Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([S:9][CH3:10])[N:3]=1.[F:11][CH:12]([F:25])[C:13]1[NH:17][C:16]2[CH:18]=[CH:19][CH:20]=[C:21]([O:22][CH2:23][CH3:24])[C:15]=2[N:14]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Cl:8][C:6]1[N:5]=[C:4]([S:9][CH3:10])[N:3]=[C:2]([N:17]2[C:16]3[CH:18]=[CH:19][CH:20]=[C:21]([O:22][CH2:23][CH3:24])[C:15]=3[N:14]=[C:13]2[CH:12]([F:11])[F:25])[CH:7]=1
Reactant: CSc1nc(Cl)cc(Cl)n1
Reactant: CCOc1cccc2[nH]c(C(F)F)nc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1cccc2c1nc(C(F)F)n2-c1cc(Cl)nc(SC)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.9 %

Procedure:
A mixture of 4,6-dichloro-2-(methylsulfanyl)pyrimidine (700 mg), 2-(difluoromethyl)-4-ethoxy-1H-benzimidazole (761 mg), potassium carbonate (744 mg), and N,N-dimethylformamide (7 mL) was stirred at room temperature overnight. To the mixture was added water, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The desiccant was removed by filtration and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=100:0-80:20) to obtain 1-[6-chloro-2-(methylsulfanyl)pyrimidin-4-yl]-2-(difluoromethyl)-4-ethoxy-1H-benzimidazole (464 mg) (Preparation Example 86-1) and 1,1′-[2-(methylsulfanyl)pyrimidine-4,6-diyl]bis[2-(difluoromethyl)-4-ethoxy-1H-benzimidazole]. 1,1′-[2-(Methylsulfanyl)pyrimidine-4,6-diyl]bis[2-(difluoromethyl)-4-ethoxy-1H-benzimidazole] was suspended in ethyl acetate and warmed. After leaving to be cooled, the insoluble matter was collected by filtration to obtain 1,1′-[2-(methylsulfanyl)pyrimidine-4,6-diyl]bis[2-(difluoromethyl)-4-ethoxy-1H-benzimidazole] (275 mg) (Preparation Example 86-2).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([Br:7])[N:6]=1.[CH:8]12[NH:15][CH:12]([CH2:13][CH2:14]1)[CH2:11][O:10][CH2:9]2.CCN(C(C)C)C(C)C>CN(C=O)C>[Br:7][C:5]1[N:6]=[C:2]([N:15]2[CH:8]3[CH2:14][CH2:13][CH:12]2[CH2:11][O:10][CH2:9]3)[S:3][CH:4]=1
Reactant: C1CC2COCC1N2
Reactant: Brc1csc(Br)n1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Brc1csc(N2C3CCC2COC3)n1
Temperature: 80 °C
Reaction time: 18 h
Yield: 46.7 %

Procedure:
To a stirred solution of 2,4-dibromothiazole (0.585 g, 2.41 mmol) in DMF (10 ml) were added 3-oxa-8-azabicyclo[3.2.1]octane (prepared according to the procedure given in WO 2010/120854, 0.3 g, 2.65 mmol) and DIPEA (0.47 gm, 0.63 ml, 3.62 mmol) under a stream of nitrogen. The reaction mixture was then stirred at 80° C. for 18 hrs and the progress of reaction was monitored by TLC. The reaction mixture was cooled to room temperature; quenched with cold water (20 ml) and extracted with ethyl acetate (3×30 ml). The combined organic layer was washed with water (2×10 ml), dried over sodium sulphate and concentrated to give crude compound; which was purified by flash column chromatography using 20% ethyl acetate in hexanes as an eluent to obtain the title compound (0.31 g, 46.7%). MS: m/z 276 (M+1).
Reaction SMILES: C([O:4][C:5]1[CH:10]=[C:9]([I:11])[CH:8]=[CH:7][C:6]=1[O:12][CH:13]([CH3:15])[CH3:14])(=O)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.C(OCC)C>CO.C1COCC1.[Li+].[OH-]>[I:11][C:9]1[CH:8]=[CH:7][C:6]([O:12][CH:13]([CH3:15])[CH3:14])=[C:5]([OH:4])[CH:10]=1
Reactant: CC(=O)Oc1cc(I)ccc1OC(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CO
Product: CC(C)Oc1ccc(I)cc1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 82.7 %

