Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:13]([CH3:17])([CH3:16])[CH:14]=[CH2:15])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:18](=O)(O)[O-].[Na+].CI.O>CN(C=O)C>[C:1]([O:5][C:6]([NH:8][CH:9]([C:13]([CH3:17])([CH3:16])[CH:14]=[CH2:15])[C:10]([O:12][CH3:18])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CC(C)(C)C(NC(=O)OC(C)(C)C)C(=O)O
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: C=CC(C)(C)C(NC(=O)OC(C)(C)C)C(=O)OC
Temperature: 25 °C
Reaction time: 27 h
Yield: 87.3 %

Procedure:
To a stirred mixture of 2(R/S)-(tert-butoxycarbonyl)amino-3,3-dimethyl-4-pentenoic acid (3.6 g, 15 mmol) and anhydrous sodium bicarbonate (3.78 g, 45 mmol) in 25 mL of DMF was added methyl iodide (1.03 mL, 17 mmol) dropwise. The mixture was stirred for 27 hours at room temperature, and then poured into water (100 mL). The mixture was extracted with 2:1 ethyl acetate:hexane (3×50 mL), and the combined organic layers were washed with 5% aq. sodium thiosulfate solution, water, sat. aq. sodium bicarbonate, and finally with brine. The organic layer was dried over magnesium sulfate, and concentrated to provide methyl 2(R/S)-(tert-butoxycarbonyl)amino-3,3-dimethyl-4-pentenoate (3.37 g, 87%) as a syrup which was used without further purification.
Reaction SMILES: [CH:1]1([C:7]2[CH:8]=[CH:9][C:10]3[O:14][C:13](B(O)O)=[CH:12][C:11]=3[CH:18]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[C:20]1[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[CH:22][CH:21]=1.C(N(CC)CC)C>C(O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[CH:1]1([C:7]2[CH:8]=[CH:9][C:10]3[O:14][C:13]([C:20]4[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[CH:22][CH:21]=4)=[CH:12][C:11]=3[CH:18]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=Cc1ccc(Br)cc1
Reactant: OB(O)c1cc2cc(C3CCCCC3)ccc2o1
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=Cc1ccc(-c2cc3cc(C4CCCCC4)ccc3o2)cc1
Yield: 50.2 %

Procedure:
A mixture of 5-cyclohexylbenzofuran-2-ylboronic acid (75 mg, 0.37 mmol), 4-bromobenzaldehyde (62 mg, 0.34 mmol), triethylamine (1.1 mL, 7.5 mmol) and bis(triphenylphosphine)palladium(II)chloride (13 mg, 0.05 mmol) in ethanol (11 mL) was irradiated in a microwave instrument at 100° C. for 20 min. The reaction mixture was cooled, and the solvent was removed. The residue was purification by silica gel chromatography on ISCO system gave the title compound (52 mg, 46% yield): >95% purity by LCMS, ESI-MS: 305.2 M+H+). 1H NMR (400 MHz, CDCl3) δ 10.03 (s, 1H), 8.00 (d, 2H), 7.95 (d, 2H), 7.46 (d, 2H), 7.19 (d, 1H), 7.16 (s, 1H), 2.63-2.58 (m, 1H), 1.94-1.76 (m, 4H), 1.53-1.42 (m, 4H), 1.38-1.25 (m, 2H). MS (ESI) m/z: Calculated: 304.38; Observed: 305.2 (M++1).
Reaction SMILES: Br[C:2]1[C:3]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[CH:4][C:5]([CH3:16])=[C:6]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:7]=1.C(N(CC)CC)C.[C:30]([C:32]1[CH:33]=[C:34]([CH:36]=[CH:37][CH:38]=1)[NH2:35])#[CH:31]>O1CCCC1.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:35][C:34]1[CH:33]=[C:32]([C:30]#[C:31][C:2]2[C:3]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:4][C:5]([CH3:16])=[C:6]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:7]=2)[CH:38]=[CH:37][CH:36]=1
Reactant: C#Cc1cccc(N)c1
Reactant: Cc1cc(N2CCOCC2)c(Br)cc1NC(=O)OC(C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cc(N2CCOCC2)c(C#Cc2cccc(N)c2)cc1NC(=O)OC(C)(C)C
Temperature: 80 °C
Yield: 20.4 %

