Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C([NH:20][CH:21]2[C:49](=[O:50])[N:23]3[CH:24]([C:29]4[N:33]([CH2:34][C:35]5[CH:40]=[CH:39][C:38]([O:41][CH2:42][C:43]6[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=6)=[CH:37][CH:36]=5)[N:32]=[N:31][N:30]=4)[C:25]([CH3:28])([CH3:27])[S:26][C@H:22]23)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.CC(C)=O>CCOCC>[NH2:20][CH:21]1[C:49](=[O:50])[N:23]2[CH:24]([C:29]3[N:33]([CH2:34][C:35]4[CH:36]=[CH:37][C:38]([O:41][CH2:42][C:43]5[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=5)=[CH:39][CH:40]=4)[N:32]=[N:31][N:30]=3)[C:25]([CH3:28])([CH3:27])[S:26][C@H:22]12
Reactant: CC1(C)S[C@@H]2C(NC(c3ccccc3)(c3ccccc3)c3ccccc3)C(=O)N2C1c1nnnn1Cc1ccc(OCc2ccccc2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)=O
Solvent: CCOCC
Product: CC1(C)S[C@@H]2C(N)C(=O)N2C1c1nnnn1Cc1ccc(OCc2ccccc2)cc1
Reaction time: 0.05 h
Yield: 69 %

Procedure:
A solution consisting of 558 mg. of 6-(triphenylmethylamino)-2,2-dimethyl-3-(1-[p-benzyloxybenzyl]tetrazol-5-yl)penam, 156 mg. of p-toluenesulfonic acid monohydrate and 1 ml. of acetone is stored at ambient temperature for 2.5 hrs. It is then added with stirring to 50 ml. of ether. After stirring for a further 10 min., the solid which precipitates is filtered. This affords 394 mg. of the p-toluenesulfonate of the product. A 304-mg. aliquot of this p-toluenesulfonate salt is dissolved in 10 ml. of methylene chloride, and to the solution is added 69.7 μl. of triethylamine. After 3 min., 5 ml. of water is added and the mixture is stirred vigorously. The organic phase is then separated off, diluted with ether, dried over anhydrous magnesium sulfate, and evaporated to dryness in vacuo. The residue is 189 mg. (69% yield) of 6-amino-2,2-dimethyl-3-(1-[p-benzyloxybenzyl]tetrazol-5-yl)penam. The NMR spectrum (in CDCl3) of the product shows absorption bands at 7.40 ppm (singlet, phenyl hydrogens), 7.15 ppm (quartet, phenylene hydrogens), 5.55 ppm (broad singlet, C-5 and benzyl hydrogens), 5.20 ppm (singlet, C-3 hydrogens), 5.10 ppm (singlet, benzyl hydrogens) 4.60 ppm (doublet, C-6 hydrogen), 1.50 ppm (singlet, C-2 methyl hydrogens) and 0.90 ppm (singlet, C-2 hydrogens).
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:19])[NH:10][C@@H:11]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:12]([OH:14])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.[CH2:48]([NH:55][NH2:56])[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1.CCN(CC)CC>>[CH2:1]([NH:8][C:9]([NH:10][C@H:11]([C:12]([NH:56][NH:55][CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)=[O:14])[C:15]([CH3:18])([CH3:17])[CH3:16])=[O:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[C@H](NC(=O)NCc1ccccc1)C(=O)O
Reactant: NNCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN1CCOCC1
Product: CC(C)(C)[C@H](NC(=O)NCc1ccccc1)C(=O)NNCc1ccccc1