Procedure:
To a solution of 5-iodo-2-isopropoxyphenyl acetate (10 mmol) in MeOH (5 mL) and THF (15 mL), LiOH (1.0 M, 15 mL) was added at 0° C. After the mixture was stirred at rt for 3.0 h, 5% citric acid (30 mL) and diethyl ether (150 mL) was added. The organic extract was washed with brine, dried over Na2SO4 and evaporated to give 5-iodo-2-isopropoxyphenol (2.3 g) as an oil.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:17][C:18]1[N:27]([CH3:28])[C:26](=[O:29])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]=1>CN(C=O)C.CCOC(C)=O>[CH3:28][N:27]1[C:26](=[O:29])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]=[C:18]1[CH2:17][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: Cn1c(CCl)nc2ccccc2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cn1c(COc2ccc(C=O)cc2)nc2ccccc2c1=O
Temperature: 30 °C
Reaction time: 0.25 h
Yield: 71.9 %

Procedure:
A mixture of 4-hydroxybenzaldehyde (3.21 g, 26.3 mmol) and K2CO3 (3.64 g, 26.3 mmol) in dry DMF (50 ml) was stirred for 15 min at 30° C. To the above stirred mixture a solution of 2-chloromethyl-3-methyl-4-oxo-3,4-dihydroquinazoline (5.0 g, 24.0 mmol) was added and stirred further for 90 minutes at the same temperature. The reaction mixture was diluted with EtOAc (200 ml), washed with aqueous Na2CO3 solution (3×50 ml) and then with brine dried over anhydrous Na2SO4 and concentrated to yield the title compound (5.08 g, 72%).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([S:10]([N:13]([CH2:42][CH:43]([CH3:45])[CH3:44])[CH2:14][C@@H:15]([OH:41])[C@@H:16]([NH:29][C:30](=[O:40])[O:31][C@@H:32]3[C@H:39]4[C@H:35]([O:36][CH2:37][CH2:38]4)[O:34][CH2:33]3)[CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27]I)=[CH:20][CH:19]=3)(=[O:12])=[O:11])=[CH:9][C:4]=2[O:3][CH2:2]1.[S:46]1[CH2:50][CH2:49][NH:48][CH2:47]1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([S:10]([N:13]([CH2:42][CH:43]([CH3:45])[CH3:44])[CH2:14][C@@H:15]([OH:41])[C@@H:16]([NH:29][C:30](=[O:40])[O:31][C@@H:32]3[C@H:39]4[C@H:35]([O:36][CH2:37][CH2:38]4)[O:34][CH2:33]3)[CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][N:48]4[CH2:49][CH2:50][S:46][CH2:47]4)=[CH:20][CH:19]=3)(=[O:12])=[O:11])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: C1CSCN1
Reactant: CC(C)CN(C[C@@H](O)[C@H](Cc1ccc(OCCCI)cc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc2c(c1)OCO2
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)CN(C[C@@H](O)[C@H](Cc1ccc(OCCCN2CCSC2)cc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 66.3 %

