Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[CH:7][C:8]2[NH:14][C:13](=[O:15])[CH2:12][C:11](=[O:16])[N:10]([CH3:17])[C:9]=2[CH:18]=1.[CH2:19](I)[CH3:20].O>CN(C)C=O.C(OCC)(=O)C>[CH2:19]([N:14]1[C:13](=[O:15])[CH2:12][C:11](=[O:16])[N:10]([CH3:17])[C:9]2[CH:18]=[C:5]([O:4][CH3:3])[CH:6]=[CH:7][C:8]1=2)[CH3:20]
Reactant: COc1ccc2c(c1)N(C)C(=O)CC(=O)N2
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCN1C(=O)CC(=O)N(C)c2cc(OC)ccc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 76.6 %

Procedure:
Sodium hydride (60% in oil, 44 mg, 1.1 mmol) was suspended in dimethylformamide (DMF) (8 ml), and cooled in an ice water bath to 0° C. 8-Methoxy-1-methyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione (220 mg, 1.0 mmol) was added to the suspension at the same temperature, and stirred at 0° C. for 1 hour. Ethyl iodide (187 mg, 1.2 mmol) was added to the mixture and stirred at room temperature overnight. Water was added to the reaction mixture, and extraction with ethyl acetate was performed. The organic layer was dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=4:1→1:1). The purified product was concentrated to dryness under reduced pressure to thereby obtain 190.2 mg (yield: 77%) of 1-ethyl-7-methoxy-5-methyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione as a yellow solid.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:11])[NH:5][O:6][CH2:7][C:8]([OH:10])=O)[CH3:2].[NH2:12][C@@H:13]([CH2:36][C:37]1[CH:42]=[CH:41][C:40]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[CH:39][CH:38]=1)[C:14]([N:16]([CH2:26][C:27]1[C:28]2[CH:35]=[CH:34][CH:33]=[CH:32][C:29]=2[S:30][CH:31]=1)[C@@H:17]([CH3:25])[CH:18]([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[O:15]>>[S:30]1[CH:31]=[C:27]([CH2:26][N:16]([C@@H:17]([CH3:25])[CH:18]([O:19][CH2:20][CH3:21])[O:22][CH2:23][CH3:24])[C:14](=[O:15])[C@@H:13]([NH:12][C:8](=[O:10])[CH2:7][O:6][NH:5][C:4]([NH:3][CH2:1][CH3:2])=[O:11])[CH2:36][C:37]2[CH:38]=[CH:39][C:40]([O:43][C:44]([CH3:45])([CH3:47])[CH3:46])=[CH:41][CH:42]=2)[C:28]2[CH:35]=[CH:34][CH:33]=[CH:32][C:29]1=2
Reactant: CCNC(=O)NOCC(=O)O
Reactant: CCOC(OCC)[C@H](C)N(Cc1csc2ccccc12)C(=O)[C@@H](N)Cc1ccc(OC(C)(C)C)cc1
Product: CCNC(=O)NOCC(=O)N[C@@H](Cc1ccc(OC(C)(C)C)cc1)C(=O)N(Cc1csc2ccccc12)[C@@H](C)C(OCC)OCC

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(3-ethylureidooxy)acetic acid (Compound VI-13) 47 mg (0.29 mmol) was coupled with (S)-2-amino-N-(benzo[b]thiophen-3-ylmethyl)-3-(4-tert-butoxyphenyl)-N—((S)-1,1-diethoxypropan-2-yl)propanamide (Compound IV-6) 100 mg (0.20 mmol) to obtain the title compound.
Reaction SMILES: [OH:1][C:2]1[C:7](=[O:8])[N:6]2[CH2:9][CH2:10][CH2:11][CH2:12][C:5]2=[N:4][C:3]=1[C:13]([O:15]C)=O.[F:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][NH2:23])=[CH:20][CH:19]=1>CO>[F:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][NH:23][C:13]([C:3]2[N:4]=[C:5]3[CH2:12][CH2:11][CH2:10][CH2:9][N:6]3[C:7](=[O:8])[C:2]=2[OH:1])=[O:15])=[CH:20][CH:19]=1
Reactant: NCc1ccc(F)cc1
Reactant: COC(=O)c1nc2n(c(=O)c1O)CCCC2
Solvent: CO
Product: O=C(NCc1ccc(F)cc1)c1nc2n(c(=O)c1O)CCCC2
Temperature: 65 °C

