Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH2:2]([NH2:6])[CH2:3][C:4]#[CH:5].C(N(CC)CC)C.[N:14]1([C:20](Cl)=[O:21])[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1>C(Cl)Cl>[CH2:2]([NH:6][C:20]([N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)=[O:21])[CH2:3][C:4]#[CH:5]
Reactant: O=C(Cl)N1CCOCC1
Reactant: C#CCCN
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C#CCCNC(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.6 %

Procedure:
To a suspension of but-3-yn-1-amine hydrochloride (200 mg, 1.89 mmol) and triethylamine (425 μL, 3.78 mmol) in DCM (60 mL) was added morpholine-4-carbonyl chloride (218 μL, 1.89 mmol). The reaction was stirred at RT overnight and then washed with aq hydrochloric acid (2 M, 2×20 mL), saturated aq sodium bicarbonate (2×20 mL), dried, filtered and evaporated in vacuo. The residue was purified by flash column chromatography, eluting with 0-100% ethyl acetate in heptane, to afford the title compound (13) (164 mg, 48%) as a white solid. 1H NMR (500 MHz, DMSO-d6) δ: 2.28 (2H, td), 2.82 (1H, t), 3.09-3.18 (2H, m), 3.20-3.27 (4H, m), 3.48-3.57 (4H, m), 6.74 (1H, t).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:24]=[C:23]([N:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)[CH:22]=[CH:21][C:16]=2[C:17]([O:19]C)=[O:18])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-].CO>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:24]=[C:23]([N:25]3[CH2:26][CH2:27][CH2:28][CH2:29]3)[CH:22]=[CH:21][C:16]=2[C:17]([OH:19])=[O:18])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc(N2CCCC2)cc1OC1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(N3CCCC3)ccc2C(=O)O)CC1
Temperature: 60 °C
Yield: 78.2 %

Procedure:
A mixture of methyl 2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-(pyrrolidin-1-yl)benzoate (9.133 g, 22.6 mmol), 1 M LiOH (40 mL, 40 mmol), MeOH (30 mL) and THF (90 mL) was heated at 60° C. for 14 h. The reaction mixture was concentrated to one-third of its initial volume, diluted with EtOAc (700 mL), and washed with satd citric acid (3×50 mL), and water (3×50 mL) before it was dried (Na2SO4), filtered, and concentrated to give the title compound (6.90 g, 78%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[CH3:9].[N+:10]([O-])([OH:12])=[O:11].S(=O)(=O)(O)O>C(OC(=O)C)(=O)C>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][C:3]=1[CH3:9]
Reactant: Cc1ccc(C)c(Br)c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: CC(=O)OC(C)=O
Product: Cc1cc([N+](=O)[O-])c(C)cc1Br
Temperature: 25 °C
Reaction time: 1 h