Procedure:
(L)-tert-Leucine (0.500 g, 3.81 mmol) was dissolved in dioxane (23 mL) and 2M NaOH (6.3 mL, 12.6 mmol) was added. After stirring for 10 min, phenylisocyanate (0.900 mL, 7.29 mmol) was added drop wise to yield a clear solution. The reaction mixture was stirred at room temperature for 18 h and then made acidic by addition of concentrated HCl and thereafter extracted with EtOAc. The organic phase was dried and evaporated to afford (2S)-2-(3-benzyl-ureido)-3,3-dimethyl-butyric acid (0.36 g, 36% yield), which was analysed by NMR and then used without further purification. The general procedure for the preparation of hydrazides described above was then followed using the crude (2S)-2-(3-benzyl-ureido)-3,3-dimethyl-butyric acid (0.646 g, 2.44 mmol), EDAC (0.515 g, 2.67 mmol), HOBT (0.363 g, 2.69 mmol), NMM (0.300 mL, 2.73 mmol), benzylhydrazine×2HCl (0.528 g, 2.71 mmol) and Et3N (0.753 mL, 5.38 mmol). The product was filtered through a short silica column (CHCl3/MeOH, 100:0-95:5) and then used without further purification in the next step.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:7]=[CH:6][S:5][C:4]=1[C:8]([OH:10])=O.S(Cl)([Cl:13])=O>>[CH3:1][S:2][C:3]1[CH:7]=[CH:6][S:5][C:4]=1[C:8]([Cl:13])=[O:10]
Reactant: O=S(Cl)Cl
Reactant: CSc1ccsc1C(=O)O
Product: CSc1ccsc1C(=O)Cl

Procedure:
3-Methylthio-2-thiophenecarboxylic acid (prepared according to Carpenter, A. J., et al., Tetrahedron Letters 26:1777 (1985)) (2.61 g, 15.0 mmoles) was reacted with 10 ml of thionyl chloride to give 2.83 g of crude 3-methylthio-2-thiophenecarbonyl chloride as a light yellow solid. The acid chloride was then coupled to 2.57 g (12.2 mmoles) 5-chloro-2-oxindole-1-carboxamide in the presence of 4.47 g (36.6 mmoles) 4-(N,N-dimethylamino)pyridine as described in Example 32 to give 3.73 g of crude product as an orange solid. The product was partially purified by recrystallization from 2-butanone to give 1.44 g of greenish-yellow solid. Pure title compound was obtained by a second recrystallization from ethyl acetate to give 0.92 g (2.51 mmoles, 21% yield) as a yellow solid. The pure compound initially melts at 178° C. then resolidifies and melts again above 275° C. (dec.).
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=1[O:21][CH3:22].CN(C)[CH:25]=[O:26]>O1CCCC1>[Br:13][C:14]1[C:15]([O:21][CH3:22])=[C:16]([C:17]([F:20])=[CH:18][CH:19]=1)[CH:25]=[O:26]
Reactant: CN(C)C=O
Reactant: COc1cc(F)ccc1Br
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COc1c(Br)ccc(F)c1C=O
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 63.7 %

Procedure:
1.6 M Solution of n-butyllithium in hexanes (3.35 mL, 5.36 mmol) was added dropwise to a solution of N,N-diisopropylamine (0.960 mL, 6.85 mmol) in tetrahydrofuran (10 mL) at −78° C. and the resultant reaction mixture was stirred at −78° C. for 10 min. A solution of 1-bromo-4-fluoro-2-methoxybenzene (1.0 g, 4.9 mmol) in tetrahydrofuran (2 mL) was added to the reaction mixture dropwise at −78° C. and the reaction mixture was stirred at −78° C. for 1 h. N,N-dimethylformamide (0.412 mL, 5.32 mmol) was added to the reaction mixture dropwise at −78° C. and the reaction mixture was stirred at −78° C. for 1 h. Reaction mixture was quenched with saturated ammonium chloride, warmed to 20° C., and diluted with ether and 1M aqueous solution of HCl. Layers were separated and the aqueous layer was and re-extracted with ether. The combined organic layers were washed with brine, dried with magnesium sulfate, filtered, and concentrated in vacuo to give a crude residue. Purification by flash column chromatography (100% hexanes to 30% EtOAc/hexanes) gave the desired product (727 mg, 64%) as a yellow solid. LCMS calculated for C8H7BrFO2 (M+H)+: m/z=233.0, 235.0. found: 233.0, 234.8.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7][C:8]([O:10][CH3:11])=[O:9])=[C:5]([N+:12]([O-:14])=[O:13])[CH:4]=[N:3]1.[H-].[Na+].[CH2:17](Br)[CH:18]=[CH2:19]>CN(C=O)C>[CH3:1][N:2]1[C:6]([CH:7]([CH2:19][CH:18]=[CH2:17])[C:8]([O:10][CH3:11])=[O:9])=[C:5]([N+:12]([O-:14])=[O:13])[CH:4]=[N:3]1
Reactant: C=CCBr
Reactant: COC(=O)Cc1c([N+](=O)[O-])cnn1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCC(C(=O)OC)c1c([N+](=O)[O-])cnn1C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 68.4 %

