)c1ccccc1
Product: COc1cc(OC)c2c(CNC(=O)OC(C)(C)C)ncc(C(=O)N(C)C(C)c3ccccc3)c2c1

Procedure:
As described in example 1E, 100 mg of 1-(tert-butoxycarbonylamino-methyl)-6,8-dimethoxy-isoquinoline-4-carboxylic acid was coupled with methyl-(1-phenyl-ethyl)-amine to give 112 mg of {6,8-dimethoxy-4-[methyl-(1-phenyl-ethyl)-carbamoyl]-isoquinolin-1-ylmethyl}-carbamic acid tert-butyl ester. MS: APCI (M+H) calc'd for C27H33N3O5+H 480.6; found 480.0.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[N:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:21]=[C:22]3[C:27](=[CH:28][CH:29]=2)[CH2:26][NH:25][CH2:24][CH2:23]3)=[CH:16][CH:15]=1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:25]3[CH2:24][CH2:23][C:22]4[C:27](=[CH:28][CH:29]=[C:20]([C:17]5[CH:18]=[CH:19][N:14]=[CH:15][CH:16]=5)[CH:21]=4)[CH2:26]3)=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Reactant: c1cc(-c2ccc3c(c2)CCNC3)ccn1
Product: O=C(c1cc2ncc(Cl)cn2n1)N1CCc2cc(-c3ccncc3)ccc2C1

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 6-Pyridin-4-yl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9](Cl)=[O:10])[CH2:5][CH2:4]1.[NH3:14]>C1COCC1>[F:1][C:2]([F:13])([F:12])[C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([NH2:14])=[O:10])[CH2:5][CH2:4]1
Reactant: N
Reactant: O=C(Cl)[C@H]1CC[C@H](C(F)(F)F)CC1
Solvent: C1CCOC1
Product: NC(=O)[C@H]1CC[C@H](C(F)(F)F)CC1
Reaction time: 0.25 h

Procedure:
A mixture of trans-4-trifluoromethyl-cyclohexanecarbonyl chloride (17.3 g, 80.6 mmol) and THF (150 mL) is added dropwise at 15° C. to conc. NH3 (400 mL). The reaction mixture is stirred for 15 min, concentrated and the precipitate is filtered off, washed with water and dried to give the sub-title compound.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[N:24]=[CH:23][CH:22]=[C:21]([C:25]3[CH:30]=[C:29]([NH:31][C:32]4[CH:45]=[C:35]5[CH2:36][N:37]([C:40](=[O:44])[CH:41]([CH3:43])[CH3:42])[CH2:38][CH2:39][N:34]5[N:33]=4)[C:28](=[O:46])[N:27]([CH3:47])[CH:26]=3)[C:18]=1[CH:19]=[O:20])[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>ClCCl.CO>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[C:18]([CH2:19][OH:20])=[C:21]([C:25]3[CH:30]=[C:29]([NH:31][C:32]4[CH:45]=[C:35]5[CH2:36][N:37]([C:40](=[O:44])[CH:41]([CH3:42])[CH3:43])[CH2:38][CH2:39][N:34]5[N:33]=4)[C:28](=[O:46])[N:27]([CH3:47])[CH:26]=3)[CH:22]=[CH:23][N:24]=1)[N:9]=[CH:8]2)([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)C(=O)N1CCn2nc(Nc3cc(-c4ccnc(-n5ncc6cc(C(C)(C)C)cc(F)c6c5=O)c4C=O)cn(C)c3=O)cc2C1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CC(C)C(=O)N1CCn2nc(Nc3cc(-c4ccnc(-n5ncc6cc(C(C)(C)C)cc(F)c6c5=O)c4CO)cn(C)c3=O)cc2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 44.3 %