Procedure:
740 g of bromo-p-xylene were initially introduced in acetic anhydride (ice-bath cooling) and nitrating acid (prepared from 400 ml of fuming nitric acid and 480 ml of concentrated sulfuric acid) was slowly added dropwise. During the addition, it was ensured that the internal temperature remained between 22° C.-25° C. When the addition was complete (duration about 5 hours), the ice bath was removed, and the mixture was stirred at RT for about a further 1 hour.
Reaction SMILES: C(OC([O:8][C:9]1[CH:10]=[CH:11][C:12]([C@@H:20]([O:82][Si](C(C)(C)C)(C)C)[CH2:21][N:22]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][O:36][CH2:37][CH2:38][CH2:39][CH2:40][C:41]2[CH:46]=[CH:45][C:44]([NH:47][C:48](=[O:81])[C:49]3[CH:54]=[CH:53][CH:52]=[C:51]([S:55]([C:58]4[CH:59]=[C:60]5[C:65](=[C:66]([CH3:68])[CH:67]=4)[N:64]=[CH:63][C:62]([C:69](=[O:71])[NH2:70])=[C:61]5[NH:72][C:73]4[CH:78]=[CH:77][CH:76]=[C:75]([O:79][CH3:80])[CH:74]=4)(=[O:57])=[O:56])[CH:50]=3)=[CH:43][CH:42]=2)C(=O)OC(C)(C)C)=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[CH:14]2)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[OH:82][C@H:20]([C:12]1[CH:11]=[CH:10][C:9]([OH:8])=[C:18]2[C:13]=1[CH:14]=[CH:15][C:16](=[O:19])[NH:17]2)[CH2:21][NH:22][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][O:36][CH2:37][CH2:38][CH2:39][CH2:40][C:41]1[CH:46]=[CH:45][C:44]([NH:47][C:48]([C:49]2[CH:50]=[C:51]([S:55]([C:58]3[CH:59]=[C:60]4[C:65](=[C:66]([CH3:68])[CH:67]=3)[N:64]=[CH:63][C:62]([C:69]([NH2:70])=[O:71])=[C:61]4[NH:72][C:73]3[CH:78]=[CH:77][CH:76]=[C:75]([O:79][CH3:80])[CH:74]=3)(=[O:56])=[O:57])[CH:52]=[CH:53][CH:54]=2)=[O:81])=[CH:43][CH:42]=1
Reactant: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)Nc5ccc(CCCCOCCCCCCN(C[C@H](O[Si](C)(C)C(C)(C)C)c6ccc(OC(=O)OC(C)(C)C)c7[nH]c(=O)ccc67)C(=O)OC(C)(C)C)cc5)c4)cc23)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)Nc5ccc(CCCCOCCCCCCNC[C@H](O)c6ccc(O)c7[nH]c(=O)ccc67)cc5)c4)cc23)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The concentrated reaction mixture containing Intermediate 159 was taken up in dichloromethane (5 mL) and treated with trifluoroacetic acid (1 mL). After stirring overnight at room temperature, the mixture was concentrated under reduced pressure. The residue was taken up in tetrahydrofuran (1 mL) and treated with TBAF solution (1.0 M in THF, 1 mL) and glacial acetic acid (0.30 mL). The mixture was stirred overnight in a 40° C. oil bath, and then concentrated under reduced pressure. The residue was purified by reverse-phase high performance liquid chromatography (RP-HPLC, acetonitrile/water/0.1% TFA) to provide, after concentration, the trifluoroacetic acid salt of the title compound as a yellow powder (16 mg).
Reaction SMILES: C(OC(=O)[N:7]([C:17]1[CH:22]=[CH:21][C:20]([CH:23]([C:25]2[C:33]3[C:28](=[N:29][CH:30]=[C:31]([Br:34])[CH:32]=3)[N:27]([S:35]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)(=[O:37])=[O:36])[CH:26]=2)O)=[C:19]([F:44])[N:18]=1)CC1C=CC(OC)=CC=1)(C)(C)C.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>ClCCCl>[C:38]1([S:35]([N:27]2[C:28]3=[N:29][CH:30]=[C:31]([Br:34])[CH:32]=[C:33]3[C:25]([CH2:23][C:20]3[CH:21]=[CH:22][C:17]([NH2:7])=[N:18][C:19]=3[F:44])=[CH:26]2)(=[O:36])=[O:37])[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: COc1ccc(CN(C(=O)OC(C)(C)C)c2ccc(C(O)c3cn(S(=O)(=O)c4ccccc4)c4ncc(Br)cc34)c(F)n2)cc1
Agent: CC[SiH](CC)CC
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccc(Cc2cn(S(=O)(=O)c3ccccc3)c3ncc(Br)cc23)c(F)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 52.9 %

Procedure:
In a round bottom flask, {5-[(1-benzenesulfonyl-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-hydroxy-methyl]-6-fluoro-pyridin-2-yl}-(4-methoxy-benzyl)-carbamic acid tert-butyl ester (166, 1.15 g, 1.65 mmol) was combined with 50 mL of 1,2-dichloroethane, trifluoroacetic acid (0.635 mL, 8.24 mmol), and triethylsilane (1.32 mL, 8.24 mmol). The reaction was heated at reflux for 20 hours, then concentrated under vacuum. The residue was dissolved in 10 mL of trifluoroacetic acid and stirred at room temperature for 18 hours, then concentrated under vacuum and combined with aqueous sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with sodium bicarbonate, water and brine, then dried over magnesium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material was purified by silica gel column chromatography eluting with ethyl acetate and hexane. Appropriate fractions were combined and concentrated under vacuum to provide the desired compound (167, 403 mg). MS (ESI) [M−H+]−=460.8 and 462.8.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[OH:9].O.[CH2:11](OC(OCC)OCC)C>Cl>[O:9]1[C:3]2[CH:4]=[CH:5][C:6]([OH:8])=[CH:7][C:2]=2[N:1]=[CH:11]1
Reactant: Nc1cc(O)ccc1O
Reactant: CCOC(OCC)OCC
Agent: Cl
Solvent: O
Product: Oc1ccc2ocnc2c1
Temperature: 65 °C
Reaction time: 16 h
Yield: 81 %