Procedure:
To a solution of methyl 2-(2-methyl-4-nitro-pyrazol-3-yl)acetate (869 mg, 4.36 mmol) in anhydrous DMF (10 mL) was added at 0° C. sodium hydride (218 mg, 5.45 mmol, 60 mass %), the mixture became dark red right away. After stirring at 0° C. for 15 min, allyl bromide (0.57 mL, 6.54 mmol) was added slowly, stirred at 0° C. for 10 min then room temp for 1 h. The reaction was quenched with water (20 mL) and extracted with EA (200 mL, 50 mL). Combined organic layer was washed with water (15×3 mL), brine (10 mL), dried (MgSO4) and the solvent removed under reduced pressure. The residue was purified via silica gel chromatography (0-100% EtOAc/heptane) to afford methyl 2-(2-methyl-4-nitro-pyrazol-3-yl)pent-4-enoate (713 mg, 68%). 1H NMR (400 MHz, CDCl3) δ 8.10 (s, 1H), 5.71-5.54 (m, 1H), 5.01 (d, J=13.1 Hz, 2H), 4.43 (dd, J=9.8, 5.5 Hz, 1H), 3.86 (s, 3H), 3.72 (s, 3H), 3.14-3.02 (m, 1H), 2.79-2.62 (m, 1H).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[C:15]([F:21])[CH:16]=[C:17]([F:20])[CH:18]=3)[CH:13]=[CH:12][C:11]2=[O:22])[CH:4]([CH3:23])[CH2:3]1.[O:24]1[C:33]2[CH:32]=[C:31]([CH:34]=O)[N:30]=[CH:29][C:28]=2[O:27][CH2:26][CH2:25]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.CO>[O:24]1[C:33]2[CH:32]=[C:31]([CH2:34][NH:1][CH:2]3[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]4[C:19]5[C:14](=[C:15]([F:21])[CH:16]=[C:17]([F:20])[CH:18]=5)[CH:13]=[CH:12][C:11]4=[O:22])[CH:4]([CH3:23])[CH2:3]3)[N:30]=[CH:29][C:28]=2[O:27][CH2:26][CH2:25]1
Reactant: CC1CC(N)CCN1CCn1c(=O)ccc2c(F)cc(F)cc21
Reactant: O=Cc1cc2c(cn1)OCCO2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: CC(Cl)Cl
Product: CC1CC(NCc2cc3c(cn2)OCCO3)CCN1CCn1c(=O)ccc2c(F)cc(F)cc21
Temperature: 0 °C
Reaction time: 16 h
Yield: 60.1 %

