Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[CH3:57][O:58][C:59]1[CH:64]=[CH:63][C:62]([N:65]2[CH2:69][CH2:68][CH:67]([C:70](O)=[O:71])[C:66]2=[O:73])=[CH:61][CH:60]=1>CN(C=O)C>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH:14][C:70]([CH:67]1[CH2:68][CH2:69][N:65]([C:62]2[CH:63]=[CH:64][C:59]([O:58][CH3:57])=[CH:60][CH:61]=2)[C:66]1=[O:73])=[O:71]
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Reactant: COc1ccc(N2CCC(C(=O)O)C2=O)cc1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(N2CCC(C(=O)NCCc3c[nH]c4ccc(Cl)cc34)C2=O)cc1
Yield: 42.3 %

Procedure:
A mixture of 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.098 g; 0.425 mmol), PyBOP (0.332 g; 0.638 mmol), N,N-diisopropylethylamine (0.220 mL; 1.28 mmol) and 1-(4-methoxyphenyl)-2-oxopyrrolidine-3-carboxylic acid (0.100 g; 0.425 mmol) was stirred in DMF (3 mL) overnight. The reaction mixture was partitioned between ethyl acetate and sodium hydrogen sulfate, the organic layer was washed with sodium carbonate, brine, dried and concentrated under reduced pressure. The crude mixture was purified flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane) to yield 0.074 g (42%) of the title compound as a solid.
Reaction SMILES: Br[C:2]1[C:3]([F:14])=[CH:4][N:5]=[C:6]2[C:11]=1[N:10]=[C:9]([O:12][CH3:13])[CH:8]=[CH:7]2.C(=O)([O-])O.[Na+].[H][H]>CO.[Pd]>[F:14][C:3]1[CH:2]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([O:12][CH3:13])=[N:10]2)=[N:5][CH:4]=1
Reactant: [H][H]
Reactant: COc1ccc2ncc(F)c(Br)c2n1
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: COc1ccc2ncc(F)cc2n1
Yield: 87 %

Procedure:
8-Bromo-7-fluoro-2-(methoxy)-1,5-naphthyridine (for a synthesis see WO2004058144, Example 53(g)) (5.040 g, 19.61 mmol) was stirred in MeOH (200 ml) with sodium hydrogen carbonate (3.29 g, 39.22 mmol) and 10% palladium on carbon (2.5 g), and the resulting suspension was hydrogenated at 1 atmosphere of hydrogen pressure under for 4 h. The mixture was filtered with suction through celite and the solids were washed with MeOH (500 ml). The combined filtrate plus washings were concentrated to about 50 ml under reduced pressure and then treated with water (200 ml) and DCM (300 ml). The aqueous phase was separated and extracted twice more with DCM (300 ml). The combined organic phases were separated, dried over anhydrous magnesium sulphate, filtered and evaporated to give the desired compound as an off-white solid (3.044 g, 87%).
Reaction SMILES: BrCC#C[C@H](OC(=O)C)CCCCC.C(OC1(C#CCBr)CCCCC1)(=O)C.C([O:32][C:33]1([C:39]#[C:40][CH2:41][N:42]([CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][C:53]([O:55]CC)=[O:54])[S:43]([CH3:46])(=[O:45])=[O:44])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1)(=O)C>>[OH:32][C:33]1([CH2:39][CH2:40][CH2:41][N:42]([CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][C:53]([OH:55])=[O:54])[S:43]([CH3:46])(=[O:45])=[O:44])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]1
Reactant: CCOC(=O)CCCCCCN(CC#CC1(OC(C)=O)CCCCC1)S(C)(=O)=O
Agent: CC(=O)OC1(C#CCBr)CCCCC1
Agent: CCCCC[C@H](C#CCBr)OC(C)=O
Product: CS(=O)(=O)N(CCCCCCC(=O)O)CCCC1(O)CCCCC1

