Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18]C=CN=3)[N:12]=[C:11]([C:20]([OH:22])=[O:21])[CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.Cl.[N:25]1C=CC(NN)=[CH:27][CH:26]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][N:25]=[CH:26][CH:27]=3)[N:12]=[C:11]([C:20]([OH:22])=[O:21])[CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: O=C(O)c1cc(-c2cc(F)cc(Cl)c2)n(-c2ccccn2)n1
Reactant: NNc1ccncc1
Agent: Cl
Product: O=C(O)c1cc(-c2cc(F)cc(Cl)c2)n(-c2ccncc2)n1

Procedure:
1.30 g (3.97 mmol) of the compound of Example 1A is reacted analogously to the synthesis of the compound of Example 20A with 1.08 g (5.95 mmol) of 4-pyridylhydrazine dihydrochloride. After hydrolysis, 9 mg (0.7% of theory) of the title compound is obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]([CH:13]([C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1)[C:14]([NH2:16])=[O:15])[C:7]2=[O:12].CN(C)C=O.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.[Cl:62][C:63]1[CH:68]=[CH:67][C:66]([C@H:69]([CH3:73])[C:70](O)=[O:71])=[CH:65][CH:64]=1>>[NH2:16][C:14](=[O:15])[CH:13]([N:6]1[CH:5]=[CH:4][C:3]2[C:8](=[CH:9][CH:10]=[CH:11][C:2]=2[NH:1][C:70](=[O:71])[C@H:69]([C:66]2[CH:67]=[CH:68][C:63]([Cl:62])=[CH:64][CH:65]=2)[CH3:73])[C:7]1=[O:12])[C:17]1[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=1
Reactant: C[C@H](C(=O)O)c1ccc(Cl)cc1
Reactant: NC(=O)C(c1ccc(Cl)cc1)n1ccc2c(N)cccc2c1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@H](C(=O)Nc1cccc2c(=O)n(C(C(N)=O)c3ccc(Cl)cc3)ccc12)c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
A round bottom flask was charged with 2-(5-amino-1-oxoisoquinolin-2(1H)-yl)-2-(4-chlorophenyl)acetamide (100 mg, 0.3 mmol), N,N-dimethylformamide (1 mL, 10 mmol), N,N-diisopropylethylamine (0.1 mL, 0.6 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (200 mg, 0.6 mmol) and (S)-2-(4-chlorophenyl)propanoic acid (68 mg, 0.37 mmol) and the reaction stirred at room temperature over night. The solvent was removed and the residue purified by flash chromatography (12 g silica gel, 0-10% MeOH/DCM) followed by preparative HPLC (reverse phase) to obtain the product as an off white solid. MS m/z=477.1 (M+H). 1H NMR (400 MHz; DMSO-d6) δ 9.97 (s, 1H), 8.12-8.10 (d, J=8.18 Hz, 1H), 8.03 (s, 1H), 7.75-7.70 (dd, J=8.18&5.63 Hz, 1H), 7.59 (s, 1H), 7.501-7.34 (m, 9H), 7.03-7.00 (d, J=8.01 Hz, 1H), 6.71 (s, 1H), 6.40-6.38 (d, J=8.27 Hz, 1H), 4.00-3.94 (q, J=6.97 Hz, 1H), 1.44-1.41 (d, J=7.11 Hz, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[O:12][CH2:11][CH2:10][C:9]2=O)([O-:3])=[O:2].[BH4-].[Na+]>C(O)C>[N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[O:12][CH2:11][CH:10]=[CH:9]2)([O-:3])=[O:2]
Reactant: O=C1CCOc2c1cccc2[N+](=O)[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: O=[N+]([O-])c1cccc2c1OCC=C2