Procedure:
To a solution of 2-aminobenzene-1,4-diol (2.40 g, 19.2 mmol) in triethylorthoformate (10 mL) was added 3 drops of concentrated HCl. After heating to 65° C. for 30 minutes and stirring at room temperature for 16 hours, the mixture was poured into water and extracted with ethyl acetate (2×). The organic phase was washed with HCl (2N) and saturated NaHCO3, dried, and concentrated under reduced pressure to provide the product (2.09 g, 81%) as red-black solid.
Reaction SMILES: [C:1](SC)(=O)[S:2]C.[C:7]([OH:13])(=[O:12])/[CH:8]=[CH:9]/[CH2:10][CH3:11].[OH-].[K+]>>[CH3:1][S:2][CH:9]([CH2:10][CH3:11])[CH2:8][C:7]([OH:13])=[O:12]
Reactant: CSC(=O)SC
Reactant: CC/C=C/C(=O)O
Agent: [K+]
Agent: [OH-]
Product: CCC(CC(=O)O)SC
Temperature: 90 °C
Reaction time: 3 h
Yield: 151.8 %

Procedure:
S,S-dimethyl carbonodithioate (1.467 g, 12.00 mmol) was added with vigorous stirring to a solution of (E)-pent-2-enoic acid (2.002 g, 20 mmol) in 30% KOH solution (prepared from potassium hydroxide (3.87 g, 69 mmol) and Water (10 mL)). The reaction mixture was slowly heated to 90° C. over a period of 20-30 min Heating was continued for 3 hours before the reaction was cooled down to 25° C. and quenched slowly with HCl. The mixture was then extracted with DCM (3×30 mL), combined organic layer dried and concentrated to give 3-(methylthio)pentanoic acid (2.7 g, 18.22 mmol, 91% yield) as light orange oil: IR (Thin film) 2975, 1701 cm−1; 1H NMR (400 MHz, CDCl3) δ 2.92 (qd, J=7.3, 5.6 Hz, 1H), 2.63 (d, J=7.2 Hz, 2H), 2.08 (s, 3H), 1.75-1.51 (m, 2H), 1.03 (t, J=7.4 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 178.14, 43.95, 39.78, 27.04, 12.95, 11.29; EIMS m/z 148.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:11])[CH2:7][C:8]([CH3:10])=[O:9].[CH2:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH2:14][NH:13]1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH2:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH2:14][N:13]1[CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:11])[CH2:7][C:8]([CH3:10])=[O:9]
Reactant: CC(=O)CC(=O)NCCCBr
Reactant: c1ccc2c(c1)CCNC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)CC(=O)NCCCN1CCc2ccccc2C1
Temperature: 25 °C

Procedure:
A suspension of N-(3-bromopropyl)acetoacetamide (4.50 g, 20.3 mmol, 1.00 equiv), 1,2,3,4-tetrahydroisoquinoline (3.30 mL, 26.3 mmol, 1.30 equiv), K2CO3 (3.64 g, 26.3 mmol, 1.30 equiv), and KI (330 mg, 1.99 mmol, 0.10 equiv) in acetone (60 mL) was stirred at reflux for 14 hours. The mixture was cooled to room temperature, filtered, and concentrated. The residue was purified by flash chromatography (SiO2, MeOH--EtOAc 0:1 to 1:9) to give 1.78 g (43%) of light yellow oil, which was characterized spectroscopically. N-(3-Bromopropyl)acetoacetamide (1.20 g) was also recovered.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11]C)[CH:8]=[CH:7][C:5]=2[N:6]=1.B(Br)(Br)Br>ClCCl>[NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: COc1ccc2nc(N)sc2c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Nc1nc2ccc(O)cc2s1
Temperature: 0 °C
Reaction time: 3 h
Yield: 78.6 %