Procedure:
tert-Butyl (5-bromo-2-methyl-4-morpholin-4-ylphenyl)carbamate (110 mg, 0.3 mmol), copper(I) iodide (4 mg, 0.02 mmol) and bis(triphenylphosphine)palladium(II) chloride (10 mg, 0.01 mmol) were stirred in tetrahydrofuran (0.5 mL) and triethylamine (50 μL, 0.4 mmol) was added. 3-Ethynylaniline (100 μL, 1.0 mmol) was added and the mixture was heated to 80° C. for 1 hour. The mixture was filtered through celite and purified by preparative LCMS (pH 2). The product fractions were neutralized with saturated sodium bicarbonate solution, evaporated to remove acetonitrile and extracted with ethyl acetate. The extracts were evaporated to give the desired compound (25 mg, 31%). LCMS for C24H30N3O3 (M+H)+: m/z=408.1.
Reaction SMILES: [O:1]=[C:2]1[N:7]([CH3:8])[C:6](=[O:9])[N:5]([CH3:10])[CH2:4][N:3]1[CH3:11].[Cl-:12]>O>[Cl-:12].[O:1]=[C:2]1[N:7]([CH3:8])[C:6](=[O:9])[N:5]([CH3:10])[CH2:4][NH+:3]1[CH3:11]
Reactant: CN1CN(C)C(=O)N(C)C1=O
Agent: [Cl-]
Solvent: O
Product: CN1C[NH+](C)C(=O)N(C)C1=O

Procedure:
15.7 g (0.1 mol) of 2,4-dioxo-hexahydro-1,3,5-trimethyl-s-triazine are dissolved in 50 ml of water. 7 g (0.1 mol) of chloride are slowly passed into this solution. The temperature is kept at 25 -30° C by occassional cooling. The aqueous solution is then evaporated in vacuo, and 18 g (94%) of 2,4-dioxo-1,2,3,4-tetrahydro--1,3,5-s-triazinium chloride are thereby obtained as white crystals, which are strongly hygroscopic.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:16][C:10]3([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]3)[CH2:9][C:8](=[O:17])[C:7]=2[CH:18]=1.Cl.N1C=CC=CC=1>>[OH:2][C:3]1[CH:4]=[CH:5][C:6]2[O:16][C:10]3([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]3)[CH2:9][C:8](=[O:17])[C:7]=2[CH:18]=1
Reactant: COc1ccc2c(c1)C(=O)CC1(CCCCC1)O2
Agent: Cl
Solvent: c1ccncc1
Product: O=C1CC2(CCCCC2)Oc2ccc(O)cc21
Yield: 85.9 %