Procedure:
A solution of 1-[2-(4-amino-2-methylpiperidin-1-yl)ethyl]-5,7-difluoroquinolin-2(1H)-one (Intermediate 213, crude, 220 mg, 0.69 mmol) and 2,3-dihydro[1,4]dioxino[2,3-c]pyridine-7-carbaldehyde (WO 2004/058144) (114 mg, 0.69 mmol) in dry dichloroethane/methanol (4 mL, 4:1) was heated over 3 Å molecular sieves at 80° C. for 3 hours. The reaction mixture was cooled to 0° C., and sodium triacetoxy borohydride (299 mg, 1.38 mmol) was added. The resulting reaction mixture was stirred at room temperature for 16 hours and then was filtered through a 0.45 μm membrane and concentrated to dryness under reduced pressure. The residue was taken up in dichloromethane (20 mL) and saturated aqueous sodium hydrogen carbonate solution (5 mL). The pH of the aqueous phase was adjusted to pH˜10 with 1M aqueous sodium hydroxide solution. The aqueous phase was back extracted twice with dichloromethane (4×20 mL) and the combined organic phases were dried over sodium sulfate and concentrated under reduced pressure. Chromatography on silica gel with dichloromethane/methanol (17:3) gave 195 mg (69%) of the title compound as a white foam.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C@@H:4]([C@H:6]([C@@H:8]([C@@H:10]([CH2:12][OH:13])[OH:11])[OH:9])[OH:7])[OH:5].C(N(CC)CC)C.[N+:21]([C:24]1[CH:25]=[C:26]([CH:30]=[C:31]([N+:33]([O-:35])=[O:34])[CH:32]=1)[C:27](Cl)=[O:28])([O-:23])=[O:22]>CN(C=O)C.O1CCOCC1>[N+:21]([C:24]1[CH:25]=[C:26]([CH:30]=[C:31]([N+:33]([O-:35])=[O:34])[CH:32]=1)[C:27]([N:2]([CH3:1])[CH2:3][C@@H:4]([C@H:6]([C@@H:8]([C@@H:10]([CH2:12][OH:13])[OH:11])[OH:9])[OH:7])[OH:5])=[O:28])([O-:23])=[O:22]
Reactant: CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: O=C(Cl)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CN(C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO)C(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Reaction time: 2 h

Procedure:
N-Methylglucamine (21.4 g, 0.11 mol) was suspended in DMF (200 ml). Triethylamine (11.5 g, 0.11 mol) was added. To this suspension was at 4° added by stirring 3,5-dinitrobenzoyl chloride (23.0 g, 0.1 mol) dissolved in dioxane (100 ml). The temperature rose to 10°. The stirring was continued at this temperature for 2 hours followed by 16 hours at room temperature. Triethylamine hydrochloride was filtered off and the DMF distilled off from the filtrate. The residue, a pale brown oil, was dissolved in water (200 ml), the pH adjusted to 1 and the solution extracted with phenol according to standard procedure. The final aqueous solution was treated with charcoal at room temperature for 24 hours and the filtrate evaporated to dryness in vacuo. The residue -- a pale brown oil -- was further dried in vacuo at 65°. Yield: 25.5 g (65%). The IR-spectrum showed a characteristic carbonyl absorption band at 1670 -- 1620 cm -1. Rf value: 0.55 - 0.6 (paper, n-BuOH: EtOH: NH3 : H2O= 4 : 1 : 2 : 1).
Reaction SMILES: CCN(C(C)C)C(C)C.Cl.[NH2:11][C@@H:12]([CH2:17][CH:18]=[CH2:19])[C:13]([O:15][CH3:16])=[O:14].[CH2:20]([CH:23]([CH2:27][CH2:28][CH3:29])[C:24](O)=[O:25])[CH2:21][CH3:22].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.Cl>CN(C=O)C>[CH2:20]([CH:23]([CH2:27][CH2:28][CH3:29])[C:24]([NH:11][C@@H:12]([CH2:17][CH:18]=[CH2:19])[C:13]([O:15][CH3:16])=[O:14])=[O:25])[CH2:21][CH3:22]
Reactant: C=CC[C@H](N)C(=O)OC
Reactant: CCCC(CCC)C(=O)O
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: C=CC[C@H](NC(=O)C(CCC)CCC)C(=O)OC
Reaction time: 18 h
Yield: 115.5 %