Procedure:
A solution of 20 g of 8-nitro-4-chromanone and 3.9 g of sodium borohydride in 200 ml of ethanol is heated at reflux for 45 minutes and then evaporated to dryness. The residue is taken up in 200 ml of water and extracted three times with 250 ml of dichloromethane each time. The combined organic phases are dried over magnesium sulphate, filtered and then concentrated under reduced pressure. The liquid residue is taken up in 300 ml of toluene; 0.5 g of para-toluenesulphonic acid is then added and heating at reflux is carried out until the full amount of water expected has been recovered. After cooling, washing with a 5% sodium carbonate solution and then with water, and concentrating under reduced pressure, a liquid residue corresponding to the expected product is isolated.
Reaction SMILES: C([Si]([O:8][CH2:9][CH:10]1[CH2:14][C:13]2[CH:15]=[CH:16][CH:17]=[C:18]([O:19][CH3:20])[C:12]=2[O:11]1)(C)C)(C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.O>[CH3:20][O:19][C:18]1[C:12]2[O:11][CH:10]([CH2:9][OH:8])[CH2:14][C:13]=2[CH:15]=[CH:16][CH:17]=1
Reactant: COc1cccc2c1OC(CO[Si](C)(C)C(C)(C)C)C2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: COc1cccc2c1OC(CO)C2
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of (±)-tert-butyl[(7-methoxy-2,3-dihydro-1-benzofuran-2-yl)methoxy]dimethylsilane (34.12 g; 0.116 mol) in tetrahydrofuran (700 mL) cooled to 0° C. was added via an addition funnel tetrabutylammonium fluoride (140 mL, 1.0 M solution in tetrahydrofuran) and the reaction mixture was allowed to stir at room temperature for 6 h. The reaction was diluted with water (500 mL) and extracted with ethyl acetate (2×300 mL). The combined organic extracts were washed with saturated aqueous sodium chloride (400 mL), dried (magnesium sulfate) and the solvent was removed in vacuo to give (±)-(7-methoxy-2,3-dihydro-1-benzofuran-2-yl)methanol, a crude oil. The alcohol was dissolved in dichloromethane (700 mL) and p-toluenesulfonyl chloride (33.14 g, 0.174 mol) was added followed by triethylamine (21.11 g, 0.209 mol) and then 4-(dimethylamino)pyridine (2.12 g, 0.017 mol). The reaction mixture was allowed to stir at 50° C. for 12 h. The reaction mixture was cooled to room temperature and the solvent was removed in vacuo to give a crude solid. Purification by flash column chromatography (silica, ethyl acetate:hexanes 3:7) provided 26.45 g (68%) of (±)-(7-methoxy-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate as a white crystalline solid. Rf=0.38 (silica, ethyl acetate:hexanes 3:7); mp 98-103° C.; Anal. calcd. for C17H18O5S: C, 61.06; H, 5.43. Found: C, 60.80; H, 5.37.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]=[C:14]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[CH:13]=[CH:12][N:11]=1.C[O:23][C:24](=O)[C:25]1[CH:30]=[CH:29][C:28]([CH:31]([Cl:33])[Cl:32])=[CH:27][CH:26]=1.C[Al](C)C>C1(C)C=CC=CC=1>[Cl:32][CH:31]([Cl:33])[C:28]1[CH:27]=[CH:26][C:25]([C:24]([NH:8][C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[C:3]([NH:9][C:10]3[N:15]=[C:14]([C:16]4[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=4)[CH:13]=[CH:12][N:11]=3)[CH:4]=2)=[O:23])=[CH:30][CH:29]=1
Reactant: COC(=O)c1ccc(C(Cl)Cl)cc1
Reactant: Cc1ccc(N)cc1Nc1nccc(-c2cccnc2)n1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: Cc1ccc(NC(=O)c2ccc(C(Cl)Cl)cc2)cc1Nc1nccc(-c2cccnc2)n1
Temperature: 45 °C
Reaction time: 3.5 h