Procedure:
A solution of 35 mg (0.046 mmol) of (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl (1S,2R)-3-[(1,3-benzodioxol-5-ylsulfonyl)(isobutyl)amino]-2-hydroxy-1-[4-(3-iodopropoxy)benzyl]propylcarbamate, 11 μL (0.14 mmol) of thiazolidine, and 32 μL (0.18 mmol) of N,N-diisopropylethylamine in 0.5 mL of anhydrous DMF was heated to 80° C. with stirring. After 1.5 hours TLC indicated the reaction to be complete. The solution was cooled to RT and concentrated in vacuo. The residue was subjected to flash chromatography (SiO2, 95:5 CH2Cl2/MeOH) to afford 22 mg (67%) of the desired compound as a white foam. 1H NMR (CDCl3): 7.29 (d, 1H), 7.13 (s, 1H), 7.08 (d, 2H), 7.85 (d, 1H), 6.77 (d, 2H), 6.04 (s, 2H), 5.60 (d, 1H), 5.00 (q, 1H), 4.88 (d, 1H), 4.01 (s, 2H), 4.00-3.88 (m, 3H), 3.80 (m, 3H), 3.67 (m, 2H), 3.55 (br s, 1H), 3.19-3.01 (m, 4H), 3.00-2.65 (m, 7H), 2.52 (t, 2H), 1.93 (m, 2H), 1.79 (m, 1H), 1.70-1.42 (m, 2H), 0.89 (d, 3H), 0.83 (d, 3H). MS(ESI): 722(M+H).
Reaction SMILES: [BrH:1].[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([C:11]([C:19]2[CH:24]=[CH:23][C:22]([CH2:25]OCCC(C)C)=[CH:21][CH:20]=2)=[CH:12][C@@H:13]2[NH:17][C:16](=[O:18])[CH2:15][CH2:14]2)=[N:7][C:8]=1[O:9]C.C(=O)(O)[O-].[Na+].O>C(#N)C>[Br:1][CH2:25][C:22]1[CH:23]=[CH:24][C:19]([C:11]([C:6]2[NH:7][C:8](=[O:9])[C:3]([Cl:2])=[CH:4][CH:5]=2)=[CH:12][C@H:13]2[CH2:14][CH2:15][C:16](=[O:18])[NH:17]2)=[CH:20][CH:21]=1
Reactant: COc1nc(C(=C[C@H]2CCC(=O)N2)c2ccc(COCCC(C)C)cc2)ccc1Cl
Reactant: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: O=C1CC[C@H](C=C(c2ccc(CBr)cc2)c2ccc(Cl)c(=O)[nH]2)N1
Temperature: 70 °C
Reaction time: 3 h
Yield: 85 %

Procedure:
48% hydrobromic acid (4 mL) was added to a solution of (5R)-5-[2-(5-chloro-6-methoxypyridin-2-yl)-2-{4-[(3-methylbutoxy)methyl]phenyl}ethenyl]pyrrolidin-2-one (E:Z=1:2 mixture) (396 mg) in acetonitrile (4 mL) at room temperature, and the mixture was stirred at 70° C. for three hours. Saturated aqueous sodium bicarbonate and water were sequentially added to the reaction solution at room temperature, followed by extraction with chloroform. The organic layers were dried over anhydrous sodium sulfate and filtered. The solvent was then evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:methanol=50:1→5:1) to give 6-{1-[4-(bromomethyl)phenyl]-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}-3-chloropyridin-2(1H)-one (E:Z=1:2 mixture) (321 mg, 85%).
Reaction SMILES: C([O:4][CH:5]1[CH2:18][O:17][C:16]2[C:15]3[CH:14]=[CH:13][CH:12]=[N:11][C:10]=3[N:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:8](=[O:25])[C:7]=2[CH2:6]1)(=O)C>CO>[OH:4][CH:5]1[CH2:18][O:17][C:16]2[C:15]3[CH:14]=[CH:13][CH:12]=[N:11][C:10]=3[N:9]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:8](=[O:25])[C:7]=2[CH2:6]1
Reactant: CC(=O)OC1COc2c(c(=O)n(-c3ccccc3)c3ncccc23)C1
Solvent: CO
Product: O=c1c2c(c3cccnc3n1-c1ccccc1)OCC(O)C2