Procedure:
A mixture of 6-methoxyspiro[2H-1-benzopyran-2,1'-cyclohexan]-4(3H)-one (prepared in Preparation 3) (1.0 g, 4.06 mmol) in dry pyridine HCl (6 g, 52 mmol) is heated to 210°-215° C. on an oil bath for 45 minutes with stirring, and allowed to cool. The mixture is extracted with water and diethyl ether. The ether layer is separated, washed with dilute hydrochrolic acid and then water, dried and concentrated. The residue is placed on a silica gel column and eluted with a mixture of acetonitrile and dichloromethane (1:9 to 1:4) to obtain the title compound as an oil (0.81 g, yield 85.5%). ##STR9##
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:34]=[CH:33][C:13]([O:14][C:15]2[CH:16]=[C:17]([CH:21]=[C:22]([O:24][C:25]3[CH:30]=[CH:29][C:28]([C:31]#[N:32])=[CH:27][CH:26]=3)[CH:23]=2)[C:18]([OH:20])=[O:19])=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:35]([O:42][C:43](=[O:52])[NH:44][CH:45]1[CH2:50][CH2:49][CH:48](O)[CH2:47][CH2:46]1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>>[CH2:35]([O:42][C:43]([NH:44][CH:45]1[CH2:50][CH2:49][CH:48]([O:19][C:18](=[O:20])[C:17]2[CH:21]=[C:22]([O:24][C:25]3[CH:26]=[CH:27][C:28]([C:31]#[N:32])=[CH:29][CH:30]=3)[CH:23]=[C:15]([O:14][C:13]3[CH:33]=[CH:34][C:10]([CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])=[CH:11][CH:12]=3)[CH:16]=2)[CH2:47][CH2:46]1)=[O:52])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: O=C(NC1CCC(O)CC1)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NCc1ccc(Oc2cc(Oc3ccc(C#N)cc3)cc(C(=O)O)c2)cc1
Product: CC(C)(C)OC(=O)NCc1ccc(Oc2cc(Oc3ccc(C#N)cc3)cc(C(=O)OC3CCC(NC(=O)OCc4ccccc4)CC3)c2)cc1
Yield: 39.1 %

Procedure:
Following the procedure of Example 9(e) 3-[4-(tert-butoxycarbonylamino-methyl)-phenoxy]-5-(4-cyano-phenoxy)-benzoic acid (0.85 g, 1.85 mmol) and (4-hydroxy-cyclohexyl)-carbamic acid benzyl ester (0.50 g, 2.03 mmol) were used to afford 0.5 g of the required product. Percentage purity (LCMS): 67.0%, (M+1) 691.2+1.
Reaction SMILES: [OH:1]O.[CH:3]1([C:6]2[N:10](C(=O)C)[N:9]=[C:8]([NH:14][C:15]3[C:20](B4OC(C)(C)C(C)(C)O4)=[CH:19][N:18]=[C:17]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[N:16]=3)[CH:7]=2)[CH2:5][CH2:4]1.O>C1COCC1>[CH:3]1([C:6]2[NH:10][N:9]=[C:8]([NH:14][C:15]3[C:20]([OH:1])=[CH:19][N:18]=[C:17]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[N:16]=3)[CH:7]=2)[CH2:5][CH2:4]1
Reactant: OO
Reactant: CC(=O)n1nc(Nc2nc(-c3ccccc3)ncc2B2OC(C)(C)C(C)(C)O2)cc1C1CC1
Solvent: O
Solvent: C1CCOC1
Product: Oc1cnc(-c2ccccc2)nc1Nc1cc(C2CC2)[nH]n1
Reaction time: 1 h
Yield: 8 %

Procedure:
30% H2O2 (10 mL) was added to the solution of 1-(5-cyclopropyl-3-(2-phenyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-4-ylamino)-1H-pyrazol-1-yl)ethanone (200 mg, 0.45 mmol, 1.0 eq) in THF (5 mL) at 0° C. The mixture was stirred for 1 h and water was added. The solid was collected and dissolved in methanol (8 mL). To the solution was added 5 N NaOH (4 mL). The mixture was stirred for 2 h at room temperature and concentrated. To the residue was added ethanol and EtOAc. The emerged solid was filtered off. The filtrate was concentrated and the residue was recrystallized with CH2Cl2 and ethyl ether to give 4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-2-phenylpyrimidin-5-ol (Compound 55) (10 mg, 8% over 2 steps). LC-MS (m/z)=294.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 0.69-0.74 (m, 2H), 0.93-0.98 (m, 2H), 1.85-1.89 (m, 1H), 6.52 (bs, 1H), 7.40-7.47 (m, 3H), 7.93 (s, 1H), 8.22 (d, J=7.6 Hz, 2H), 8.41 (bs, 1H), 10.43 (bs, 1H), 12.09 (bs, 1H).
Reaction SMILES: [N:1](=[C:3]1[N:7]=[C:6]([CH3:8])[C:5]([CH3:15])([CH2:9][CH:10]=[C:11]([CH3:14])[CH2:12][CH3:13])[S:4]1)[OH:2].[CH3:16][N:17]=[C:18]=[O:19]>>[CH3:16][NH:17][C:18]([O:2][N:1]=[C:3]1[N:7]=[C:6]([CH3:8])[C:5]([CH3:15])([CH2:9][CH:10]=[C:11]([CH3:14])[CH2:12][CH3:13])[S:4]1)=[O:19]
Reactant: CN=C=O
Reactant: CCC(C)=CCC1(C)SC(=NO)N=C1C
Product: CCC(C)=CCC1(C)SC(=NOC(=O)NC)N=C1C