Procedure:
A solution of methyl 3-hydroxy-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-2-carboxylate obtained in Step 3b or Step 5a and 4-fluoro-benzylamine (2 eq.) in methanol was stirred and heated to 65° C. for 22 h. The solvent was removed under reduced pressure and the title product was obtained by preparative RP-HPLC, using water (0.1% TFA) and acetonitrile (0.1% TFA) as eluents (column: C18). The pooled product fractions were lyophilized to afford the title compound as a fluffy white material.
Reaction SMILES: P(=O)([O-])O[C:3](CC)(CC)[S:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1.[Li]CCCC.[Si:24]([O:31][C@H:32]([CH3:35])[CH:33]=O)([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25]>O1CCCC1>[Si:24]([O:31][C@H:32]([CH3:35])/[CH:33]=[CH:3]/[S:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)([C:27]([CH3:28])([CH3:29])[CH3:30])([CH3:25])[CH3:26]
Reactant: CCC(CC)(O[PH](=O)[O-])Sc1ccc(OC)cc1
Reactant: C[C@H](C=O)O[Si](C)(C)C(C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(S/C=C/[C@@H](C)O[Si](C)(C)C(C)(C)C)cc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 90 %

Procedure:
Under the nitrogen atmosphere, 3.24g (11 mmole) of diethyl-p-methoxyphenylthiomethyl phosphonate was dissolved in 50 ml of anhydrous tetrahydrofuran and after lowering the reaction temperature to -78° C., 6.87 ml (11 mmole) of 1.6M n-BuLi was added to the mixture for ten minutes. The resultant mixture was agitated at the temperature of -78° C. for 30 minutes. At the same temperature, 1.87 g (10 mmole) of (2R)-2-(t-butyldimethylsilyloxy)propanal diluted with 10 ml of anhydrous tetrahydrofuran was added to the said reaction mixture and the reaction temperature raised to 0° C., and then the mixture agitated at 0° C. for another 1.5 hours. Once the reaction was completed, the reaction was quenched by adding saturated ammonium chloride solution. After the work-up treatment in the same manner as did in method A of EXAMPLE 32, the crude product (2.92 g) obtained therefrom was purified by a column chromatography (using n-hexane containing 3% diethyl ether as an eluent), thereby 2.59 g of desired compound having E/Z ratio of over 100/1 (yield: 80%) was stereoselectively obtained.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:14]([OH:16])=O)[CH2:10][CH2:11][CH2:12][CH3:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.ClC(OCC(C)C)=O.[CH2:32]([O:39][C:40](=[O:43])[CH2:41][NH2:42])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>CN(C)C=O>[CH2:32]([O:39][C:40](=[O:43])[CH2:41][NH:42][C:14](=[O:16])[C@@H:9]([CH2:10][CH2:11][CH2:12][CH3:13])[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CCCC[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: NCC(=O)OCc1ccccc1
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CCCC[C@@H](NC(=O)OC(C)(C)C)C(=O)NCC(=O)OCc1ccccc1
Temperature: -10 °C
Yield: 77.4 %