Procedure:
To a suspension of 4-methyl-N*3*-(4-pyridin-3-yl-pyrimidin-2-yl)-benzene-1,3-diamine (2.00 g mg, 7.21 mmol) in toluene (22 ml) at 45° C. under an atmosphere of argon is added sequentially 4-dichloromethyl-benzoic acid methyl ester (1.90 g, 8.67 mmol) and AlMe3 (2 M in toluene, 12.6 ml, 25.2 mmol). The resulting brown solution is stirred at 45° C. for a period of 3.5 hrs. The reaction mixture is then cooled to 0° C. and quenched by slow addition of a saturated aqueous solution of Rochelle salt (70 ml) which causes the precipitation of the crude product. t-Butyl methyl ether (150 ml) and methylene chloride (100 ml) are added sequentially to the suspension which are then washed with aqueous saturated NaHCO3 (100 ml) and aqueous saturated NaCl (100 ml). The aqueous phases are back-extracted with t-butyl methyl ether (100 ml). The crude product, which is contained in the combined organic phases, is filtered off with suction, washed with t-butyl methyl ether and dried in vacuo. Yield: 3.35 g of the title compound, 84% of theory, as beige crystals, (HPLC: 91% area).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH2:4][C:5]([NH:7][C:8]1[C:9]([C:14]([O:16]C)=O)=[N:10][CH:11]=[CH:12][CH:13]=1)=[O:6].C[O-].[Na+]>>[OH:16][C:14]1[C:9]2[C:8](=[CH:13][CH:12]=[CH:11][N:10]=2)[NH:7][C:5](=[O:6])[C:4]=1[C:3]([O:2][CH3:1])=[O:18]
Reactant: COC(=O)CC(=O)Nc1cccnc1C(=O)OC
Agent: C[O-]
Agent: [Na+]
Product: COC(=O)c1c(O)c2ncccc2[nH]c1=O
Reaction time: 0.5 h

Procedure:
To a solution of methyl 3-[(3-methoxy-3-oxopropanoyl)amino]pyridine-2-carboxylate (7.3 g, 29.9 mmol, prepared as described in example 1) in anhydrous TBF (100 mL) was added solid sodium methoxide (3.9 g, 72.4 mmol) at 0° C. Immediately following the addition of the sodium methoxide, solids crashed out of the solution. The ice bath was then removed and the suspension was stirred for an additional 0.5 hours. The suspension was then filtered through a medium porosity filtration funnel to afford yellow solids.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]([CH3:28])=[C:9]([C:12]2[NH:13][C:14]3[CH:20]=[C:19]([O:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH:18]=[CH:17][C:15]=3[N:16]=2)[C:10]=1[CH3:11])=[O:5])C.[OH-].[Na+].Cl>C(O)C.O1CCCC1>[O:21]([C:19]1[CH:18]=[CH:17][C:15]2[N:16]=[C:12]([C:9]3[C:10]([CH3:11])=[C:6]([C:4]([OH:5])=[O:3])[NH:7][C:8]=3[CH3:28])[NH:13][C:14]=2[CH:20]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCOC(=O)c1[nH]c(C)c(-c2nc3ccc(Oc4ccccc4)cc3[nH]2)c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1[nH]c(C(=O)O)c(C)c1-c1nc2ccc(Oc3ccccc3)cc2[nH]1
Temperature: 80 °C
Reaction time: 6 h
Yield: 97.9 %

Procedure:
The 4-(5-phenoxybenzimidazole-2-yl)-3,5-dimethylpyrrole-2-carboxylic acid ethyl ester (1.88 g, 5.0 mmol) obtained in Example 68 was dissolved in ethanol (10 ml) and tetrahydrofuran (5 ml). To this solution was added a 4 N sodium hydroxide aqueous solution (6 ml, 24 mmol), and the mixture was stirred at 80° C. for 6 hours. The reaction mixture was cooled to 0° C., and neutralized with a 1 N hydrochloric acid solution. The precipitate was collected by filtration, and washed with water and dried at reduced pressure to afford 4-(5-phenoxybenzimidazole-2-yl)-3,5-dimethylpyrrole-2-carboxylic acid (1.70 g, 98%) as a light yellow solid.
Reaction SMILES: [OH-].[K+].[CH3:3][C:4]([C:7]1[CH:8]=[C:9]([CH:14]=[C:15]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:16]=1[OH:17])[C:10]([NH:12][NH2:13])=[O:11])([CH3:6])[CH3:5].[C:22](=S)=[S:23]>C(O)C>[CH3:6][C:4]([C:7]1[CH:8]=[C:9]([C:10]2[O:11][C:22](=[S:23])[NH:13][N:12]=2)[CH:14]=[C:15]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:16]=1[OH:17])([CH3:3])[CH3:5]
Reactant: CC(C)(C)c1cc(C(=O)NN)cc(C(C)(C)C)c1O
Reactant: S=C=S
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)c1cc(-c2n[nH]c(=S)o2)cc(C(C)(C)C)c1O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 37.8 %