Procedure:
Step A (1): DIEA (2.52 mL, 14.5 mmol) was added to a mixture of (S)-methyl 2-aminopent-4-enoate hydrochloride (500 mg, 3.03 mmol) [Del Valle, J. R.; Goodman, M. J. of Org. Chem. 2004, 69, 8946-8948], 2-propylpentanoic acid (417 mg, 2.89 mmol), EDC (581 mg, 3.03 mmol), and HOBt (409 mg, 3.03 mmol) in DMF (15 mL) at rt. The mixture was stirred for 18 h and subsequently poured into 200 mL 1M HCl. The aqueous layer was extracted with EtOAc/hexanes (95:5) (2×200 mL). The combined organic extracts were washed with brine, dried with MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography to give (S)-methyl 2-(2-propylpentanamido)pent-4-enoate 852 mg (quantitative yield) as a white solid. LC-MS (M+H)+=256.16. 1H NMR (500 MHz, CDCl3) δ 5.90 (s, 1H) 5.64-5.85 (m, 1H) 4.95-5.14 (m, 2H) 4.04 (dd, J=5.04, 2.29 Hz, 2H) 3.75 (s, 3H) 2.28-2.46 (m, 1H) 2.07-2.29 (m, 2H) 1.62-1.64 (m, 1H) 1.46-1.47 (m, 1H) 1.18-1.36 (m, 4H) 0.87 (t, J=6.87 Hz, 3H).
Reaction SMILES: B.O1CCCC1.[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:19][N:18]([CH2:20][CH2:21][CH3:22])[C:17](=O)[CH2:16][O:15]2)=[CH:10][C:9]=1[O:24][CH3:25]>C1COCC1>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:19][N:18]([CH2:20][CH2:21][CH3:22])[CH2:17][CH2:16][O:15]2)=[CH:10][C:9]=1[O:24][CH3:25]
Reactant: CCCN1CC(c2ccc(Cl)c(OC)c2)OCC1=O
Agent: B
Solvent: C1CCOC1
Product: CCCN1CCOC(c2ccc(Cl)c(OC)c2)C1
Yield: 99.1 %

Procedure:
Borane-tetrahydrofuran complex (1M in THF) (3.5 mL, 3.5 mmol) was added dropwise to a solution of the product from example 52 (0.33 g, 1.16 mmol) in dry THF (3 mL) under an atmosphere of nitrogen. The reaction mixture was refluxed for 2.5 hours then cooled and quenched by addition of methanol (1 mL). The reaction mixture was concentrated in vacuo and the residue suspended in 4N HCl (aq., 8 mL) and refluxed for 2 hours. The reaction mixture was cooled and extracted with dichloromethane (2×10 mL). The organic layers were discarded. The aqueous layer was rendered basic (pH 9-10) by addition of solid potassium carbonate before re-extracting with dichloroethane (2×15 mL). The dichloromethane extracts were washed with water (10 mL), dried over anhydrous magnesium sulphate, filtered and concentrated in vacuo to give the title compound as an oil (0.31 g, 1.15 mmol, 99%). 1H NMR (CDCl3, 400 MHz) δ: 0.95 (t, 3H), 1.45-1.60 (m, 2H), 2.00 (t, 1H), 2.20 (t, 1H), 2.35 (t, 2H), 2.80 (d, 1H), 2.90 (d, 1H), 3.80 (t, 1H), 3.90 (s, 3H), 4.03 (dd, 1H), 4.55 (d, 1H), 6.85 (dd, 1H), 7.00 (S, 1H), 7.30 (dd, 1H). LRMS (APCI): m/z 270 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([CH2:13][NH2:14])=[CH:11][C:10]([C:15]([F:18])([F:17])[F:16])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.CCN(CC)CC.[F:26][C:27]1[CH:28]=[C:29]([NH:35][C:36](=O)[O:37]C2C=CC=CC=2)[CH:30]=[CH:31][C:32]=1[CH2:33][OH:34]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([CH2:13][NH:14][C:36]([NH:35][C:29]3[CH:30]=[CH:31][C:32]([CH2:33][OH:34])=[C:27]([F:26])[CH:28]=3)=[O:37])=[CH:11][C:10]([C:15]([F:16])([F:17])[F:18])=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Nc1ccc(CO)c(F)c1)Oc1ccccc1
Reactant: NCc1cc(C(F)(F)F)nn1-c1cccc(Cl)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCc1cc(C(F)(F)F)nn1-c1cccc(Cl)c1)Nc1ccc(CO)c(F)c1
Reaction time: 16 h
Yield: 57.2 %