Procedure:
2-oxo-4,5-dimethyl-5-(3-methyl-2-pentenyl)-3-thiazoline-oxime was reacted with methylisocyanate as described in Example 4 to yield 2-oxo-4,5-dimethyl-5-(3-methyl-2-pentenyl)-3-thiazoline-O-(methylcarbamoyl)-oxime as a viscous oil; nD20 =1.5424.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.CO[CH:16](OC)[N:17]([CH3:19])[CH3:18]>O1CCOCC1>[C:10]([O:9][C:7]([N:4]1[CH2:3][C:2](=[O:1])[C:6](=[CH:16][N:17]([CH3:19])[CH3:18])[CH2:5]1)=[O:8])([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C1
Reactant: COC(OC)N(C)C
Solvent: C1COCCO1
Product: CN(C)C=C1CN(C(=O)OC(C)(C)C)CC1=O
Yield: 46.4 %

Procedure:
A solution of tert-butyl 3-oxopyrrolidine-1-carboxylate (25.0 g, 135 mmol), dimethylformamide dimethylacetal (27 mL, 202 mmol) and 1,4-dioxane (170 mL) was heated at 100° C. for 17 hours. The dioxane was removed in vacuo. The resulting red solid was triturated with hexanes (180 mL) for one hour, and filtered. The solid was rinsed with hexanes (2×80 mL) and air dried. Chromatography on silica gel eluting with dichloromethane:methanol 39:1 then 19:1 to give the title compound (15.04 g, 46%).
Reaction SMILES: C([N:8]1[C:16]2[CH:15]=[CH:14][N:13]=[C:12]([O:17][CH3:18])[C:11]=2[C:10]([C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[CH:21][CH:20]=2)=[N:9]1)C1C=CC=CC=1.CC(C)([O-])C.[K+].[Cl-].[NH4+]>CS(C)=O.C1COCC1>[CH3:18][O:17][C:12]1[C:11]2[C:10]([C:19]3[CH:20]=[CH:21][C:22]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[CH:23][CH:24]=3)=[N:9][NH:8][C:16]=2[CH:15]=[CH:14][N:13]=1
Reactant: COc1nccc2c1c(-c1ccc(N3CCOCC3)cc1)nn2Cc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: COc1nccc2[nH]nc(-c3ccc(N4CCOCC4)cc3)c12
Temperature: 25 °C
Reaction time: 5 h
Yield: 70.2 %

Procedure:
To a solution of 1-benzyl-4-methoxy-3-(4-(morpholin-4-yl)phenyl)-1H-pyrazolo[4,3-c]pyridine (0.68 g) in DMSO/THF (10 mL/2.5 mL) was added potassium tert-butoxide (1.90 g) under ice-cooling. The reaction mixture was stirred at room temperature for 5 hr. The reaction mixture was added to saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate/petroleum ether) to give the title compound (0.37 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([O:24][CH2:25][C:26]2[N:27]([CH3:31])[N:28]=[CH:29][N:30]=2)=[N:10][N:11]2[C:16]=1[CH:15]=[N:14][N:13]=[C:12]2[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1F.[F:32]C1C=CC(C(NN)=O)=CC=1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([O:24][CH2:25][C:26]2[N:27]([CH3:31])[N:28]=[CH:29][N:30]=2)=[N:10][N:11]2[C:16]=1[CH:15]=[N:14][N:13]=[C:12]2[C:17]1[CH:18]=[CH:19][C:20]([F:32])=[CH:21][CH:22]=1
Reactant: NNC(=O)c1ccc(F)cc1
Reactant: Cn1ncnc1COc1nn2c(-c3ccccc3F)nncc2c1-c1ccccc1F
Product: Cn1ncnc1COc1nn2c(-c3ccc(F)cc3)nncc2c1-c1ccccc1F