Procedure:
A suspension of 2-amino-6-methoxybenzothiazole (5.00 g, 27.8 mmol) in dichloromethane (70 mL) was cooled to 0° C. under nitrogen and boron tribromide (3.93 mL, 41.6 mmol) was added dropwise. The light yellow mixture was stirred for 3 h, allowing to warm-up slowly from 0° C. to 10° C. The reaction was slowly quenched by dropwise addition of methanol and tafter stirring overnight at room temperature, the white solid was collected by filtration (6.04 g, 88% yield). This hydrobromic salt was dissolved in water, washed with ethyl acetate, and neutralized with a saturated aqueous solution of NaHCO3. The resulting crystals were collected by filtration and dried in the oven at 135° C. for 1 h to afford the title compound 225 as colorless crystals (3.63 g, 79% yield). 1H NMR: (CD3OD) δ (ppm): 7.27 (d, J=8.8 Hz, 1H), 7.08 (d, J=2.2 Hz, 1H), 6.80 (dd, J=8.4, 2.2 Hz, 1H).
Reaction SMILES: C(OCC)(=O)C.[C:7]1([S:13][C:14]2[CH:21]=[CH:20][C:17]([CH2:18][NH2:19])=[CH:16][CH:15]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C.CC1C=CC(OC2C=CC(CN[C:41]([C:43]3[N:47]([CH3:48])[N:46]=[C:45]([CH2:49][CH3:50])[C:44]=3[Cl:51])=[O:42])=CC=2)=CC=1>O>[C:7]1([S:13][C:14]2[CH:21]=[CH:20][C:17]([CH2:18][NH:19][C:41]([C:43]3[N:47]([CH3:48])[N:46]=[C:45]([CH2:49][CH3:50])[C:44]=3[Cl:51])=[O:42])=[CH:16][CH:15]=2)[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: NCc1ccc(Sc2ccccc2)cc1
Reactant: CCc1nn(C)c(C(=O)NCc2ccc(Oc3ccc(C)cc3)cc2)c1Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: CCc1nn(C)c(C(=O)NCc2ccc(Sc3ccccc3)cc2)c1Cl
Reaction time: 1.5 h

Procedure:
Into 50 ml solution of ethyl acetate containing 3.50 g of 4-phenylthiobenzylamine and 2.2 g of triethylamine, was dropped 3.60 g of 4-chloro-3-ethyl-1-methyl-5-pyrazolecarboxylic acid chloride synthesized in Example 2. After the completion of dropping, the mixture was stirred for 1.5 hours, poured into iced water and then extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous solution of sodium carbonate, water and a saturated aqueous solution of sodium chloride. After drying over anhydrous sodium sulfate, the solution was concentrated under a reduced pressure. The residue was purified on silica gel column chromatography to obtain 4.70 g of the titled compound (No. 76) shown in Table 1.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[NH:15][C:16]1[CH:25]=[C:24]([C:26]#[N:27])[C:19]([C:20]([O:22]C)=O)=[C:18]([C:28]2[CH:29]=[N:30][N:31]([CH3:33])[CH:32]=2)[N:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>[Pd].CO.CC(O)=O>[CH3:33][N:31]1[CH:32]=[C:28]([C:18]2[C:19]3[C:20](=[O:22])[NH:27][CH2:26][C:24]=3[CH:25]=[C:16]([NH:15][C@@H:10]3[CH2:11][CH2:12][CH2:13][CH2:14][C@@H:9]3[NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:4])[CH3:2])[N:17]=2)[CH:29]=[N:30]1
Reactant: COC(=O)c1c(C#N)cc(N[C@@H]2CCCC[C@@H]2NC(=O)OC(C)(C)C)nc1-c1cnn(C)c1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: Cn1cc(-c2nc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)cc3c2C(=O)NC3)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58.1 %