Procedure:
Hydrolysis of the product of Example 4 with methanol:1.0N sodium hydroxide solution followed by recrystallization of the resultant product from methanol yields the title compound, m.p. 296°-298° C.
Reaction SMILES: [OH:1][C@@H:2]1[C@@H:21]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH2:20][C@@:19]2([CH3:28])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:18]2[CH2:17][CH2:16][C@@:15]2([CH3:29])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:12](=[O:14])[CH3:13])[CH2:3]1.Cl.C(Cl)(=O)C.[Br:35]Br.C(=O)([O-])[O-].[Na+].[Na+]>CO.O>[Br:35][CH2:13][C:12](=[O:14])[C@@H:11]1[C@:15]2([CH3:29])[C@H:8]([C@H:7]3[C@H:18]([CH2:17][CH2:16]2)[C@:19]2([CH3:28])[C@H:4]([CH2:3][C@H:2]([OH:1])[C@@H:21]([N:22]4[CH2:23][CH2:24][O:25][CH2:26][CH2:27]4)[CH2:20]2)[CH2:5][CH2:6]3)[CH2:9][CH2:10]1
Reactant: BrBr
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)[C@@H](N5CCOCC5)C[C@]4(C)[C@H]3CC[C@]12C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CC(=O)Cl
Product: C[C@]12C[C@H](N3CCOCC3)[C@@H](O)C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](C(=O)CBr)CC[C@@H]12
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a stirred suspension of 100 g of (2β,3α,5α)-3-hydroxy-2-(4-morpholinyl)pregnan-20-one, prepared according to British Patent 1,039,441, in 2.5 l of methanol were added 81 ml of 3M methanolic hydrogen chloride and 10 ml of acetyl chloride. Bromine (16.6 ml) in 1 l of methanol was added dropwise over 1.5 h. The mixture was stirred at room temperature for a further 20 min and then poured into 18 l of water. Aqueous sodium carbonate solution was added until the pH exceeded 9.0 and the precipitated solid was filtered, washed with water and dissolved in dichloromethane. The solution was dried over sodium sulfate, the solvent removed, and the residue crystallized from acetone-hexane to give 46 g of (2β,3α,5α)-21-bromo-3-hydroxy-2-(4-morpholinyl)pregnan-20-one. 5.0 g of this 21-bromo compound were dissolved in 50 ml of 1-methyl-2-pyrrolidinone and 2.5 g of lithium chloride were added. The mixture was stirred at 80° C. under nitrogen for 2 h, cooled to room temperature and poured into 500 ml of water. The precipitated solid was filtered off, washed with water and dissolved in dichloromethane. The solution was dried over sodium sulfate, the solvent removed, and the residue crystallized from acetone-hexane to give 2 g of (2β,3α,5α)-21-chloro-3-hydroxy-2-(4-morpholinyl)pregnan-20-one as in Example 1.
Reaction SMILES: [ClH:1].[NH2:2][C@H:3]([C:21]([OH:23])=[O:22])[CH2:4][CH2:5][C:6]([NH:8][C@@H:9]([C:14]([NH:16][CH2:17][C:18]([OH:20])=[O:19])=[O:15])[C:10]([SH:13])([CH3:12])[CH3:11])=[O:7].[N:24](OCC)=[O:25].Cl.CO>CO.C(O)C>[ClH:1].[NH2:2][C@H:3]([C:21]([OH:23])=[O:22])[CH2:4][CH2:5][C:6]([NH:8][C@H:9]([C:14]([NH:16][CH2:17][C:18]([OH:20])=[O:19])=[O:15])[C:10]([S:13][N:24]=[O:25])([CH3:11])[CH3:12])=[O:7]
Reactant: CCON=O
Reactant: CC(C)(S)[C@@H](NC(=O)CC[C@H](N)C(=O)O)C(=O)NCC(=O)O
Agent: Cl
Solvent: CCO
Solvent: CO
Product: CC(C)(SN=O)[C@H](NC(=O)CC[C@H](N)C(=O)O)C(=O)NCC(=O)O
Reaction time: 0.5 h

Procedure:
To the solution of (N-γ-L-glutamyl-D-penicillamyl)glycine hydrochloride (0.5 g) in methanol (5 ml), was added at 0° C. the solution of ethyl nitrite in ethanol (10%) (1.1 ml). At the same temperature a drop of 4N-hydrochloric acid-methanol solution was added, and the mixture was stirred for 30 minutes. The solvent was evaporated off under reduced pressure, and the resultant crystals were washed with diethyl ether, to give (N-γ-L-glutamyl-S-nitroso-L-penicillamyl)glycine hydrochloride (0.5 g).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6](C(Br)C)[N:5]=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+]>CS(C)=O.O>[Cl:1][C:2]1[CH:3]=[CH:4][N:5]=[C:6]2[CH:11]([CH3:12])[O:10][C:8](=[O:9])[C:7]=12
Reactant: CCOC(=O)c1c(Cl)ccnc1C(C)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC1OC(=O)c2c(Cl)ccnc21