Procedure:
This compound was prepared using the procedure described in Example 21, steps b) to f), using 3-(2-fluorophenyl)-4-hydroxy-2-furanone (cf. Example 2) instead of 3-tert-butyl-4-hydroxy-2-furanone and 4-fluorobenzoic hydrazide instead of 2,5-difluorobenzoic hydrazide in step e). Data for the title compound: mp=191° C.; 1H NMR (400 MHz, CDCl3) δ 3.92 (3H, s), 5.66 (2H, s), 7.22-7.32 (4H, m), 7.39-7.44 (1H, m), 7.58 (1H, m), 7.90 (1H, s), 8.51-8.55 (2H, m), 9.21 (1H, s); MS (ES+) m/e 420 [MH]+; Anal. Found: C, 60.11; H, 3.52; N, 23.37%. C21H15F2N7O requires: C, 60.14; H, 3.61; N, 23.38%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][C:30]=1[Cl:31])[O:5][CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][CH:13]([OH:27])[CH2:14][CH2:15][N:16]2C(=O)C3C(=CC=CC=3)C2=O)[CH2:8][CH2:7]1>C(O)C.NN>[NH2:16][CH2:15][CH2:14][CH:13]([OH:27])[CH2:12][N:9]1[CH2:8][CH2:7][CH:6]([O:5][C:4]2[CH:28]=[CH:29][C:30]([Cl:31])=[C:2]([Cl:1])[CH:3]=2)[CH2:11][CH2:10]1
Reactant: O=C1c2ccccc2C(=O)N1CCC(O)CN1CCC(Oc2ccc(Cl)c(Cl)c2)CC1
Agent: NN
Solvent: CCO
Product: NCCC(O)CN1CCC(Oc2ccc(Cl)c(Cl)c2)CC1
Yield: 97.3 %

Procedure:
A solution of mixture of 2-{4-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-3-hydroxybutyl}-1H-isoindole-1,3(2H)-dione (3.00 g) in a mixture of ethanol (75 ml) and 35% aqueous hydrazine (15 ml) was heated at reflux 4 h. The mixture was cooled down and the solvents removed under vacuum. The residue was triturated with warm dichloromethane. The white solid was removed by filtration and the filtrate dried over sodium sulfate. The mixture was filtered and the solvent was evaporated to afford the title compound as a yellow oil (2.10 g) which was used without further purification in the next step.
Reaction SMILES: [CH2:1]([N:4]=[C:5]=[O:6])[CH2:2][CH3:3].[NH2:7][C:8]1[CH:13]=[C:12]([CH2:14][S:15][C:16]2[C:21]([C:22]([NH:24][C:25]3[CH:30]=[C:29]([CH3:31])[CH:28]=[C:27]([CH3:32])[CH:26]=3)=[O:23])=[CH:20][CH:19]=[CH:18][N:17]=2)[CH:11]=[CH:10][N:9]=1.C(OCC)(=O)C>CN(C)C=O>[CH3:32][C:27]1[CH:26]=[C:25]([NH:24][C:22]([C:21]2[C:16]([S:15][CH2:14][C:12]3[CH:11]=[CH:10][N:9]=[C:8]([NH:7][C:5]([NH:4][CH2:1][CH2:2][CH3:3])=[O:6])[CH:13]=3)=[N:17][CH:18]=[CH:19][CH:20]=2)=[O:23])[CH:30]=[C:29]([CH3:31])[CH:28]=1
Reactant: CCCN=C=O
Reactant: Cc1cc(C)cc(NC(=O)c2cccnc2SCc2ccnc(N)c2)c1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCNC(=O)Nc1cc(CSc2ncccc2C(=O)Nc2cc(C)cc(C)c2)ccn1
Yield: 33 %