Procedure:
The synthesis of this compound is carried out as described in Example 3 except that, in Step A, the 1-bromo-4(R)-acetoxy-2-nonyne is replaced by an equimolar amount of 1-acetoxy-1-(3-bromo-1-propynyl)cyclohexane (Example U). The product of Step A is thus ethyl 7-{N-[3-(1-acetoxycyclohexyl)-2-propynyl]methanesulfonamido}heptanoate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.[Br:20][C:21]1[CH:22]=[C:23](F)[C:24]([N+:29]([O-:31])=[O:30])=[C:25]([CH:28]=1)[NH:26][CH3:27].CCN(CC)CC>CCOC(C)=O>[Br:20][C:21]1[CH:28]=[C:25]([NH:26][CH3:27])[C:24]([N+:29]([O-:31])=[O:30])=[C:23]([N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:19][CH:18]=2)[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[CH:22]=1
Reactant: COc1ccc(CNCc2ccc(OC)cc2)cc1
Reactant: CNc1cc(Br)cc(F)c1[N+](=O)[O-]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CNc1cc(Br)cc(N(Cc2ccc(OC)cc2)Cc2ccc(OC)cc2)c1[N+](=O)[O-]
Temperature: 120 °C
Reaction time: 16 h

Procedure:
A mixture of bis-(4-methoxy-benzyl)-amine (346 mmol), 5-bromo-3-fluoro-N-methyl-2-nitroaniline (297 mmol) and Et3N (891 mmol) was stirred at 120° C. for 16 h. The mixture was then cooled. The crude was combined with another one obtained following the same procedure described above. The resulting mixture was diluted in EtOAc and washed (2×0.2 M HCl, H2O and sat. NaHCO3). The organic phase was dried (Na2SO4) and concentrated to afford the desired product.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH:22]([CH3:24])[CH3:23])[C:5]([C:7]1[N:16]=[C:15]2[N:9]([CH2:10][CH2:11][O:12][C:13]3[CH:20]=[C:19](Br)[CH:18]=[CH:17][C:14]=32)[CH:8]=1)=[O:6].B1([C:34]2[CH2:39][CH2:38][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:36][CH:35]=2)OC(C)(C)C(C)(C)O1.C(=O)([O-])[O-].[K+].[K+].C(Cl)Cl>CN(C=O)C>[C:43]([O:42][C:40]([N:37]1[CH2:36][CH:35]=[C:34]([C:19]2[CH:18]=[CH:17][C:14]3[C:15]4[N:9]([CH2:10][CH2:11][O:12][C:13]=3[CH:20]=2)[CH:8]=[C:7]([C:5](=[O:6])[N:4]([CH2:3][CH2:2][OH:1])[CH:22]([CH3:24])[CH3:23])[N:16]=4)[CH2:39][CH2:38]1)=[O:41])([CH3:46])([CH3:44])[CH3:45]
Reactant: CC(C)N(CCO)C(=O)c1cn2c(n1)-c1ccc(Br)cc1OCC2
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)N(CCO)C(=O)c1cn2c(n1)-c1ccc(C3=CCN(C(=O)OC(C)(C)C)CC3)cc1OCC2
Temperature: 100 °C
Yield: 82.7 %

Procedure:
8-Bromo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-2-carboxylic acid (2-hydroxy-ethyl)-isopropyl-amide (114 mg, 0.28 mmol), 3,6-dihydro-2H-pyridine-1-N-Boc-4-boronic acid pinacol ester (129 mg, 0.62 mmol), potassium carbonate (96 mg, 0.69 mmol) and PdCl2dppf.DCM (20 mg, 0.02 mmol) were suspended in DMF (1.5 mL), and the reaction mixture purged with argon. The reaction mixture was heated at 100° C. for 3 h. The reaction mixture was washed with water, extracted with ethyl acetate (2×15 mL) and the combined organic extracts washed with brine, dried (Na2SO4) and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 0-2% MeOH in DCM) to yield 4-{2-[(2-Hydroxy-ethyl)-isopropyl-carbamoyl]-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl}-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (115 mg, 80%). LCMS: RT=3.48 min, [M+H]+=497
Reaction SMILES: Br[C:2]1[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[CH:3]=1.[C:9]1(B(O)O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C([O-])([O-])=O.[K+].[K+]>[Pd].C(O)C>[C:9]1([C:2]2[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[CH:3]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C1C=C(Br)CCC1
Reactant: OB(O)c1ccccc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: O=C1C=C(c2ccccc2)CCC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 75.3 %