Procedure:
Potassium hydroxide (1.1 g, 0.019 mole) is added in one portion to a stirred 0° C. solution of 3,5-bis(1,1-dimethylethyl)-4-hydroxybenzoic acid hydrazide (5.0 g, 0.019 mole) and carbon disulfide (3.4 g, 0.044 mole) in absolute ethanol (60 ml). The resulting mixture is stirred 30 minutes at 0° C. before warming to room temperature and stirring one hour. The solution is then heated to reflux for 2.5 hours. The solvent is removed in vacuo and the residue dissolved in water (100 ml) and washed with ether. The aqueous layer is made acidic with 2M HCl and the product extracted with a 1:1 mixture of ethyl acetate/ether. The organic layer is washed with saturated aqueous NaCl and dried over MgSO4. Filtration and concentration gives a solid which is recrystallized from ethyl acetate/isopropyl ether to give 2.2 g (5.8 g theor., 38%) desired 5-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-1,3,4-oxadiazole-2(3H)-thione, mp 253.5° C.
Reaction SMILES: [CH3:1][Si:2]1([CH2:7][CH:8]([C:15]#[N:16])[CH2:9][C:10]([O:12]CC)=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3]1.[OH-].[Li+]>>[CH3:1][Si:2]1([CH2:7][CH:8]([C:15]#[N:16])[CH2:9][C:10]([OH:12])=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: CCOC(=O)CC(C#N)C[Si]1(C)CCCC1
Agent: [Li+]
Agent: [OH-]
Product: C[Si]1(CC(C#N)CC(=O)O)CCCC1
Yield: 100.4 %

Procedure:
Ethyl 4-(1-methyl-1-silacyclopentan-1-yl)-3-cyanobutanoate (1.306 g, 5.46 mmol) was hydrolyzed with lithium hydroxide in the same manner as that of Example 16, and then the reaction mixture was treated in a conventional manner. The residue was purified by silica gel column chromatography (2% methanol/chloroform) to obtain 4-(1-methyl-1-silacyclopentan-1-yl)-3-cyanobutanoic acid (1.158 g, quant.) mentioned in the title as colorless oil.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][N:8]2[C:16]3[C:11](=[CH:12][C:13]([NH2:17])=[CH:14][CH:15]=3)[CH:10]=[CH:9]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C[Al](C)C.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[S:30][C:31]3[C:37](=[O:38])[O:36][CH2:35][CH2:34][C:32]=3[N:33]=2)=[CH:25][CH:24]=1>C(Cl)Cl>[N:1]1([CH2:6][CH2:7][N:8]2[C:16]3[C:11](=[CH:12][C:13]([NH:17][C:37]([C:31]4[S:30][C:29]([C:26]5[CH:27]=[CH:28][C:23]([Cl:22])=[CH:24][CH:25]=5)=[N:33][C:32]=4[CH2:34][CH2:35][OH:36])=[O:38])=[CH:14][CH:15]=3)[CH:10]=[CH:9]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1OCCc2nc(-c3ccc(Cl)cc3)sc21
Reactant: Nc1ccc2c(ccn2CCN2CCCC2)c1
Agent: C[Al](C)C
Solvent: ClCCl
Product: O=C(Nc1ccc2c(ccn2CCN2CCCC2)c1)c1sc(-c2ccc(Cl)cc2)nc1CCO
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 79.2 %