Procedure:
A mixture of ethyl 4-chloro-2-(1-bromoethyl)nicotinate (7.45 g) and sodium bicarbonate (4.00 g) in 50 ml of DMSO is heated at 120°, under nitrogen, for 2 hours, after which it is cooled, diluted with water, filtered and extracted with ether. The combined organic layers are washed with water and concentrated. The residue is taken into ethyl acetate, washed with brine, dried, concentrated and purified by flash chromatography to give 4-chloro-7-methylfuro-[3,4-b]-pyridin-5-(7H)-one, which is then reacted with N-bromosuccinimide and 2,2'-azobis(2-methylpropionitrile), as above, to give 7-bromo-4-chloro-7-methylfuro-[3,4-b]-pyridin-5-(7H)-one.
Reaction SMILES: [S:1]1[C:7]2[CH:8]=[CH:9][S:10][C:6]=2[C:5](=S)[NH:4][CH2:3][CH2:2]1.Br[CH:13]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15].C(=O)([O-])O.[K+]>C(Cl)Cl>[S:1]1[C:7]2[C:8](=[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:9][S:10][C:6]=2[CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)C(Br)C(=O)OCC
Reactant: S=C1NCCSc2ccsc21
Agent: O=C([O-])O
Agent: [K+]
Solvent: ClCCl
Product: CCOC(=O)C(C(=O)OCC)=C1CSC2=C1SCCNC2
Reaction time: 2.5 h

Procedure:
(ca) 8.05 g of 3,4-dihydro-thieno[2,3-f][1,4]thiazepine-5(2H)-thione were suspended in 40 ml of methylene chloride and treated under argon with a solution of 7.1 ml of diethyl bromomalonate in 40 ml of methylene chloride. After stirring for 2.5 hours, 50 ml of 10 percent potassium hydrogen carbonate solution were added thereto and the mixture was stirred for 30 minutes. The organic phase was separated and the aqueous phase was extracted twice with methylene chloride. After drying with sodium sulfate, the extract was chromatographed on silica gel, whereby diethyl [3,4-dihydrothieno[2,3-f][1,4]thiazepine-8-(5H)-ylidene]malonate was obtained in the form of slightly yellowish crystals of m.p. 87°-89° (cyclohexane).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Br[CH2:8][C:9]([C:11]1[CH:12]=[CH:13][C:14]([O:31][CH2:32][CH2:33][CH3:34])=[C:15]([C:17]2[NH:18][C:19](=[O:30])[C:20]3[N:25]([CH3:26])[N:24]=[C:23]([CH2:27][CH2:28][CH3:29])[C:21]=3[N:22]=2)[CH:16]=1)=[O:10]>>[CH3:26][N:25]1[C:20]2[C:19](=[O:30])[NH:18][C:17]([C:15]3[CH:16]=[C:11]([C:9](=[O:10])[CH2:8][N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)[CH:12]=[CH:13][C:14]=3[O:31][CH2:32][CH2:33][CH3:34])=[N:22][C:21]=2[C:23]([CH2:27][CH2:28][CH3:29])=[N:24]1
Reactant: CCCOc1ccc(C(=O)CBr)cc1-c1nc2c(CCC)nn(C)c2c(=O)[nH]1
Reactant: C1COCCN1
Product: CCCOc1ccc(C(=O)CN2CCOCC2)cc1-c1nc2c(CCC)nn(C)c2c(=O)[nH]1
Yield: 47 %

Procedure:
This compound was prepared from morpholine and 5-(5-bromoacetyl-2-n-propoxyphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo [4,3-d]pyrimidin-7-one (Preparation 11), following the procedure of Example 1, and was obtained as white crystals (47%), m.p. 128°-129° C. Found C,63.62; H,7.07; N,15.53. C24H31N5O4 requires C,63.56; H,6.89; N,15.44.%
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:9])=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[C:10]1([CH3:20])[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1>N1C=CC=CC=1>[Cl:1][C:2]1[C:3]([CH3:9])=[C:4]([NH:5][S:16]([C:13]2[CH:14]=[CH:15][C:10]([CH3:20])=[CH:11][CH:12]=2)(=[O:18])=[O:17])[CH:6]=[CH:7][CH:8]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1c(N)cccc1Cl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Nc2cccc(Cl)c2C)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.4 %