Procedure:
11.57 g (50 mmoles) of tert.-butoxycarbonyl-D-norleucine and 5.6 ml (50 mmoles) of N-methylmorpholine are dissolved in 50 ml of dimethyl formamide. The solution is cooled to -10° C., and 6.6 ml (50 mmoles) of isobutyl chloroformate are added with stirring. After 10 minutes the mixture is cooled to -20° C., and a solution of 18.6 g (55 mmoles) of glycine benzyl ester p-toluolsulfonate and 6.1 ml (55 mmoles) of N-methylmorpholine in 80 ml of dimethyl formamide, cooled to -20° C., is added. The reaction mixture is stirred at -10° C. for 10 minutes, at 0° C. for one hour and then at room temperature overnight. The mixture is filtered, and the filtrate is evaporated under reduced pressure. The residue is dissolved in a mixture of 300 ml of ethyl acetate and 100 ml of water. The ethyl acetate phase is separated, washed successively with 5% aqueous sodium hydrocarbonate solution (2×60 ml), water (2×60 ml), 1 n hydrochloric acid cooled with ice water (2×60 ml) and water (2×60 ml) again, dried over sodium sulfate, decolourized with carbon, filtered, and the filtrate is evaporated under reduced pressure. The crystalline residue is triturated with diisopropyl ether, the solid is filtered off, washed with diisopropyl ether and dried. 14.65 g (76.9%) of tert.-butoxycarbonyl-D-norleucyl-glycine benzyl ester are obtained; m.p.: 85°-86° C., Rf13 =0.75-0.85, [α]D20 =+12.2° (c=1%, in dimethyl formamide).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:13](O)=O)[C@@H:10]([CH3:12])[OH:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:16]([C:20]1[CH:25]=[CH:24][C:23]([NH2:26])=[C:22]([NH2:27])[CH:21]=1)([CH3:19])([CH3:18])[CH3:17]>>[C:16]([C:20]1[CH:25]=[CH:24][C:23]2[NH:26][C:13]([C@@H:9]([NH:8][C:1](=[O:2])[O:3][C:4]([CH3:5])([CH3:6])[CH3:7])[C@H:10]([OH:11])[CH3:12])=[N:27][C:22]=2[CH:21]=1)([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)c1ccc(N)c(N)c1
Reactant: C[C@@H](O)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Product: C[C@@H](O)[C@H](NC(=O)OC(C)(C)C)c1nc2cc(C(C)(C)C)ccc2[nH]1

Procedure:
The title compound was prepared according to Method 4 Steps 1 and 2 using N-Boc-L-threonine (Preparation 52) and 4-tert-butyl-diaminobenzene.
Reaction SMILES: C([O:3][C:4]([C:6]([C:12]1[S:13][CH:14]=[CH:15][CH:16]=1)=[N:7][N:8]=[C:9](Cl)[CH3:10])=O)C.O.[NH2:18][NH2:19]>C(O)(C)C>[NH2:18][N:19]1[C:4](=[O:3])[C:6]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)=[N:7][N:8]=[C:9]1[CH3:10]
Reactant: NN
Reactant: CCOC(=O)C(=NN=C(C)Cl)c1cccs1
Solvent: O
Solvent: CC(C)O
Product: Cc1nnc(-c2cccs2)c(=O)n1N
Reaction time: 8 h

Procedure:
234 g (0.92 mol) of crude 1-ethoxycarbonyl-4-chloro-4-methyl-1-thien-2-yl-2,3-diazabutadiene were dissolved in 600 ml of isopropanol and 125 g (2.5 mol) of hydrazine hydrate were added at 60° C., whilst stirring. Stirring was continued for 8 hours at 60° C. The reaction solution was concentrated to one-third and water was added. The solid which had precipitated was then filtered off, thoroughly rinsed with water and dried. 125g (65.3% of theory) of 4-amino-3-methyl-6-thien-2-yl-1,2,4-triazin-5-one of melting point 210° C. were obtained.
Reaction SMILES: [NH2:1][C:2]1[C:11]([OH:12])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(O[C:16]([S-])=[S:17])C.[K+].Cl>N1C=CC=CC=1>[S:17]=[C:16]1[NH:1][C:2]2=[C:3]([C:4]([O:6][CH3:7])=[O:5])[CH:8]=[CH:9][CH:10]=[C:11]2[O:12]1
Reactant: CCOC(=S)[S-]
Reactant: COC(=O)c1cccc(O)c1N
Agent: Cl
Agent: [K+]
Solvent: c1ccncc1
Product: COC(=O)c1cccc2oc(=S)[nH]c12
Temperature: 25 °C
Yield: 74.3 %