Procedure:
Dissolve 1-(2-pyrrolidin-1-yl-ethyl)-1H-indol-5-ylamine (247 mg, 1.08 mmol) in CH2Cl2 (5 mL), cool to 0° C., and treat with a solution of trimethylaluminum (2.0 M in hexanes, 0.7 mL, 1.40 mmol). Stir the solution at 0° C. for 15 min and then at room temperature for 30 min. Add 2-(4-chloro-phenyl)-6,7-dihydro-pyrano[4,3-d]thiazol-4-one (272 mg, 1.02 mmol) neat and stir the reaction at room temperature overnight. Carefully quench the mixture with saturated Rochelles salt solution (5 mL) and stir at room temperature for 1 h. Dilute with additional saturated Rochelles salt solution (10 mL) and extract with CH2Cl2 (3×20 mL). Combine the organic portions, dry, filter, and concentrate under vacuum. Triturate the crude solid with diethyl ether to give the title compound as a white powder (400 mg, 75%). MS (ES+) 495.1 (M+1)+MS (ES−) 493.2 (M−1)−. 1H NMR (400 MHz, DMSO-d6): δ 10.78 (s, 1H), 8.01 (d, 2H, J=8.3 Hz), 7.92 (s, 1H), 7.60 (d, 2H, J=8.8 Hz), 7.46 (d, 1H, J=8.8 Hz), 7.40 (d, 1H, J=3.1 Hz), 7.34 (dd, 1H, J=8.8, 1.8 Hz), 6.41 (d, 1H, J=3.1 Hz), 5.84 (m, 1H), 4.26 (t, 2H, J=6.6 Hz), 3.91 (q, 2H, J=5.3 Hz), 3.21 (t, 2H, J=5.9 Hz), 2.78 (t, 2H, J=6.8 Hz), 2.46 (s, 4H), 1.65 (m, 4H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[N:7][CH:8]=1)#[N:2].C[O-].[Na+].[C:12](O)(=[O:14])C>CO.CCOCC>[CH3:12][O:14][C:1]([C:3]1[CH:4]=[N:5][CH:6]=[N:7][CH:8]=1)=[NH:2]
Reactant: CC(=O)O
Reactant: N#Cc1cncnc1
Agent: C[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CO
Product: COC(=N)c1cncnc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 76 %

Procedure:
To a stirred suspension of 5-cyanopyrimidine (5.0 g, 47 mmol) in methanol (50 mL) was added 25% by weight sodium methoxide in methanol (1.2 g, 23 mmol). The mixture was stirred at room temperature for 17 h under nitrogen atmosphere and then acetic acid (2.72 ml, 47 mmol) was added dropwise. The resulting mixture was stirred for 4 h and then evaporated under reduced pressure to remove methanol and yield a residue. The residue was dissolved in ether (150 mL) and the solids were removed by filtration. The filtrate was concentrated under reduced pressure to yield methylpyrimidine-5-carbimidate (4.9 g, 75% yield). The crude product was used without further purification. 1H NMR (400 MHz, DMSO-d6, δ): 3.83 (s, 3H); 9.18 (s, 2H); 9.30 (s, 1H); 9.54 (s, 1H). ES-MS: [M++1]=138.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[CH3:15][NH2:16]>CN(C=O)C>[CH3:9][O:8][C:6](=[O:7])[C:5]1[CH:10]=[CH:11][C:2]([NH:16][CH3:15])=[C:3]([N+:12]([O-:14])=[O:13])[CH:4]=1
Reactant: COC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CN
Solvent: CN(C)C=O
Product: CNc1ccc(C(=O)OC)cc1[N+](=O)[O-]