Procedure:
To a solution of 148e (90 mg, 0.141 mmol) in dichloromethane (5 mL) and methanol (5 mL) was added NaBH4 (10.7 mg, 0.282 mmol). After stirring at room temperature for 1 h, the reaction mixture was quenched with aqueous NH4Cl and concentrated under reduced pressure. The residue was extracted with dichloromethane (3×15 mL). The combined organic layer was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by reverse-phase prep-HPLC to afford 148 (40 mg, 44%) as a white solid. MS-ESI: [M+H]+ 640.8. 1H NMR (500 MHz, DMSO-d6) δ 8.57 (d, J=5.0 Hz, 1H), 8.54 (d, J=2.5 Hz, 1H), 8.35-8.28 (m, 1H), 8.06 (s, 1H), 7.90 (d, J=1.5 Hz, 1H), 7.78 (dd, J=1.0, 13.0 Hz, 1H), 7.51 (d, J=5.0 Hz, 1H), 7.40 (d, J=2.5 Hz, 1H), 6.01 (s, 1H), 4.90-4.88 (m, 1H), 4.78-4.76 (m, 1H), 4.64-4.62 (m, 1H), 4.42-4.41 (m, 2H), 4.03-3.92 (m, 4H), 3.59 (s, 3H), 3.00-2.96 (m, 1H), 1.40 (s, 9H), 1.04-1.01 (m, 6H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([C:12]1[O:13][C:14]2[C:20]([Cl:21])=[CH:19][C:18]([F:22])=[CH:17][C:15]=2[N:16]=1)[CH2:9][C:10]#[CH:11]>>[Cl:21][C:20]1[C:14]2[O:13][C:12]([CH2:8][CH2:9][C:10]#[C:11][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=3)=[N:16][C:15]=2[CH:17]=[C:18]([F:22])[CH:19]=1
Reactant: Brc1ccccn1
Reactant: C#CCCc1nc2cc(F)cc(Cl)c2o1
Product: Fc1cc(Cl)c2oc(CCC#Cc3ccccn3)nc2c1
Yield: 59.6 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromopyridine (141 mg, 0.89 mmol) and 2-(but-3-ynyl)-7-chloro-5-fluorobenzo[d]oxazole (200 mg, 0.89 mmol). The crude residue was purified by flash chromatography (DCM/MeOH 99:1) to yield 160 mg (0.53 mmol, 59%) of 7-chloro-5-fluoro-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]oxazole as an orange solid.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([NH:9][CH3:10])[C:6]([N+:11]([O-:13])=[O:12])=[C:5]([NH:14][CH3:15])[N:4]=1.ClC1C=CC=C(C(OO)=[O:24])C=1>C(Cl)Cl.CO>[CH3:1][S:2]([C:3]1[N:4]=[C:5]([NH:14][CH3:15])[C:6]([N+:11]([O-:13])=[O:12])=[C:7]([NH:9][CH3:10])[N:8]=1)=[O:24]
Reactant: CNc1nc(SC)nc(NC)c1[N+](=O)[O-]
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CO
Product: CNc1nc(S(C)=O)nc(NC)c1[N+](=O)[O-]

Procedure:
Prepared from 2-methylsulphenyl-4,6-bis(methylamino)-5-nitro-pyrimidine by reacting with m-chloroperbenzoic acid, Rf value: 0.36 (silica gel; methylene chloride/methanol=3:1)
Reaction SMILES: [CH2:1]([O:19][CH2:20][CH:21]([NH:43][C:44]([CH2:46][CH2:47][C:48]([OH:50])=O)=[O:45])[CH2:22][O:23][C:24]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C([O-])(=[O:53])C.[Na+]>C(OC(=O)C)(=O)C>[CH2:1]([O:19][CH2:20][CH:21]([N:43]1[C:48](=[O:50])[CH2:47][CH2:46][C:44]1=[O:45])[CH:22]([O:23][C:24]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)[OH:53])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCCCOCC(COC(c1ccccc1)(c1ccccc1)c1ccccc1)NC(=O)CCC(=O)O
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: CCCCCCCCCCCCCCCCCCOCC(C(O)OC(c1ccccc1)(c1ccccc1)c1ccccc1)N1C(=O)CCC1=O
Temperature: 100 °C