Procedure:
18.7 g of 3-chloro-2-methylaniline was dissolved in 120 mL of pyridine, and 22.9 g of p-toluene sulfonylchloride was added portionwise thereto over 30 minutes, followed by stirring at room temperature overnight. The reaction liquid was concentrated under reduced pressure, and to the obtained residue was added water, followed by extraction with ethyl acetate. The organic layer was washed with 1 M hydrochloric acid, saturated brine, an aqueous saturated sodium hydrogen carbonate solution, and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain 34.6 g of N-(3-chloro-2-methylphenyl)-4-methylbenzenesulfonamide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([CH2:7][N:8]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][NH:27][C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.Br[C:42]1[CH:47]=[CH:46][C:45]([C:48]([N:50]2[CH2:55][CH2:54][N:53]([CH2:56][CH2:57][OH:58])[CH2:52][CH2:51]2)=[O:49])=[CH:44][C:43]=1[CH3:59]>>[CH3:38][O:37][C:34]1[CH:33]=[CH:32][C:31]([CH2:30][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:40][CH:39]=2)[C:9]2[N:10]=[CH:11][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:42]5[CH:47]=[CH:46][C:45]([C:48]([N:50]6[CH2:51][CH2:52][N:53]([CH2:56][CH2:57][OH:58])[CH2:54][CH2:55]6)=[O:49])=[CH:44][C:43]=5[CH3:59])[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:13][N:14]=2)=[CH:36][CH:35]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4)cn2)cc1
Reactant: Cc1cc(C(=O)N2CCN(CCO)CC2)ccc1Br
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(C(=O)N4CCN(CCO)CC4)cc3C)cn2)cc1

Procedure:
Using bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (100 mg) and (4-bromo-3-methyl-phenyl)-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-methanone (168 mg) instead of 4-chloropicolinic acid t-butylamide, in the same manner as Example 1-D-07, a crude product of [4-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-3-methyl-phenyl]-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-methanone was obtained, and then the PMB groups were removed according to the above Deprotection method 3, to obtain the desired compound (D-147) as a pale yellow powder (28 mg, 28%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:32][CH:33]([F:35])[F:34])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][CH2:26][NH:27][CH2:28][CH2:29]SC)[N:9]=2)[CH:7]=1.Br[CH2:37][CH2:38][N:39]1[CH:43]=[C:42](NC(C2C=NN3C=CC=NC=23)=O)C(C2C=C(Cl)C=CC=2OC(F)F)=N1.N1C=CC(CN)=CC=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:32][CH:33]([F:35])[F:34])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][CH2:26][NH:27][CH2:28][C:29]3[CH:42]=[CH:43][N:39]=[CH:38][CH:37]=3)[N:9]=2)[CH:7]=1
Reactant: O=C(Nc1cn(CCBr)nc1-c1cc(Cl)ccc1OC(F)F)c1cnn2cccnc12
Reactant: CSCCNCCn1cc(NC(=O)c2cnn3cccnc23)c(-c2cc(Cl)ccc2OC(F)F)n1
Agent: NCc1ccncc1
Product: O=C(Nc1cn(CCNCc2ccncc2)nc1-c1cc(Cl)ccc1OC(F)F)c1cnn2cccnc12

Procedure:
Using synthetic method analogous to that of N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-(2-[[2-(methylsulfanyl)ethyl]amino]ethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide, the title compound was prepared from N-[1-(2-bromoethyl)-3-[5-chloro-2-(difluoromethoxy)phenyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide and pyridin-4-ylmethanamine. LCMS (Method 25) [M+H]+=539.1, RT=1.45 min. 1H NMR (400 MHz, DMSO-d6) δ: (ppm) 9.74 (s, 1H), 9.34 (dd, 1H, J=1.6, 6.8 Hz), 8.68 (dd, 1H, J=1.6, 4.4 Hz), 8.45 (d, 2H, J=6.0 Hz), 8.38 (s, 1H), 7.64-7.59 (m, 2H), 7.44 (d, 1H, J=8.8 Hz), 7.32-7.28 (m, 3H), 7.07 (t, 1H, J=73.2 Hz), 4.26 (t, 2H, J=6.0 Hz), 3.76 (s, 2H), 2.93 (t, 2H, J=6.0 Hz).
Reaction SMILES: [CH2:1]([NH:5][C:6](=[O:39])[C:7]([CH2:30][CH2:31][O:32][CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][O:34]1)=[CH:8][C@@H:9]1[O:13]C(C)(C)[N:11](C(OCC2C=CC=CC=2)=O)[C@H:10]1[CH2:26][CH:27]([CH3:29])[CH3:28])[CH:2]([CH3:4])[CH3:3]>C(O)C.[Pd]>[CH2:1]([NH:5][C:6](=[O:39])[CH:7]([CH2:30][CH2:31][O:32][CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][O:34]1)[CH2:8][C@H:9]([OH:13])[C@@H:10]([NH2:11])[CH2:26][CH:27]([CH3:29])[CH3:28])[CH:2]([CH3:3])[CH3:4]
Reactant: CC(C)CNC(=O)C(=C[C@@H]1OC(C)(C)N(C(=O)OCc2ccccc2)[C@H]1CC(C)C)CCOC1CCCCO1
Agent: [Pd]
Solvent: CCO
Product: CC(C)CNC(=O)C(CCOC1CCCCO1)C[C@H](O)[C@@H](N)CC(C)C
Yield: 92.7 %