Procedure:
4-Methylamino-3-nitro-benzoic acid methyl ester (822 mg) was prepared by following General Procedure A using methyl 4-chloro-3-nitrobenzoate (1.0 g) and methylamine (2 M in THF, 6.95 mL) in DMF (5 mL). The crude product was used in the next step without further purification.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[C@@H:13]([O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[C@H:12]([N:22]2[CH:27]=[CH:26][C:25](=[O:28])[N:24]([CH2:29][C:30]3[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=3)[C:23]2=[O:38])[O:11][CH:10]1[C@H:39]([OH:83])[C@@H:40]([C:76]([O:78][C:79]([CH3:82])([CH3:81])[CH3:80])=[O:77])[NH:41][CH2:42][CH2:43][CH2:44][NH:45][C:46](=[O:75])[CH2:47][CH2:48][CH2:49][CH:50](C1C2C=CC=CC=2C2C1=CC=CC=2)[CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][NH:57]C(=O)OC)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>N1CCCCC1>[NH2:57][CH2:56][CH2:55][CH2:54][CH2:53][CH2:52][CH2:51][CH2:50][CH2:49][CH2:48][CH2:47][C:46]([NH:45][CH2:44][CH2:43][CH2:42][NH:41][C@@H:40]([C@H:39]([CH:10]1[C@@H:9]([O:8][Si:1]([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:2])[CH3:3])[C@@H:13]([O:14][Si:15]([C:18]([CH3:19])([CH3:20])[CH3:21])([CH3:17])[CH3:16])[C@H:12]([N:22]2[CH:27]=[CH:26][C:25](=[O:28])[N:24]([CH2:29][C:30]3[CH:31]=[CH:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=3)[C:23]2=[O:38])[O:11]1)[OH:83])[C:76]([O:78][C:79]([CH3:80])([CH3:81])[CH3:82])=[O:77])=[O:75]
Reactant: COC(=O)NCCCCCCC(CCCC(=O)NCCCN[C@H](C(=O)OC(C)(C)C)[C@@H](O)C1O[C@@H](n2ccc(=O)n(Cc3ccc(OC)cc3)c2=O)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C)C1c2ccccc2-c2ccccc21
Solvent: C1CCNCC1
Product: COc1ccc(Cn2c(=O)ccn([C@@H]3OC([C@H](O)[C@H](NCCCNC(=O)CCCCCCCCCCN)C(=O)OC(C)(C)C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]3O[Si](C)(C)C(C)(C)C)c2=O)cc1
Yield: 50.8 %

Procedure:
By using an analogous procedure to that described for Reference Example 32, a solution of tert-butyl (21S)-21-[(R)-[(3R,4R,5R)-3,4-bis{[tert-butyl(dimethyl)silyl]oxy}-5-(3-(4-methoxybenzyl)-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl)tetrahydro-2-furanyl](hydroxy)methyl]-11-(9H-fluoren-9-yl)-3,15-dioxo-2-oxa-4,16,20-triazadocosan-22-oate (106 mg, 0.09 mmol, obtained from Example 24) in piperidine (3 ml) was stirred for 1.5 hours under nitrogen at room temperature. The product was purified by chromatography (flash column, silica gel, 60-100% methanol in methylene chloride) to provide tert-butyl (2S,3R)-2-({3-[(11-aminoundecanoyl)amino]propyl}amino)-3-[(3R,4R,5R)-3,4-bis{[tert-butyl (dimethyl)silyl]oxy}-5-(3-(4-methoxybenzyl)-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl)tetrahydro-2-furanyl]-3-hydroxypropanoate (44 mg, 51%) as a white solid.
Reaction SMILES: CS(C)=O.[H-].[Na+].[I-].[CH3:8][S+](C)C.[C:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:14])[CH3:13]>C1COCC1>[CH3:13][C:12]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:8][O:14]1
Reactant: C[S+](C)C
Reactant: CC(=O)c1ccccc1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: CC1(c2ccccc2)CO1
Temperature: 65 °C
Reaction time: 0.17 h

Procedure:
DMSO is added to NaH (1-1.8 equiv.) and heated to 65° C. for 1 h. THF is added at the same temperature and heated for another 10 min. After 10 min., the reaction mixture is cooled to 0° C. Trimethylsulfonium iodide (1-1.2 equiv.) is added and the contents are stirred for 10 min. after which the solution of acetophenone (1 equiv.) in THF is added dropwise. After complete addition, the reaction mixture is stirred at RT for 2 h; the reaction is monitored by LCMS. The reaction mixture is poured in ice water, extracted in diethyl ether, dried over sodium sulfate and concentrated at 25° C. to get the crude product.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[NH:12][C@H:11]([C:13]([F:16])([F:15])[F:14])[CH2:10][CH2:9][N:5]2[C:6](=[O:8])[CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:24][C:25](=[O:29])[CH:26]([CH3:28])[CH3:27]>C(#N)C>[Cl:1][C:2]1[N:3]=[C:4]2[N:12]([CH2:24][C:25](=[O:29])[CH:26]([CH3:28])[CH3:27])[C@H:11]([C:13]([F:14])([F:15])[F:16])[CH2:10][CH2:9][N:5]2[C:6](=[O:8])[CH:7]=1
Reactant: CC(C)C(=O)CBr
Reactant: O=c1cc(Cl)nc2n1CC[C@@H](C(F)(F)F)N2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC(C)C(=O)CN1c2nc(Cl)cc(=O)n2CC[C@H]1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 97.2 %