Procedure:
A mixture of 2.21 g of the carboxyl compound obtained in Example 8 and 0.45 g of sodium acetate in 10 ml of acetic anhydride was heated at 100° C. for 2 hours, and the mixture was concentrated under reduced pressure. n-Hexane was added to the mixture and the insoluble matter was filtered off. The filtrate was concentrated to dryness to give a crude product of 3-octadecyloxy-2-succinimido-1-trityloxypropanol. This crude trityl compound in 20 ml of 70% acetic acid was heated at 100° C. for 2 hours. The reaction mixture was concentrated to dryness and the residue was purified by silica gel chromatography (chloroform-methanol=20:1) to give 1.316 g (95%) of the desired compound as a colorless powder.
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:35])=[C:4]([NH:8][C:9]2[N:14]3[N:15]=[CH:16][C:17]([C:18](O)=[O:19])=[C:13]3[N:12]=[CH:11][C:10]=2[C:21]([N:23]2[CH2:28][CH2:27][CH:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:25][CH2:24]2)=[O:22])[CH:5]=[CH:6][CH:7]=1.[CH:36]1([S:39]([NH2:42])(=[O:41])=[O:40])[CH2:38][CH2:37]1>>[F:1][C:2]1[C:3]([CH3:35])=[C:4]([NH:8][C:9]2[N:14]3[N:15]=[CH:16][C:17]([C:18]([NH:42][S:39]([CH:36]4[CH2:38][CH2:37]4)(=[O:41])=[O:40])=[O:19])=[C:13]3[N:12]=[CH:11][C:10]=2[C:21]([N:23]2[CH2:28][CH2:27][CH:26]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH2:25][CH2:24]2)=[O:22])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(F)cccc1Nc1c(C(=O)N2CCC(c3ccccc3)CC2)cnc2c(C(=O)O)cnn12
Reactant: NS(=O)(=O)C1CC1
Product: Cc1c(F)cccc1Nc1c(C(=O)N2CCC(c3ccccc3)CC2)cnc2c(C(=O)NS(=O)(=O)C3CC3)cnn12
Yield: 11.3 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-(3-fluoro-2-methylphenylamino)-6-(4-phenylpiperidine-1-carbonyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (125 mg, 0.26 mmol) obtained in Example 55, step 2 and cyclopropanesulfonamide (160 mg, 1.32 mmol), the title compound (17 mg, 11%) was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[C:4]#[N:5].C(=O)(O)[O-].[Na+].[I:16]Cl>C(Cl)Cl.CO>[NH2:1][C:2]1[C:3]([C:4]#[N:5])=[C:6]([F:10])[C:7]([I:16])=[CH:8][CH:9]=1
Reactant: ClI
Reactant: N#Cc1c(N)cccc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: N#Cc1c(N)ccc(I)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 43.4 %

Procedure:
To a solution of 2-amino-6-fluorobenzonitrile (3 g, 0.022 mol) in CH2Cl2 (200 mL) and MeOH (50 mL) was added sodium bicarbonate (3.7 g, 0.044 mmol) and ICl (3.75 g, 0.023 mol) in CH2Cl2 (20 mL). The suspension was stirred at room temperature for 2 h. The reaction mixture was concentrated and the residue was partitioned between CH2Cl2 and water. The organic layer was washed with Na2S2O3, water, and brine. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The crude material was triturated with ether. Filtration gave the title compound as a brown solid (2.5 g, 43% yield). LC/MS: Example 104A @ 2.86 min (RT) (Condition G). MS (ES): m/z=262.93, [M+H]+. 1H NMR (400 MHz, CDCl3) δ ppm 7.60 (1 hr, dd, J=8.78, 7.03 Hz), 6.39 (1 hr, d, J=8 Hz).
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7](Br)=[CH:8][N:9]=1)(=[O:3])[CH3:2].[NH2:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14]([SH:18])[N:13]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:1]([NH:4][C:5]1[S:6][C:7]([S:18][C:14]2[N:13]=[C:12]([NH2:11])[CH:17]=[CH:16][N:15]=2)=[CH:8][N:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ncc(Br)s1
Reactant: Nc1ccnc(S)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1ncc(Sc2nccc(N)n2)s1
Temperature: 90 °C
Yield: 48.9 %