Procedure:
A solution of methyl 6-((1R,2S)-2-(tert-butoxycarbonylamino)cyclohexylamino)-4-cyano-2-(1-methyl-1H-pyrazol-4-yl)nicotinate (110 mg, 0.242 mmol) and palladium on carbon (2.58 mg, 0.024 mmol) in MeOH (5 mL) and HOAc (1 mL) was stirred at RT overnight under H2 atmosphere. After reaction, the mixture was filtered through Celite, the filtrate was evaporated, and the residue was diluted with MeOH and sat aq NaHCO3. The mixture was stirred at RT for 30 min and extracted with EtOAc. The organic phase was washed with brine, dried over MgSO4, and evaporated. The residue was purified by chromatography on SiO2 and preparative HPLC to give the title compound (60 mg, 58.1%). 1H NMR (500 MHz, CDCl3) δ ppm 1.26-1.87 (m, 17 H), 3.91 (s, 3 H), 4.25 (br s, 2 H), 5.16-5.49 (m 2 H), 6.23 (br s, 1 H), 6.75 (br s, 1 H), 8.18-8.44 (m, 1 H), 8.76-9.05 (m, 1 H).
Reaction SMILES: C[Mg]Br.[CH2:4]([N:11]1[CH2:16][CH2:15][C:14](=[O:17])[CH2:13][CH2:12]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.O1CCC[CH2:19]1.[Cl-].[NH4+]>C(OCC)C>[CH2:4]([N:11]1[CH2:16][CH2:15][C:14]([CH3:19])([OH:17])[CH2:13][CH2:12]1)[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: C1CCOC1
Agent: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CC1(O)CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 72 %

Procedure:
To a solution of methyl magnesium bromide (6.00 mmol) in ethyl ether (27 mL) was added 1-benzyl-piperidin-4-one (0.53 g, 0.28 mmol) at 0° C. followed by tetrahydrofuran (10 mL). The reaction mixture was warmed to room temperature and stirred for 18 h. Saturated ammonium chloride was added and the aqueous layer was extracted with ethyl acetate (3×). The combined organic extracts were dried over sodium sulfate, filtered and concentrated. Column chromatography on silica (2-10% methanol in dichloromethane) afforded 1-benzyl-4-methylpiperidin-4-ol (0.42 g, 72% yield).
Reaction SMILES: B(F)(F)F.CCOCC.[C:10]([O:20][CH2:21][CH3:22])([O:17][CH2:18][CH3:19])([O:14][CH2:15][CH3:16])OCC.C([Li])CCC.[CH3:28][Si:29]([C:32]#[CH:33])([CH3:31])[CH3:30].F[B-](F)(F)F.C(O[C+](OCC)OCC)C.C(=O)([O-])[O-].[K+].[K+]>C(OCC)C>[CH3:28][Si:29]([CH3:31])([CH3:30])[C:32]#[C:33][C:10]([O:14][CH2:15][CH3:16])([O:17][CH2:18][CH3:19])[O:20][CH2:21][CH3:22]
Reactant: C#C[Si](C)(C)C
Reactant: CCOC(OCC)(OCC)OCC
Agent: CCO[C+](OCC)OCC
Agent: FB(F)F
Agent: F[B-](F)(F)F
Solvent: CCOCC
Product: CCOC(C#C[Si](C)(C)C)(OCC)OCC
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 98.4 %