Procedure:
101 mg of 3-[(4S,5S)-3-benzyloxycarbonyl-2,2-dimethyl-4-isobutyloxazolidin-5-yl]-2-[2-(2-tetrahydropyranyloxy)ethyl]-2-propenoic acid isobutylamide in 1 ml of ethanol and hydrogenated by using palladium black under atmospheric pressure. The reaction mixture was subjected to filtration, and the solvent was distilled off from the filtrate under reduced pressure to obtain 64 mg of (2RS,4S,5S)-5-amino-4-hydroxy-2-[2-(2-tetrahydropyranyloxy)ethyl]-7-methyl-octanoic acid isobutylamide as a colorless oily substance.
Reaction SMILES: [N+:1]([C:4]1[C:5]([C:17]#[N:18])=[C:6]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:7]2=[C:8]([CH:16]=1)[CH2:9][O:10][CH2:11]3)([O-])=O.[Sn]Cl.Cl.[OH-].[Na+]>COCCOCCOC>[NH2:1][C:4]1[C:5]([C:17]#[N:18])=[C:6]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:7]2=[C:8]([CH:16]=1)[CH2:9][O:10][CH2:11]3
Reactant: N#Cc1c([N+](=O)[O-])cc2c3c(cccc13)COC2
Agent: Cl
Agent: Cl[Sn]
Agent: [Na+]
Solvent: COCCOCCOC
Product: N#Cc1c(N)cc2c3c(cccc13)COC2
Temperature: 5 °C
Reaction time: 2 h

Procedure:
5-Nitro-6-cyano-1H,3H benzo[de]isochromene (14.3 g, 59.5 mmol) was dissolved in diglyme (297 mL). The reaction vessel was cooled in an ice bath, and a mixed solution of tin (I) chloride (45.1 g, 238 mmol) and concentrated hydrochloric acid (159 mL) was added slowly while the internal temperature was kept below 5° C. The reaction solution was stirred at 5° C. for 2 hours, and then added to a mixture of 50% aqueous sodium hydroxide solution (476 mL) and ice (1400 mL) while stirring vigorously. The precipitate was collected by filtration, and then dissolved in ethyl acetate. The solution was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography using ethyl acetate, and dried under reduced pressure. The title compound was obtained as pale yellow solid (6.7 g, 53%).
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([CH3:4])=[CH2:3].[CH2:7]([O:11][CH2:12][C:13]1[O:17][CH:16]=[CH:15][CH:14]=1)[CH:8]1[O:10][CH2:9]1>CCOCC>[C:1]([O:6][CH2:9][CH:8]([OH:10])[CH2:7][O:11][CH2:12][C:13]1[O:17][CH:16]=[CH:15][CH:14]=1)(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: c1coc(COCC2CO2)c1
Reactant: C=C(C)C(=O)O
Solvent: CCOCC
Product: C=C(C)C(=O)OCC(O)COCc1ccco1
Temperature: 100 °C
Reaction time: 2 h
Yield: 94.8 %

Procedure:
A mixture of methacrylic acid (10 g), furfuryl glycidyl ether (15 g) and triethylaminc (0.3 g) was heated to 100° C. for 2 hours then to 105° C. for an additional 2 hours. GC analysis showed 96% conversion. The mixture was taken up into ether, washed with water, followed by saturated sodium bicarbonate, dried with MgSO4 filtered and rotary evaporated to provide 23.7 g of a faintly yellow oil (94.8%).