Procedure:
A microwave vial was charged with a stir bar, 3-bromocyclohex-2-enone (65 mg, 1 equiv., 0.37 mmol), phenyl boronic acid (55 mg, 1.2 equiv., 0.45 mmol) and ethanol (4 mL). To the solution was added 1M K2CO3 (1.2 equiv., 0.45 mmol) followed by the addition of the polymer supported palladium FC 1001 (27 mg, 3 mol % Pd) catalyst. The reaction was subjected to the following microwave conditions: Power 250 W, Temperature 110° C., ramp time 1:00 min, time holds 5 min, Power Max on (continuous air cooling). The reaction was then cooled to room temperature and filtered through a plug of celite eluding with ethyl acetate. The solvent was evaporated on a rotary evaporator. The residue was diluted in methylene chloride and washed with brine. The organic layers were dried over MgSO4 and the residue was purified by automated silica gel chromatography using gradient elution (0 to 20% ethyl acetate/hexanes) affording the desired product as a white solid (48 mg, 75% yield). 1H NMR (300 MHz, CDCl3): δ 7.50-7.53 (m, 2H), 7.36-7.41 (m, 3H), 6.40 (t, J=1.4 Hz, 1H), 2.76 (td, J=6.9, 1.2 Hz, 2H), 2.48 (t, J=6.9 Hz, 2H), 2.14 (quintet, J=6.9 Hz, 2H). 13C (75 MHz, CDCl3): 199.6, 159.6, 138.6, 129.8, 128.6, 125.9, 125.3, 37.3, 28.1, 22.9. LCMS (ESI): mass calcd for (C12H12O) m/z 172.09; measured [M+H]+: m/z 173.17.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][C@@H:15]([C:24]([NH:26][C@H:27]1[CH2:31][CH2:30][CH2:29][C@H:28]1[C:32]([O:34][CH3:35])=[O:33])=[O:25])[NH:16]C(OC(C)(C)C)=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C(OCC)(=O)C>C(OCC)(=O)C>[CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][C@@H:15]([C:24]([NH:26][C@H:27]1[CH2:31][CH2:30][CH2:29][C@H:28]1[C:32]([O:34][CH3:35])=[O:33])=[O:25])[NH2:16])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)[C@@H]1CCC[C@@H]1NC(=O)[C@H](CCCNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H]1CCC[C@@H]1NC(=O)[C@@H](N)CCCNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.8 %

Procedure:
Methyl (1R,2S)-2-({N5-[(benzyloxy)carbonyl]-N2-(tert-butoxycarbonyl)-L-ornithyl}amino)cyclopentanecarboxylate (11.33 g) was suspended in ethyl acetate (34 ml), and a 4 M hydrogen chloride/ethyl acetate solution (52 ml) was added thereto, followed by stirring at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and to the residue were added ethyl acetate (150 ml) and a saturated sodium bicarbonate solution (150 ml), followed by stirring for 5 minutes and performing a liquid separation operation. The aqueous layer was extracted with ethyl acetate (100 ml), and then the organic layer was combined, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was removed by evaporation under reduced pressure to obtain methyl (1R,2S)-2-({N5-[(benzyloxy)carbonyl]-L-ornithyl}amino)cyclopentanecarboxylate (9.0 g).
Reaction SMILES: [CH3:1][C:2]1([OH:12])[CH:9]2[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:11][CH:3]1[CH2:4]3)[CH2:8]2.C(OC(C)C)(C)C.[C:20]([O:25][CH2:26][CH2:27][N:28]=[C:29]=[O:30])(=[O:24])[C:21]([CH3:23])=[CH2:22].CS(O)(=O)=O.C([O-])(O)=O.[Na+]>CCCCCC>[C:20]([O:25][CH2:26][CH2:27][NH:28][C:29](=[O:30])[O:12][C:2]1([CH3:1])[CH:3]2[CH2:11][CH:7]3[CH2:6][CH:5]([CH2:10][CH:9]1[CH2:8]3)[CH2:4]2)(=[O:24])[C:21]([CH3:23])=[CH2:22]
Reactant: CC1(O)C2CC3CC(C2)CC1C3
Reactant: C=C(C)C(=O)OCCN=C=O
Agent: CS(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCCC
Solvent: CC(C)OC(C)C
Product: C=C(C)C(=O)OCCNC(=O)OC1(C)C2CC3CC(C2)CC1C3
Temperature: 5.5 °C
Reaction time: 15 h
Yield: 39.5 %