Procedure:
Boron trifluoride diethyl etherate (36.0 mL, 280 mmol) was added to diethyl ether (50 mL) under argon. The mixture was transferred to a dropping funnel and added dropwise under argon to a solution of tetraethyl orthocarbonate (40.0 g, 208 mmol) in diethyl ether (100 mL) at 0° C. After the addition was complete, the mixture was stirred for 5 min and then cooled to −78° C. In a separate reaction flask, n-butyllithium (166 mL, 2.5 M solution in hexanes, 416 mmol) was added dropwise to a solution of trimethylsilyl acetylene (59.0 mL, 416 mmol) in diethyl ether (200 mL) at 0° C. under argon. After stirring for 1 h at 0° C., the solution was cooled to −78° C. This solution was added via cannula to the triethoxycarbenium tetrafluoroborate formed previously. The mixture was stirred at −78° C. for 1 h before being warming to room temperature. Saturated aqueous potassium carbonate was added and mixture was extracted with diethyl ether. The organic extracts were dried with magnesium sulfate and the solvent was removed under reduced pressure to give the title compound (50.0 g, 100% yield) as yellow oil. 1H NMR (CDCl3) δ 3.68(q, 6H, J=7.2 Hz), 1.23 (t, 9H, J=7.2 Hz), 0.20, (s, 9H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Cl:7][C:8]1[N:16]=[C:15]2[C:11]([NH:12][CH:13]=[N:14]2)=[C:10](Cl)[N:9]=1>C(O)C>[Cl:7][C:8]1[N:16]=[C:15]2[C:11]([N:12]=[CH:13][NH:14]2)=[C:10]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)[N:9]=1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Reactant: C1COCCN1
Solvent: CCO
Product: Clc1nc(N2CCOCC2)c2nc[nH]c2n1
Yield: 98.2 %

Procedure:
Morpholine (46.9 ml, 538.2 mmol) was added to an ethanol solution (1.2 l) of 2,6-dichloropurine (50.9 g, 269.1 mmol) at room temperature and the resulting mixture was stirred and heated to reflux for 2.5 hours. The reaction mixture was left standing to cool and then concentrated until the solvent was reduced nearly by half in volume and the solid was collected by filtration. The solid was washed with ethanol and dried at 50° C. under reduced pressure to give a mixture (63.3 g, 95%) of the title compound and morpholine hydrochloride (approx. 13:1) as a white solid.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:4]([CH2:8][C:9]([OH:11])=O)[CH:5]=[CH:6][N:7]=1.[C:12]([O:15][CH2:16][C:17]1[CH2:24][S:23][CH:22]2[N:19]([C:20](=[O:26])[CH:21]2[NH2:25])[C:18]=1[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])(=[O:14])[CH3:13].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[C:12]([O:15][CH2:16][C:17]1[CH2:24][S:23][CH:22]2[N:19]([C:20](=[O:26])[CH:21]2[NH:25][C:9](=[O:11])[CH2:8][N:4]2[CH:5]=[CH:6][N:7]=[C:3]2[S:2][CH3:1])[C:18]=1[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])(=[O:14])[CH3:13]
Reactant: CSc1nccn1CC(=O)O
Reactant: CC(=O)OCC1=C(C(=O)OC(C)(C)C)N2C(=O)C(N)C2SC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Product: CSc1nccn1CC(=O)NC1C(=O)N2C(C(=O)OC(C)(C)C)=C(COC(C)=O)CSC12
Temperature: 50 °C
Reaction time: 18 h
Yield: 42.6 %

Procedure:
(2-methylthio-imidazol-1-yl)-acetic acid (10.3 g.) is dissolved in dimethylformamide (360 cc.), by heating to 50° C. After cooling, 3-acetoxymethyl-7-amino-2-(tertiary butoxycarbonyl)-8-oxo-5-thia-1-aza-bicyclo[4,2,0]oct-2-ene (21.4 g.) and dicyclohexylcarbodiimide (13.5 g.) are added. The reagents are contacted for 18 hours, with stirring, at a temperature of about 20° C., and then the solid is filtered off. The filtrate is taken up in ethyl acetate (2.5 liters) and is washed with a saturated aqueous solution of sodium bicarbonate and then with water. Extraction is then effected using N hydrochloric acid (400 cc.), and the acid aqueous phase is washed with ethyl ether and then brought to pH 8 by adding a 4 N solution of sodium hydroxide. The oil which separates out is extracted with methylene chloride (500 cc.). The methylene chloride extracts are washed with water, dried over sodium sulphate, treated with decolorising charcoal and concentrated to dryness under reduced pressure (20 mm.Hg.). An orange-yellow oily residue (30.2 g.) is obtained and is purified by crystallisation from a mixture of methanol (32 cc.) and isopropyl ether (210 cc.) to give 3-actoxymethyl-2-(tertiary butoxycarbonyl)-7-[(2-methylthio-imidazol-1-yl)-acetamido]-8-oxo-5-thia-1-aza-bicyclo[4,2,0]oct-2-ene (12.3 g.), m.p. 170° C.
Reaction SMILES: CS(OCCC1C=CC=C(C2C=CSC=2)C=1)(=O)=O.[S:19]1[CH:23]=[CH:22][C:21]([C:24]2[CH:25]=[C:26]([CH:31]=[CH:32][CH:33]=2)[O:27][CH2:28][CH2:29]O)=[CH:20]1.CS(Cl)(=O)=O.[C:39]([O-:42])(=[S:41])[CH3:40].[K+]>C(OCC)(=O)C.CN(C)C=O.O.C(N(CC)CC)C>[C:39]([S:41][CH2:29][CH2:28][O:27][C:26]1[CH:31]=[CH:32][CH:33]=[C:24]([C:21]2[CH:22]=[CH:23][S:19][CH:20]=2)[CH:25]=1)(=[O:42])[CH3:40]
Reactant: OCCOc1cccc(-c2ccsc2)c1
Reactant: CC([O-])=S
Agent: CS(=O)(=O)Cl
Agent: CS(=O)(=O)OCCc1cccc(-c2ccsc2)c1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CC(=O)SCCOc1cccc(-c2ccsc2)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 87.8 %