Procedure:
A mixture of methyl 2-amino-3-hydroxybenzoate from Step A (2.04 g, 12.2 mmol) and potassium O-ethylxanthate (1.37 g, 8.56 mmol) in pyridine (8 mL) was heated to reflux for 2 h, then cooled to room temperature and poured into a mixture of ice-water (45 mL) and conc. HCl (4.8 mL). The resulting precipitate was collected by filtration and washed with water, dried on vacuum to give methyl 2-thioxo-2,3-dihydrobenzoxazole-4-carboxylate (1.33 g, 52%) as a light brown solid: 1H NMR (500 MHz, CDCl3) δ 10.40 (br s, 1H), 7.82 (dd, J 8.0, 1.0 Hz, 1H), 7.49 (dd, J 8.0, 1.0 Hz, 1H), 7.28 (t, J=8.0 Hz, 1H), 4.01 (s, 3H); MS (ESI+) m/z 210 (M+H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2([C:12]3[N:16]4[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:15]4=[N:14][N:13]=3)[CH2:11][CH2:10][CH2:9][CH2:8]2)[CH2:3][CH2:2]1.[CH3:23][S:24](Cl)(=[O:26])=[O:25].N1C=CC=CC=1>C(Cl)Cl.C(=O)(O)[O-].[Na+]>[CH3:23][S:24]([N:1]1[CH2:6][CH2:5][CH:4]([C:7]2([C:12]3[N:16]4[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:15]4=[N:14][N:13]=3)[CH2:8][CH2:9][CH2:10][CH2:11]2)[CH2:3][CH2:2]1)(=[O:26])=[O:25]
Reactant: C1CCCn2c(nnc2C2(C3CCNCC3)CCCC2)CC1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)N1CCC(C2(c3nnc4n3CCCCCC4)CCCC2)CC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
3-(1-Piperidin-4-ylcyclopentyl)-5,6,7,8,9,10-hexahydro[1,2,4]triazolo[4,3-a]azocine (302 mg) was dissolved in methylene chloride (5 ml) and then methanesulfonyl chloride (0.09 ml) and pyridine (0.24 ml) were added thereto, followed by stirring at room temperature for 6 hours. Furthermore, methanesulfonyl chloride (0.09 ml) and pyridine (0.57 ml) were added thereto, followed by stirring at room temperature for 16 hours. The reaction solution was diluted with a saturated aqueous sodium bicarbonate solution, followed by extraction with chloroform (10 ml×2). The organic layer was dried over anhydrous sodium sulfate and filtered and then the solvent was removed by evaporation under reduced pressure. The resulting residue was purified by column chromatography (methanol:chloroform=1:9) and then the resulting solid washed with ethyl acetate to obtain 117 mg of 3-{1-[1-(methylsulfonyl)-4-piperidinyl]cyclopentyl}-5,6,7,8,9,10-hexahydro[1,2,4]triazolo[4,3-a]azocine (white solid).
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C:6]1[N:7]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:8]2[C:13]([CH:14]=1)=[C:12]([OH:15])[CH:11]=[CH:10][CH:9]=2)=[O:5].[CH2:23]([O:25][C:26]1[CH:36]=[CH:35][C:29]2[C:30]([CH2:33]O)=[CH:31][O:32][C:28]=2[CH:27]=1)[CH3:24].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC([O-])=O>C1COCC1>[CH3:1][CH2:2][O:3][C:4]([C:6]1[N:7]([C:16]([O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:17])[C:8]2[C:13]([CH:14]=1)=[C:12]([O:15][CH2:33][C:30]1[C:29]3[CH:35]=[CH:36][C:26]([O:25][CH2:23][CH3:24])=[CH:27][C:28]=3[O:32][CH:31]=1)[CH:11]=[CH:10][CH:9]=2)=[O:5]
Reactant: CCOc1ccc2c(CO)coc2c1
Reactant: CCOC(=O)c1cc2c(O)cccc2n1C(=O)OC(C)(C)C
Agent: CCOC(=O)N=NC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2c(OCc3coc4cc(OCC)ccc34)cccc2n1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 16 h