Procedure:
In a three-necked flask having an inner volume of 50 mL equipped with a thermometer and a stirring apparatus were charged 1.66 g (9.98 mmol) of 2-methyl-2-adamantanol, 2.0 mg of 4-acetamido-2,2,6,6-tetramethylpiperidine-N-oxyl, 6.7 g of isopropyl ether, and 1.66 g (10.5 mmol) of 2-methacryloyloxyethyl isocyanate. After the mixture was cooled by ice water to an inner temperature of 5° C., 290 mg (3.0 mmol) of methanesulfonic acid was added dropwise. After stirring the reaction mixture for 15 hours with the reaction temperature maintained at 5 to 6° C., 10 g of a saturated aqueous NaHCO3 solution was added dropwise with the inner temperature maintained at 10° C. or less and, after completion of the dropwise addition, the mixture was allowed to stand still for 30 minutes. The organic layer (upper layer) formed was separated and the aqueous layer (lower layer) was extracted twice with 10 g of isopropyl ether. All the separated organic layers were combined, washed with 10 g of distilled water, and the organic layer concentrated under reduced pressure to obtain 2.82 g of a concentrate. The concentrate was dissolved in 15 g of hexane at 30° C. and the solution was cooled to −10° C. at a rate of 10° C./hour. The crystals which precipitated were separated by filtration and the crystals obtained were dried under vacuum (26.7 Pa) at 30° C. for 2 hours to obtain 1.29 g (purity 98.2%, 3.94 mmol, yield: 39.5%) of 2-methyladamantan-2-yl (2-methacryloyloxyethyl)carbamate.
Reaction SMILES: Br[C:2]1[C:7]2[N:8]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:9]([C@@H:11]([NH:13][C:14]3[N:22]=[CH:21][N:20]=[C:19]4[C:15]=3[N:16]=[CH:17][N:18]4[CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][O:24]3)[CH3:12])=[N:10][C:6]=2[CH:5]=[CH:4][C:3]=1[F:35].[CH:36]1(B(O)O)[CH2:38][CH2:37]1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.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>[CH:36]1([C:2]2[C:7]3[N:8]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)[C:9]([C@@H:11]([NH:13][C:14]4[N:22]=[CH:21][N:20]=[C:19]5[C:15]=4[N:16]=[CH:17][N:18]5[CH:23]4[CH2:28][CH2:27][CH2:26][CH2:25][O:24]4)[CH3:12])=[N:10][C:6]=3[CH:5]=[CH:4][C:3]=2[F:35])[CH2:38][CH2:37]1
Reactant: C[C@H](Nc1ncnc2c1ncn2C1CCCCO1)c1nc2ccc(F)c(Br)c2n1-c1ccccc1
Reactant: OB(O)C1CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: C[C@H](Nc1ncnc2c1ncn2C1CCCCO1)c1nc2ccc(F)c(C3CC3)c2n1-c1ccccc1
Temperature: 100 °C
Reaction time: 3 h
Yield: 44.7 %