Procedure:
n-Propyl isocyanate (20 mg, 0.23 mmol) was added to a solution of 2-(2-aminopyridin-4-ylmethylthio)-N-(3,5-dimethylphenyl)pyridine-3-carboxamide (The free base of Compound No. 3-1, 28 mg, 0.077 mmol) in N,N-dimethylformamide (0.60 mL) at room temperature, and the mixture was stirred for 4 hours at 80° C. Ethyl acetate (10 mL) was added to the reaction mixture, the whole was washed with water (15 mL) and brine (15 mL), and then the organic layer was dried over anhydrous magnesium sulfate. The organic layer was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to give 12 mg of the target compound as a colorless solid(Yield 33%).
Reaction SMILES: [OH:1][CH:2]([CH2:25][OH:26])[CH2:3][NH:4][C:5]1[N:13]=[C:12]2[C:8]([N:9]=[C:10]([O:22][CH3:23])[N:11]2[CH2:14][C:15]2[CH:16]=[N:17][C:18]([CH3:21])=[CH:19][CH:20]=2)=[C:7]([NH2:24])[N:6]=1.C(N(CC)CC)C.[C:34](OC(OC(C)(C)C)=O)(OC(C)(C)C)=[O:35]>CN(C)C=O>[CH3:23][O:22][C:10]1[N:11]([CH2:14][C:15]2[CH:16]=[N:17][C:18]([CH3:21])=[CH:19][CH:20]=2)[C:12]2[C:8]([N:9]=1)=[C:7]([NH2:24])[N:6]=[C:5]([NH:4][CH2:3][CH:2]1[CH2:25][O:26][C:34](=[O:35])[O:1]1)[N:13]=2
Reactant: COc1nc2c(N)nc(NCC(O)CO)nc2n1Cc1ccc(C)nc1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1nc2c(N)nc(NCC3COC(=O)O3)nc2n1Cc1ccc(C)nc1
Reaction time: 14 h
Yield: 26.6 %

Procedure:
2-(2,3-Dihydroxypropylamino)-8-methoxy-9-{(6-methyl-3-pyridyl)methyl}adenine (230 mg, 0.64 mmol) obtained by Reference example 18, 4-dimethylaminopyridine (5 mg, 0.04 mmol) and triethylamine (0.02 ml, 0.14 mmol) were dissolved in dimethylformamide (2 ml). Thereto was added di-t-butyl dicarbonate (410 mg, 1.9 mmol) in the oil bath kept at 50° C. and the mixture was stirred for 14 hours. The reaction mixture was concentrated and the residue was purified by preparative thin layer chromatography to give the captioned compound (64 mg, 0.17 mmol, yield 26%) as a white solid.
Reaction SMILES: [CH2:1]([C@@H:3]([CH2:6][O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:4][OH:5])[CH3:2].[S:15](Cl)([C:18]1[CH:24]=[CH:23][C:21]([CH3:22])=[CH:20][CH:19]=1)(=[O:17])=[O:16].N1C=CC=CC=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C)C1C=CN=CC=1.ClCCl>[C:21]1([CH3:22])[CH:23]=[CH:24][C:18]([S:15]([O:5][CH2:4][C@@H:3]([CH2:1][CH3:2])[CH2:6][O:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)(=[O:17])=[O:16])=[CH:19][CH:20]=1
Reactant: CC[C@H](CO)COCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC[C@@H](COCc1ccccc1)COS(=O)(=O)c1ccc(C)cc1
Temperature: 0 °C
Yield: 63.8 %