Procedure:
4-Hydroxy-indole-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester (2) (5.2 g, 17.2 mmol), (6-ethoxy-benzofuran-3-yl)-methanol (28a) (3.3 g, 17.2 mmol) and triphenylphosphine (5.4 g, 20.6 mmol) are dissolved in 30 ml of THF and cooled to 0° C. Then 40% ethyl azodicarboxylate solution in THF (9 ml, 20.6 mmol) is added drop wise. After completed addition the mixture is stirred for 16 h (TLC control) at rt. Then the mixture is evaporated under reduced pressure. The residue is diluted with ethyl acetate, washed sat. NaHCO3- and NaCl-solution, and dried over Na2SO4. The crude product is purified by Flash-chromatography (ethyl acetate/hexanes (1:9), silicagel).
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:15])=[C:4]([CH2:9][C@@H:10]([N:12]=[N+]=[N-])[CH3:11])[CH:5]=[CH:6][C:7]=1[F:8]>CCOC(C)=O.[Pd]>[F:1][C:2]1[C:3]([CH3:15])=[C:4]([CH2:9][C@@H:10]([NH2:12])[CH3:11])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Cc1c(C[C@H](C)N=[N+]=[N-])ccc(F)c1F
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cc1c(C[C@H](C)N)ccc(F)c1F
Yield: 85.3 %

Procedure:
To a solution of (1S)-2-(3,4-difluoro-2-methylphenyl)-1-methylethyl azide (503 mg, 2.38 mmol) in 50 mL of EtOAc was added Pd/C (150 mg of 10% Pd) and the mixture was hydrogenated under hydrogen balloon for 1 h. The catalyst was removed by filtration through celite, then passed through silicagel plug eluting first with EtOAc (40 mL), then MeOH/EtOAc/NH4OH 20:75:5 (120 mL). The fraction with product was evaporated to give (1S)-2-(3,4-difluoro-2-methylphenyl)-1-methylethylamine (376 mg, 85%) as pale oil. ESI-MS: m/z (MH+) 186.4. 1H NMR (300 MHz, CDCl3): δ 6.82-6.97 (m, 2H), 3.12 (m, 1H), 2.48-2.73 (m, 2H), 2.25 (s, 3H), 1.34 (s, 2H), 1.12 (d, J=6.39 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH2:15][O:16][CH:17]2[CH:22]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][CH2:32][O:33][CH2:34][C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=4[O:41][CH3:42])=[CH:25][CH:24]=3)[CH2:21][CH2:20][N:19]([C:43]([O:45][CH2:46][C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)=[O:44])[CH2:18]2)=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:11][C:12]#[N:13])[CH:8]=[C:7]2[CH3:14].B#B.CO>O1CCCC1>[NH2:13][CH2:12][CH2:11][N:9]1[C:10]2[C:6](=[CH:5][CH:4]=[C:3]([CH2:15][O:16][CH:17]3[CH:22]([C:23]4[CH:24]=[CH:25][C:26]([O:29][CH2:30][CH2:31][CH2:32][O:33][CH2:34][C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=5[O:41][CH3:42])=[CH:27][CH:28]=4)[CH2:21][CH2:20][N:19]([C:43]([O:45][CH2:46][C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=4)=[O:44])[CH2:18]3)[C:2]=2[Br:1])[C:7]([CH3:14])=[CH:8]1
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OCc3ccccc3)CC2OCc2ccc3c(C)cn(CC#N)c3c2Br)cc1
Agent: B#B
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OCc3ccccc3)CC2OCc2ccc3c(C)cn(CCN)c3c2Br)cc1