Procedure:
2-[3-(3-thienyl)phenyl]ethyl methanesulfonate, [synthesized by reacting 100 mg of 2-[3-(3-thienyl)phenoxy]ethanol with 50 μl of methanesulfonyl chloride and 190 μl of triethylamine in 1 ml of ethyl acetate] was dissolved in 1.5 ml of dimethylformamide, and 68 mg of potassium thioacetate was added. The mixture was heated at 80° C. with stirring for 3 hours, and then water and ethyl acetate were added. The organic layer separated was worked up in a customary manner to give 111 mg of S-[2-[3-(3-thienyl)phenoxy]ethyl] thioacetate as a pale brown oil.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([N+:7]([O-])=O)[C:4]([N:10]2[CH2:14][CH2:13][O:12][C:11]2=[O:15])=[N:3]1.[C:16]([O:20][C:21]([N:23]([CH2:49][C:50]([F:53])([F:52])[F:51])[C:24]1[CH:29]=[C:28]([C:30]2[O:31][CH:32]=[C:33]([C:35](OC3C(F)=C(F)C(F)=C(F)C=3F)=[O:36])[N:34]=2)[CH:27]=[CH:26][N:25]=1)=[O:22])([CH3:19])([CH3:18])[CH3:17].C(N(CC)CC)C>CO.[C].[Pd]>[CH3:1][N:2]1[CH:6]=[C:5]([NH:7][C:35]([C:33]2[N:34]=[C:30]([C:28]3[CH:27]=[CH:26][N:25]=[C:24]([N:23]([CH2:49][C:50]([F:52])([F:51])[F:53])[C:21](=[O:22])[O:20][C:16]([CH3:19])([CH3:18])[CH3:17])[CH:29]=3)[O:31][CH:32]=2)=[O:36])[C:4]([N:10]2[CH2:14][CH2:13][O:12][C:11]2=[O:15])=[N:3]1
Reactant: CC(C)(C)OC(=O)N(CC(F)(F)F)c1cc(-c2nc(C(=O)Oc3c(F)c(F)c(F)c(F)c3F)co2)ccn1
Reactant: Cn1cc([N+](=O)[O-])c(N2CCOC2=O)n1
Agent: [Pd]
Solvent: CO
Solvent: CCN(CC)CC
Product: Cn1cc(NC(=O)c2coc(-c3ccnc(N(CC(F)(F)F)C(=O)OC(C)(C)C)c3)n2)c(N2CCOC2=O)n1
Yield: 18.6 %

Procedure:
A solution of 3-(1-methyl-4-nitro-1H-pyrazol-3-yl)-1,3-oxazolidin-2-one (58 mg), pentafluorophenyl 2-(2-((tert-butoxycarbonyl) (2,2,2-trifluoroethyl)amino)pyridin-4-yl)-1,3-oxazole-4-carboxylate (197 mg), 10% palladium-carbon (29 mg) and triethylamine (76 μL) in methanol (1.4 mL) was stirred overnight at room temperature under hydrogen atmosphere. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (28 mg).