Procedure:
1.34 g (0.0069 mol) of 2-(R)-ethyl-3-benzyloxypropan-1-ol (XVIId-1), 12 ml of dichloromethane, 1.31 g (0.0069 mol) of tosyl chloride and 0.084 g (0.0007 mol) of 4-dimethylaminopyridine are introduced into a round-bottomed flask kept under an inert atmosphere. The mixture is cooled to 0° C. and then 0.89 ml (0.011 mol) of pyridine is added dropwise. After leaving overnight in a refrigerator, the mixture is hydrolyzed using a 10% aqueous citric acid solution. The phases are separated and the aqueous phase is extracted with ethyl ether. The combined organic phases are washed with water and with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue is purified by flash chromatography on silica gel (eluent: dichloromethane/cyclohexane=750:25). 1.54 g (0.0044 mol) of the title compound (XVIIId-1) are obtained.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]1[CH:7]=[N:8][C:9](Cl)=[CH:10][CH:11]=1)[CH3:2].P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH3:22][C:23]1[CH:24]=[C:25]([C:39]([C:44]2[CH:49]=[CH:48][C:47](/[CH:50]=[CH:51]/[C:52]([CH2:56][CH3:57])([OH:55])[CH2:53][CH3:54])=[C:46]([CH3:58])[CH:45]=2)([CH2:42][CH3:43])[CH2:40][CH3:41])[CH:26]=[C:27]([CH3:38])[C:28]=1B1OC(C)(C)C(C)(C)O1.C(OCC)(=O)C>CN(C)C=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]1[CH:7]=[N:8][C:9]([C:28]2[C:27]([CH3:38])=[CH:26][C:25]([C:39]([CH2:40][CH3:41])([C:44]3[CH:49]=[CH:48][C:47](/[CH:50]=[CH:51]/[C:52]([CH2:56][CH3:57])([OH:55])[CH2:53][CH3:54])=[C:46]([CH3:58])[CH:45]=3)[CH2:42][CH3:43])=[CH:24][C:23]=2[CH3:22])=[CH:10][CH:11]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(Cl)nc1
Reactant: CCC(O)(/C=C/c1ccc(C(CC)(CC)c2cc(C)c(B3OC(C)(C)C(C)(C)O3)c(C)c2)cc1C)CC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)Cc1ccc(-c2c(C)cc(C(CC)(CC)c3ccc(/C=C/C(O)(CC)CC)c(C)c3)cc2C)nc1
Temperature: 140 °C
Yield: 21.6 %

Procedure:
(6-Chloro-pyridin-3-yl)-acetic acid ethyl ester (30 mg, 0.149 mmol), tetrakis(triphenylphosphine)palladium (0) (16 mg, 0.014 mmol) and potassium phosphate (32 mg, 0.149 mmol) were added to a solution of (E)-1-(4-{1-[3,5-dimethyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1-ethyl-propyl}-2-methyl-phenyl)-3-ethyl-1-penten-3-ol (Example 38-(6); 50 mg, 0.099 mmol) in N,N-dimethylformamide (0.5 mL). After replacement with nitrogen, the mixture was stirred with microwave heating at 140° C. for 10 minutes. Then, ethyl acetate was added to the reaction mixture, which was washed with water and brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane:ethyl acetate=4:1) to give the target compound as a colorless oil (11.6 mg, 22%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]2[NH:13][N:12]=[N:11][N:10]=2)=[C:6]([CH:8]=1)[NH2:7].[Cl:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[C:18](Cl)=[O:19]>>[Cl:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[C:18]([NH:7][C:6]1[CH:8]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[C:9]1[NH:13][N:12]=[N:11][N:10]=1)=[O:19]
Reactant: Nc1cc(Cl)ccc1-c1nnn[nH]1
Reactant: O=C(Cl)c1cccc(Cl)c1
Product: O=C(Nc1cc(Cl)ccc1-c1nnn[nH]1)c1cccc(Cl)c1
Yield: 13 %