Procedure:
A mixture of [(S)-1-(7-bromo-6-fluoro-1-phenyl-1H-benzoimidazol-2-yl)ethyl]-[9-(tetrahydropyran-2-yl)-9H-purin-6-yl]amine (50 mg, 0.09 mmol), cyclopropylboronic acid (10 mg, 0.12 mmol) and Cs2CO3 (46 mg, 0.14 mmol) in a 4:1 mixture dioxane:water (2.5 mL) was degassed with a stream of argon prior to addition of Pd(PPh3)4 (5 mg) and was heated at 100° C. for 18 h in a sealed vial. Additional cyclopropylboronic acid (10 mg, 0.12 mmol) and Pd(PPh3)4 (5 mg) in dioxane (0.25 mL) were added and stirring at 100° C. in a sealed vial was continued for 3 h. The reaction mixture was diluted with water and extracted with EtOAc (×3). The combined organic fractions were washed with brine, dried (MgSO4) and concentrated in vacuo. The resulting residue was purified by reverse phase HPLC (Phenomenex Gemini 5 μm C18 on a 25 min gradient 10-90%, 0.1% HCO2H in acetonitrile/water) to afford the title compound (20 mg, 43%). LCMS (Method C): RT 3.32 min [M+H]+ 498.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([NH:13][C@H:14]1[CH2:19][CH2:18][C@H:17]([C:20]([O:22]CC)=[O:21])[CH2:16][C@H:15]1[NH:25][C:26]([C:28]1[S:29][C:30]3[CH2:31][N:32]([CH3:37])[CH2:33][CH2:34][C:35]=3[N:36]=1)=[O:27])=[O:12])=[CH:5]2.C(O)C.[OH-].[Na+].Cl>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([NH:13][C@H:14]1[CH2:19][CH2:18][C@H:17]([C:20]([OH:22])=[O:21])[CH2:16][C@H:15]1[NH:25][C:26]([C:28]1[S:29][C:30]3[CH2:31][N:32]([CH3:37])[CH2:33][CH2:34][C:35]=3[N:36]=1)=[O:27])=[O:12])=[CH:5]2
Reactant: CCOC(=O)[C@H]1CC[C@H](NC(=O)c2cc3cc(Cl)ccc3[nH]2)[C@H](NC(=O)c2nc3c(s2)CN(C)CC3)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CN1CCc2nc(C(=O)N[C@@H]3C[C@@H](C(=O)O)CC[C@@H]3NC(=O)c3cc4cc(Cl)ccc4[nH]3)sc2C1
Reaction time: 12 h
Yield: 78.4 %

Procedure:
The compound (1.6 g) obtained in Example 50 was suspended in a mixed solvent of ethanol (20 ml) and tetrahydrofuran (15 ml), and a 1N aqueous solution (5.9 ml) of sodium hydroxide was added at room temperature to stir the mixture for 12 hours at the same temperature. After adding 1N hydrochloric acid (5.9 ml), the solvent was distilled off under reduced pressure, and the residue was washed with water and diethyl ether to obtain the title compound (1.19 g).
Reaction SMILES: [BH4-].[Na+].[CH:3]12[CH2:9][CH:6]([CH:7]=[CH:8]1)[CH:5]1[C:10]([O:12][C:13](=O)[CH:4]21)=[O:11].S(=O)(=O)(O)O>C1COCC1.CO>[CH:6]12[CH2:9][CH:3]([CH2:8][CH2:7]1)[CH:4]1[CH:5]2[C:10](=[O:11])[O:12][CH2:13]1
Reactant: O=C1OC(=O)C2C3C=CC(C3)C12
Agent: O=S(=O)(O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: O=C1OCC2C3CCC(C3)C12
Temperature: 30 °C
Reaction time: 4 h
Yield: 63.9 %

Procedure:
Under nitrogen atmosphere, 176 g (4.649 mol) of sodium borohydride was put into a flask and 2000 g of THF and 9.8 g of methanol were added thereto. A solution of 954 g (5.812 mol) of 5-norbornene-2,3-dicarboxylic anhydride dissolved in 2800 g of THF was added thereto dropwise while cooling them by an ice bath to keep the reaction temperature at 35° C. or lower. After completion of the dropping, the mixture was stirred at 30° C. for 4 hours, then poured into 3000 g of 10% aqueous sulfuric acid solution at 20° C. or lower and stirred for a while. Under reduced pressure, THF was recovered, and 1800 g of MIBK was added thereto for extraction. Further 900 g of MIBK was added to the separated aqueous layer for extraction and combined with the organic layer. 63.6 g of sodium carbonate and 200 g of water were added to the organic layer and stirred for a while. The separated organic layer was washed with diluted sulfuric acid and water, then concentrated, thereby 565.3 g of a white solid desired product of a lactone compound was obtained (64.76% yield).
Reaction SMILES: [OH:1][CH2:2][C:3]([CH3:26])=[CH:4][CH2:5][C:6]1[C:14]([O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])=[C:13]2[C:9]([CH2:10][O:11][C:12]2=[O:22])=[C:8]([CH3:23])[C:7]=1[O:24][CH3:25].CCN(C(C)C)C(C)C.Cl[P:37]1[O:42]C(=O)C2C=CC=CC=2[O:38]1>O1CCOCC1>[CH3:25][O:24][C:7]1[C:8]([CH3:23])=[C:9]2[C:13]([C:12](=[O:22])[O:11][CH2:10]2)=[C:14]([O:15][CH2:16][CH2:17][Si:18]([CH3:20])([CH3:19])[CH3:21])[C:6]=1[CH2:5][CH:4]=[C:3]([CH3:26])[CH2:2][O:1][P:37]([OH:42])[OH:38]
Reactant: COc1c(C)c2c(c(OCC[Si](C)(C)C)c1CC=C(C)CO)C(=O)OC2
Reactant: O=C1OP(Cl)Oc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: COc1c(C)c2c(c(OCC[Si](C)(C)C)c1CC=C(C)COP(O)O)C(=O)OC2
Reaction time: 0.17 h