Procedure:
A suspension of 170 mg (0.670 mmol) of (8S)-2-chloro-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one and 655.21 mg (2.01 mmol) of cesium carbonate in 10 mL of acetonitrile is stirred for 15 minutes at room temperature. 132.75 mg (0.804 mmol) of 1-bromo-3-methylbutan-2-one are then added. After stirring overnight at room temperature, the reaction mixture is evaporated and the residue is taken up in water and extracted with ethyl acetate. The organic phase is dried over magnesium sulfate and evaporated to dryness to give 220 mg of (8S)-2-chloro-9-(3-methyl-2-oxobutyl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one, corresponding to the following characteristics:
Reaction SMILES: C([O:5][C:6](=[O:40])[CH2:7][N:8]1[C:16]2[C:15](=[O:17])[N:14]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:13]([C:25]3[CH:30]=[CH:29][C:28]([CH:31]([CH3:33])[CH3:32])=[CH:27][CH:26]=3)=[N:12][C:11]=2[C:10]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[N:9]1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([N:14]2[C:15](=[O:17])[C:16]3[N:8]([CH2:7][C:6]([OH:40])=[O:5])[N:9]=[C:10]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[C:11]=3[N:12]=[C:13]2[C:25]2[CH:26]=[CH:27][C:28]([CH:31]([CH3:33])[CH3:32])=[CH:29][CH:30]=2)=[CH:23][CH:22]=1
Reactant: CC(C)c1ccc(-c2nc3c(-c4ccccc4)nn(CC(=O)OC(C)(C)C)c3c(=O)n2-c2ccc(Cl)cc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)c1ccc(-c2nc3c(-c4ccccc4)nn(CC(=O)O)c3c(=O)n2-c2ccc(Cl)cc2)cc1

Procedure:
To [6-(4-chloro-phenyl)-5-(4-isopropyl-phenyl)-7-oxo-3-phenyl-6,7-dihydro-pyrazolo[4,3-d]pyrimidin-1-yl]-acetic acid tert-butyl ester (20.0 mg, 0.036 mmol) are added DCM (0.5 mL) and TFA (0.5 mL), The resultant solution is stirred at room temperature for 4 hours. Removal of the solvent under reduced pressure provides crude [6-(4-chlorophenyl)-5-(4-isopropyl-phenyl)-7-oxo-3-phenyl-6,7-dihydro-pyrazolo[4,3-d]pyrimidin-1-yl]-acetic acid, which is used directly for next reaction without further purification.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.S(Cl)(Cl)=O.[CH2:10]([S:17][CH2:18][C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[OH:27])=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(Cl)Cl>[OH:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[C:19]([C:2]1[NH:1][CH:5]=[CH:4][N:3]=1)=[CH:18][S:17][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: c1c[nH]cn1
Reactant: O=C(CSCc1ccccc1)c1ccccc1O
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: Oc1ccccc1C(=CSCc1ccccc1)c1ncc[nH]1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 4.08 g of imidazole and 30 ml of dry methylene chloride, 1.78 g of thionyl chloride was added with ice-cooling. After stirring the reaction mixture for 30 minutes, 2.58 g of 2-benzylthio-2'-hydroxyacetophenone was added, followed by further stirring at room temperature for 2 hours. Ice water was added to the reaction mixture, followed by extraction with methylene chloride. The organic, i.e., methylene chloride layer was washed with water, dried over magnesium sulfate and then concentrated. The residue was dissolved in chloroform and was then subjected to chromatography on a silica gel column. Upon concentration of the resultant eluate, there were obtained 180 mg of Isomer A (m.p. 196°-198° C.; Compound 1) and 1.0 g of Isomer B (m.p. 136.5°-138° C.; Compound 2) of 1-(2-hydroxyphenyl)-1-imidazolyl-2-benzylthioethylene (in formula (I), R1, R2, R3 =H, R4 =--SCH2C6H5), both, as colorless crystals.