Procedure:
The title compound was prepared essentially according to the method of Example 4, but using 5-Chloro-2-(1H-tetrazol-5-yl)aniline (1.0 mmol) and 3-chlorobenzoyl chloride. After precipitation, the product was further purified by reverse phase C18 preparative HPLC (water/acetonitrile w/0.1% formic acid, 30%-100% eluant gradient) to yield the desired product (46.0 mg, 13%). 1H NMR (400 MHz, d6-DMSO): δ 13.07 (s, 1H), 8.87 (s, 1H), 8.29 (s, 1H), 8.17 (s, 1H), 7.76 (m, 2H), 7.27 (s, 1H), 6.96 (s, 2H). MS (EI) for C14H9Cl2N5O: 334.2 (M+H).
Reaction SMILES: Br[C:2]1[C:10]([O:11][CH3:12])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([O:13][CH3:14])[CH:3]=1.[F:15][C:16]([F:27])([F:26])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1B(O)O.C(=O)([O-])[O-].[K+].[K+].Cl>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:12][O:11][C:10]1[CH:9]=[C:5]([C:6]([OH:8])=[O:7])[C:4]([O:13][CH3:14])=[CH:3][C:2]=1[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:16]([F:27])([F:26])[F:15]
Reactant: COc1cc(C(=O)O)c(OC)cc1Br
Reactant: OB(O)c1ccccc1C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: COc1cc(-c2ccccc2C(F)(F)F)c(OC)cc1C(=O)O

Procedure:
A suspension of 4-bromo-2,5-dimethoxybenzoic acid [prepared in the manner of Bortnik et al., Zh. Org. Khim. 8, 340 (1972)] (2.43g, 9 mmol), 2-trifluoromethylphenyl boronic acid (5.3 g, 28 mmol), and potassium carbonate (6.21 g, 60 mmol) in dioxane (40 mL) was sparged with nitrogen and treated with tetrakis(triphenylphosphine)palladium(0) (0.328 g, 0.2 mmol). The mixture was heated to reflux for 48 hours, cooled, acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extracts were dried over anhydrous magnesium sulfate, filtered and stripped to a solid which was used as such in the next step.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([N:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)=[O:12])=[CH:6][C:5]=1[N+:20]([O-])=O)[CH3:2].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[CH2:34]([N:41]1[C:45](=[O:46])[C:44](=[C:47]2[N:51]([CH3:52])[C:50]3[CH:53]=[CH:54][CH:55]=[CH:56][C:49]=3[S:48]2)[S:43][CH2+:42]1SC)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>>[CH2:34]([N:41]1[C:45](=[O:46])[C:44](=[C:47]2[N:51]([CH3:52])[C:50]3[CH:53]=[CH:54][CH:55]=[CH:56][C:49]=3[S:48]2)[S:43][C:42]1=[N:20][C:5]1[CH:6]=[C:7]([NH:10][C:11]([N:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)=[O:12])[CH:8]=[CH:9][C:4]=1[NH:3][CH2:1][CH3:2])[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: CS[CH2+]1SC(=C2Sc3ccccc3N2C)C(=O)N1Cc1ccccc1
Reactant: CCNc1ccc(NC(=O)N2CCN(C)CC2)cc1[N+](=O)[O-]
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Product: CCNc1ccc(NC(=O)N2CCN(C)CC2)cc1N=C1SC(=C2Sc3ccccc3N2C)C(=O)N1Cc1ccccc1

Procedure:
In a manner similar to Example 30, intermediate 4-methylpiperazine-1-carboxylic acid (4-ethylamino-3-nitro-phenyl)amide was hydrogenated and then condensed with 3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-methylthio-4-oxo-2-thiazolium p-toluenesulfonate to afford the title compound. MS(ESI): 614 (MH+).