Procedure:
To a solution of 6-(4-hydroxy-3-methyl-but-2-enyl)-5-methoxy-4-methyl-7-(2-trimethylsilanyl-ethoxy)-3H-isobenzofuran-1-one (75 mg, 0.20 mmol) and DIEA (49 μL, 0.28 mmol) in dioxane (2 mL) was added 2-chloro-4H-1,3,2-benzodioxaphosphorin-4-one (56.7 mg, 0.28 mmol) according the procedure of Shadid, B. et al., Tetrahedron, 1989, 45, 12, 3889. After 10 minutes, another portion of 2-chloro-4H-1,3,2-benzodioxaphosphorin-4-one (40 mg, 0.20 mmol) and DIEA (35 μL, 0.20 mmol) were added. The reaction was allowed to proceed at room temperature for an additional hour, after which it was quenched by the addition of H2O. The solution was stirred for another 10 minutes and concentrated in vacuo to a small volume. The product was triturated with diethyl ether and coevaporated from acetonitrile (4×10 mL) to provide the product. 1H NMR (300 MHz, CDCl3) δ 0.03 (s, 9H), 1.08-1.30 (m, 2H), 1.84 (br s, 3H), 2.17 (s, 3H), 3.46 (br s, 2H), 3.76 (s, 3H), 4.21-4.39 (m, 4H), 5.12 (s, 2H), 5.43-5.60 (m, 1H), 7.83 (br s, 1H); 31P (121.4 MHz, CDCl3) δ 7.22; MS (m/z) 441 [M−H]−.
Reaction SMILES: O[C:2]1[S:3][C:4]([CH2:8][CH2:9][Cl:10])=[C:5]([CH3:7])[N:6]=1.P(Cl)(Cl)([Cl:13])=O.Cl>ClC1C=CC=CC=1>[Cl:13][C:2]1[S:3][C:4]([CH2:8][CH2:9][Cl:10])=[C:5]([CH3:7])[N:6]=1
Reactant: Cc1nc(O)sc1CCCl
Reactant: O=P(Cl)(Cl)Cl
Agent: Cl
Solvent: Clc1ccccc1
Product: Cc1nc(Cl)sc1CCCl
Temperature: 100 °C
Yield: 73.9 %

Procedure:
A suspension of 177.6 g (1 mole) of 2-hydroxy-4-methyl-5-(2-chloroethyl)-thiazole in 530 cm3 of anhydrous chlorobenzene is heated to 100° C. under stirring. 306.6 g (2 moles) of phosphoryl chloride are flown into the solution in 30 minutes, then it is stirred at a temperature of 125°-130° C. until the formation of hydrogen chloride ceases (about 2 hours). The reaction mixture is cooled to 20° C., then it is poured onto 1.5 kg of ice. The phases are separated, the aqueous phase is extracted twice with 200 cm3 of chlorobenzene each. The combined phases containing the chlorobenzene are washed acid-free with water and then with a 5% sodium hydrogen carbonate solution and then evaporated under reduced pressure. The brown residue is fractionated in vacuo. 145 g (74%) of 2-chloro-4-methyl-5-(2-chloroethyl)-thiazole are obtained. The boiling point is 102° C. at a pressure of 53.2 Pa, n20D =1.5512, n30D =1.5468
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[C:16]([C:21](OC)=[O:22])=[N:17][CH:18]=[CH:19][N:20]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:26][NH2:27]>C(O)C>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[C:16]([C:21]([NH:26][NH2:27])=[O:22])=[N:17][CH:18]=[CH:19][N:20]=2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NN
Reactant: COC(=O)c1nccnc1NC1CCN(Cc2ccccc2)CC1
Solvent: O
Solvent: CCO
Product: NNC(=O)c1nccnc1NC1CCN(Cc2ccccc2)CC1
Reaction time: 2 h