Procedure:
The solution of 0.240 g of benzyl 3-(7-bromo-1-cyanomethyl-3-methyl-1H-indol-6-ylmethoxy)-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate in 1.5 ml of tetrahydrofuran is cooled to 0° C. with stirring and admixed with 1.22 ml of diborane (1M in tetrahydrofuran). The reaction mixture is stirred at 0° C. over 1 hour and subsequently admixed cautiously with 1.0 ml of methanol and concentrated by evaporation. The title compound is obtained as a yellow oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.46 (200:20:1 dichloromethane-methanol-conc. ammonia); Rt=5.45.
Reaction SMILES: [O:1]1[C@H:5]2[O:6][CH2:7][CH2:8][C@H:4]2[C@@H:3]([OH:9])[CH2:2]1.O1[C@H]2OCC[C@H]2[C@H](O)C1.O1[C@@H]2OCC[C@@H]2[C@H](O)C1.O1[C@@H]2OCC[C@@H]2[C@@H](O)C1.P([O-])([O-])(O)=O.[K+].[K+].Cl[O-].[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+].P(=O)(O)(O)O>C(C(C)=O)C.O>[O:1]1[C@H:5]2[O:6][CH2:7][CH2:8][C@H:4]2[C:3](=[O:9])[CH2:2]1
Reactant: O[C@H]1CO[C@H]2OCC[C@H]21
Agent: O=P(O)(O)O
Agent: O=P([O-])([O-])O
Agent: O=S([O-])([O-])=S
Solvent: CCC(C)=O
Solvent: O
Product: O=C1CO[C@H]2OCC[C@@H]12
Temperature: 0 °C
Reaction time: 1 h
Yield: 79.1 %

Procedure:
A mixture (287 g, content 69.7%, 1.54 mol) containing (3R,3aS,6aR)-hexahydrofuro[2,3,b]furan-3-ol, (3S,3aS,6aR)-hexahydrofuro[2,3,b]furan-3-ol, (3S,3aR,6aS)-hexahydrofuro[2,3,b]furan-3-ol and (3R,3aR,6aS)-hexahydrofuro[2,3,b]furan-3-ol obtained by the same method as in Example 4 was dissolved in methyl ethyl ketone (2000 ml), and to this was added a solution prepared by dissolving dipotassium hydrogen phosphate (937 g, 5.38 mmol) in water (600 ml). To this was added 2,2,6,6-tetramethylpiperidinyl-1-oxy (1.2 g, 7.7 mmol), and the mixture was cooled to about 0° C. A sodium hypochlorite aqueous solution (1490 g, effective chlorine concentration 13.5%, 2.83 mol) was dropped at 15° C. or less, and the mixture was stirred for 1 hour. After completion of the reaction, a 10% sodium thiosulfate aqueous solution (220 ml) was added and the mixture was stirred for 30 minutes and neutralized with 85% phosphoric acid, and liquid-partitioned. Further, the aqueous layer was extracted twice with methyl ethyl ketone (1000 ml) and the organic layers were combined. To the organic layer was added 1.0 g of hydroquinone, and 3000 ml of the solvent was distilled off. To the concentrated residue was added anhydrous magnesium sulfate (30 g), sodium bicarbonate (20 g) and activated carbon (10 g) and the mixture was stirred for 1 hour. Magnesium sulfate, sodium bicarbonate and activated carbon were filtrated, then, 2-propanol (3000 ml) was added, and the solvent (3300 ml) was distilled off, then, recrystallization was carried out to obtain a white crystal (3aR,6aR)-tetrahydrofuro[2,3-b]furan-3(2H)-one (156.5 g, purity 99.5%, yield 79.1%). At this stage, the enantiomer excess was 100% ee.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:12]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)[CH3:13])[CH:6]=[N:5]2.C([N:29]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[N:30]1)(OC(C)(C)C)=O.C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+]>O1CCOCC1.C(OCC)(=O)C.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[F:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][N:12]([CH3:13])[C:7]2[CH:6]=[N:5][C:4]3[C:9](=[CH:10][CH:11]=[C:2]([C:32]4[CH:33]=[N:29][NH:30][CH:31]=4)[CH:3]=3)[N:8]=2)=[CH:16][CH:17]=1
Reactant: CC(C)(C)OC(=O)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CN(Cc1ccc(F)cc1)c1cnc2cc(Br)ccc2n1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CN(Cc1ccc(F)cc1)c1cnc2cc(-c3cn[nH]c3)ccc2n1
Temperature: 110 °C