Procedure:
A mixture of 2-acetylamino-5-bromothiazole (2.2 g), 4-amino-2-mercaptopyrimidine (1.3 g) and potassium carbonate (2.0 g) in N,N-dimethylformamide (50 ml) was heated at 90° C. for 2 hours with stirring. The reaction mixture was concentrated under reduced pressure and the residue was triturated with water. The precipitation was collected by filtration, washed with water and dried in vacuo to give solid. The solid was subjected to column chromatography on silica gel (silica gel 60, 70-230 mesh; Merck: 200 g) and eluted with a mixture of chloroform and methanol (10:1). The fractions containing the objective compound were combined and concentrated under reduced pressure no give 2-acetylamino-5-(4-aminopyrimidin-2-ylthio)thiazole (1.3 g, yield: 48.7%).
Reaction SMILES: [C:1]([C:6]1([C:9]([OH:11])=O)[CH2:8][CH2:7]1)([O:3][CH2:4][CH3:5])=[O:2].ClC(OCC)=O.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=1.C(N(CC)CC)C>>[F:26][C:25]([F:27])([F:28])[C:22]1[CH:21]=[CH:20][C:19]([NH:18][C:9]([C:6]2([C:1]([O:3][CH2:4][CH3:5])=[O:2])[CH2:7][CH2:8]2)=[O:11])=[CH:24][CH:23]=1
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)C1(C(=O)O)CC1
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)C1(C(=O)Nc2ccc(C(F)(F)F)cc2)CC1
Yield: 50 %

Procedure:
1-Carboethoxycyclopropanecarboxylic acid (9.81 grams, 0.06 mole), ethyl chloroformate (6.73 grams, 0.06 mole) and 4-aminobenzotrifluoride (10.0 grams, 0.06 mole) were reacted sequentially in the presence of triethylamine (6.28 grams, 0.06 mole) in a manner similar to that described in Example XXXIII to give 10.25 grams (0.03 mole) of ethyl 1-(4-trifluoromethylphenylaminocarbonyl)cyclopropanecarboxylate having a melting point of 80.5° C.-82.0° C.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5](=[O:15])[C:6](=[O:14])[C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1.CS(O[CH2:21][CH2:22][O:23][C:24]1[CH:33]=[CH:32][C:31]2[C:26](=[C:27]([O:34][C:35](=[O:41])[C:36]([CH3:40])([CH3:39])[CH2:37][CH3:38])[CH:28]=[CH:29][CH:30]=2)[CH:25]=1)(=O)=O>CN(C)C=O.[Cl-].[Na+].O>[CH3:3][O:4][C:5](=[O:15])[C:6](=[O:14])[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:21][CH2:22][O:23][C:24]2[CH:33]=[CH:32][C:31]3[C:26](=[C:27]([O:34][C:35](=[O:41])[C:36]([CH3:39])([CH3:40])[CH2:37][CH3:38])[CH:28]=[CH:29][CH:30]=3)[CH:25]=2)=[CH:9][CH:8]=1
Reactant: CCC(C)(C)C(=O)Oc1cccc2ccc(OCCOS(C)(=O)=O)cc12
Reactant: COC(=O)C(=O)c1ccc(O)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCC(C)(C)C(=O)Oc1cccc2ccc(OCCOc3ccc(C(=O)C(=O)OC)cc3)cc12
Temperature: 60 °C
Yield: 40.4 %

Procedure:
To a stirred suspension of sodium hydride (55% dispersion in mineral oil, 0.105 g) in dimethylformamide (5 mL) was added dropwise a solution of 4-hydroxy-alpha-oxobenzene acetic acid methyl ester (0.432 g) in dimethylformamide (5 mL) under argon. The mixture was then treated dropwise with a solution of 2-[8-(2,2-dimethyl-1-oxobutoxy)-2naphthalenyloxy]ethyl methanesulfonate (0.76 g) in dimethylformamide (5 mL). The reaction was heated for 18 hours at 60° C., diluted with brine, and extracted with ethyl acetate. After evaporation of volatiles, the residue was purified by chromatography over silica gel (hexane-ethyl acetate; 10: 1) to yield 0.375 g of 4-[[2-[8-(2,2-dimethyl-1-oxobutoxy)-2-naphthalenyloxy]ethyl]oxy]-alpha-oxobenzeneacetic acid methyl ester as a white solid, mp 119°-120° C.