Procedure:
A mixture of methyl 3-[(1-benzylpiperidin-4-yl)amino]pyrazine-2-carboxylate (3.0 g, 9.2 mmol) and hydrazine hydrate (6 mL) in ethanol (100 mL) was refluxed with stirring for 2 h. The reaction was cooled and concentrated to give the title compound (3.0 g). MS 327 (M+1).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH3:11])=[C:4]([NH:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:3]=1.O.[NH2:22][NH2:23]>>[NH:22]([C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH3:11])=[C:4]([NH:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:3]=1)[NH2:23]
Reactant: NN
Reactant: Cn1cnc2c(NCCc3ccccc3)nc(Cl)nc21
Solvent: O
Product: Cn1cnc2c(NCCc3ccccc3)nc(NN)nc21

Procedure:
Was prepared according to Example 8 from (2-chloro-9-methyl-9H-purin-6-yl)-phenethyl-amine and hydrazine monohydrate.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[C:11]([CH:13]3[CH2:18][CH2:17][S:16](=[O:20])(=[O:19])[CH2:15][CH2:14]3)[CH:10]=[CH:9][C:8]=2[NH2:21])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[K+].[C:23]([C:25]1[N:26]=[C:27]([C:38]([O-])=[O:39])[N:28]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[CH:29]=1)#[N:24].F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[C:1]1([C:7]2[CH:12]=[C:11]([CH:13]3[CH2:18][CH2:17][S:16](=[O:19])(=[O:20])[CH2:15][CH2:14]3)[CH:10]=[CH:9][C:8]=2[NH:21][C:38]([C:27]2[N:28]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[CH:29]=[C:25]([C:23]#[N:24])[N:26]=2)=[O:39])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)[O-]
Reactant: Nc1ccc(C2CCS(=O)(=O)CC2)cc1C1=CCCCC1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)Nc1ccc(C2CCS(=O)(=O)CC2)cc1C1=CCCCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 73 %

Procedure:
To a mixture of 2-cyclohex-1-enyl-4-(1,1-dioxo-hexahydro-1λ6-thiopyran-4-yl)-phenylamine (as prepared in the previous step, 122 mg, 0.50 mmol), potassium 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylate (as prepared in Example 3, step (d), 134 mg, 0.44 mmol) and bromotri(pyrrolidino)phosphonium hexafluorophosphate (PyBroP) (205 mg, 0.44 mmol) in 5 mL of DMF was added DIEA (209 μL, 1.20 mmol). The resulting mixture was stirred at RT for 18 h under Ar, cooled to RT. Treated with 50 mL of EtOAc, the mixture was washed with H2O (3×10 mL), brine (10 mL) and dried (Na2SO4). Removal of the solvent under reduced pressure followed by flash chromatography of the residue on silica gel (1-3% EtOAc/DCM) gave 161 mg (73%) of the title compound as a colorless oil. 1H-NMR (CDCl3; 400 MHz): δ 9.69 (s, 1H), 8.29 (d, 1H, J=8.4 Hz), 7.78 (s, 1H), 7.14 (dd, 1H, J=8.4, 2.2 Hz), 7.04 (d, 1H, J=2.2 Hz), 5.95 (s, 2H), 5.83 (m, 1H), 3.66 (t, 2H, J=8.2 Hz), 3.11-3.20 (m, 4H), 2.77 (dddd, 1H, J=12.1, 12.1, 3.2, 3.2 Hz), 2.35-2.47 (m, 2H), 2.17-2.33 (m, 6H), 1.74-1.89 (m, 4H), 0.97 (t, 2H, J=8.2 Hz), 0.00 (s, 9H). Mass spectrum (ESI, m/z): Calcd. for C28H38N4O4SSi, 555.2 (M+H). found 555.3.