Procedure:
(6-Bromo-quinoxalin-2-yl)-(4-fluoro-benzyl)-methyl-amine (0.4 g, 1.1 mmol), 1-Boc-4-pyrazole boronic acid pinacol ester (0.4 g, 1.3 mmol), caesium carbonate (1.5 g, 4.6 mmol) and potassium iodide (0.018 g, 0.1 mmol) were dissolved in 1,4-dioxane (20 mL) at room temperature. The reaction mixture was degassed at RT under vacuum and placed under an atmosphere of nitrogen. The process was repeated twice and slowly Bis(tri-tert-butylphosphine)palladium(0) (0.059 g 0.1 mmol) was added at room temperature. The reaction mixture was heated by microwave irradiation at 110° C. for 180 min. After completion of the reaction, the reaction mixture was diluted with ethyl acetate (150 mL) and washed with water (3×20 mL) and brine (20 mL). The organic volatiles were removed under vacuum to give a residual solid.
Reaction SMILES: [C:1]1([NH:7][CH2:8][C:9]([OH:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:12](O)=[O:13].C(OC(=O)C)(=O)C>>[CH:12]([N:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:8][C:9]([OH:11])=[O:10])=[O:13]
Reactant: O=CO
Reactant: O=C(O)CNc1ccccc1
Solvent: CC(=O)OC(C)=O
Product: O=CN(CC(=O)O)c1ccccc1
Yield: 3503.5 %

Procedure:
7.56 g (50 mmole) of N-phenyl glycine and 54.87 g (1.19 mmole) of formic acid were transferred into a reaction vessel and 16.23 g (159 mol) of acetic anhydride was added dropwise over about 10 minutes while cooling and stirring. The reaction mixture was stirred for one hour at 0° C. and for two hours at room temperature. The resulting reaction mixture was concentrated under vacuum to obtain crude crystals. The crystals were recrystallized from ethanol-isopropyl ether to obtain 7.47 g of the title compound (yield 83.4%).
Reaction SMILES: [CH3:1][Si:2]([C:5]#[CH:6])([CH3:4])[CH3:3].I[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)=[CH:10][CH:9]=1>C(N(CC)CC)C.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.[Cu]I>[CH3:1][Si:2]([C:5]#[C:6][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)=[CH:12][CH:13]=1)([CH3:4])[CH3:3]
Reactant: C#C[Si](C)(C)C
Reactant: Ic1ccc(-c2ccccn2)cc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1ccc(-c2ccccn2)cc1
Temperature: 25 °C
Reaction time: 40 h
Yield: 71.5 %

Procedure:
Trimethylsilylacetylene (4.1 mL, 28.8 mmol) and tetrakis(triphenylphosphine)palladium (0) (832 mg, 0.72 mmol) were added to a suspension of (1) (4.06 g, 14.4 mmol) and copper (I) iodide (274 mg, 1.44 mmol) in triethylamine (120 mL) that had been deoxygenated with argon. The mixture was deoxygenated with argon and then stirred under argon at room temperature for 40 hours. Aqueous hydrochloric acid (3 M, 320 mL) and dichloromethane (250 mL) were added. The organic layer was separated and the aqueous layer was extracted with dichloromethane (3×50 mL). The combined organic layers were washed with aqueous hydrochloric acid (3 M, 30 mL), water (250 mL), brine (250 mL), dried over anhydrous magnesium sulfate, filtered and then the solvent was completely removed. The residue was purified by column chromatography over silica using a dichloromethane/light petroleum mixture (1:4) as the eluent. The main band was isolated and the solvent completely removed to give (2) (2.59 g, 72%).
Reaction SMILES: [CH:1]1([C:6]2[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=2)[CH2:9]O)[CH2:5][CH2:4][CH2:3][CH2:2]1.P(Br)(Br)[Br:15]>C(Cl)Cl>[CH:1]1([C:6]2[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=2)[CH2:9][Br:15])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: BrP(Br)Br
Reactant: OCc1cccc(C2CCCC2)c1
Solvent: ClCCl
Product: BrCc1cccc(C2CCCC2)c1
Yield: 100 %

Procedure:
According to example 17, 5.77 g of 3-cyclopentylbenzyl alcohol was treated with 1.09 mL of PBr3 in 25 mL of anhydrous CH2Cl2 to afford 7.85 g (100%) of 3-cyclopentylbenzyl bromide as a light yellow liquid.