Procedure:
To a stirred solution of (1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methanamine (100 mg, 0.316 mmol, 1.0 eq.) in DCM (2.0 mL) was added Et3N (0.07 mL, 0.632 mmol, 3.0 eq) followed by phenyl 3-fluoro-4-(hydroxymethyl)phenylcarbamate (82.4 mg, 0.316 mmol, 1.0 eq.) at RT and stirred for 16 h. After completion of the reaction, a solid precipitate was filtered and washed with DCM (2 mL) followed by n-pentane (5 mL) and dried to get 1-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-3-(3-fluoro-4-(hydroxymethyl)phenyl)urea (compound A59) (80 mg; 47%, white solid; TLC system: EtOAc/PE (3:2); Rf: 0.2).
Reaction SMILES: [CH3:1][C:2](=[N:4][OH:5])[CH3:3].[CH3:6][S:7]([O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH:17]1[O:21][N:20]=[C:19]([C:22]2[N:23]=[C:24]([CH:27]3[CH2:32][CH2:31][N:30]([C:33](=[O:36])[CH2:34]Cl)[CH2:29][CH2:28]3)[S:25][CH:26]=2)[CH2:18]1)(=[O:9])=[O:8].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH3:6][S:7]([O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH:17]1[O:21][N:20]=[C:19]([C:22]2[N:23]=[C:24]([CH:27]3[CH2:32][CH2:31][N:30]([C:33](=[O:36])[CH2:34][O:5][N:4]=[C:2]([CH3:3])[CH3:1])[CH2:29][CH2:28]3)[S:25][CH:26]=2)[CH2:18]1)(=[O:9])=[O:8]
Reactant: CC(C)=NO
Reactant: CS(=O)(=O)Oc1ccccc1C1CC(c2csc(C3CCN(C(=O)CCl)CC3)n2)=NO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)=NOCC(=O)N1CCC(c2nc(C3=NOC(c4ccccc4OS(C)(=O)=O)C3)cs2)CC1
Reaction time: 2 h
Yield: 9.3 %

Procedure:
To a solution of acetone oxime (9.3 mg) in N,N-dimethylformamide (0.28 ml) at room temperature was added 3 Å molecular sieve, and the mixture was stirred at this temperature for 2 hours. Thereafter, 2-(3-{2-[1-(chloroacetyl)piperidin-4-yl]-1,3-thiazol-4-yl}-4,5-dihydro-1,2-oxazol-5-yl)phenyl methanesulphonate (50 mg) and caesium carbonate (64 mg) were added thereto, and the mixture was stirred at room temperature for 18 hours. Subsequently, the mixture was filtered and extracted twice with ethyl acetate. The combined organic phases were dried over magnesium sulphate and concentrated. Purification by column chromatography gave 2-{3-[2-(1-{[(propan-2-ylideneamino)oxy]acetyl}piperidin-4-yl)-1,3-thiazol-4-yl]-4,5-dihydro-1,2-oxazol-5-yl}phenyl methanesulphonate (5 mg, 10%).
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[CH2:6][O:5][C:4]([C:7]2[CH:21]=[CH:20][CH:19]=[CH:18][C:8]=2[CH2:9][C:10]2[N:15]=[C:14](Cl)[CH:13]=[C:12](Cl)[N:11]=2)=[N:3]1.[O:23]([CH3:25])[Na].[CH3:26][OH:27]>C1(C)C=CC=CC=1.O>[CH3:1][C:2]1([CH3:22])[CH2:6][O:5][C:4]([C:7]2[CH:21]=[CH:20][CH:19]=[CH:18][C:8]=2[CH2:9][C:10]2[N:15]=[C:14]([O:27][CH3:26])[CH:13]=[C:12]([O:23][CH3:25])[N:11]=2)=[N:3]1
Reactant: CO
Reactant: CC1(C)COC(c2ccccc2Cc2nc(Cl)cc(Cl)n2)=N1
Reactant: CO[Na]
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cc(OC)nc(Cc2ccccc2C2=NC(C)(C)CO2)n1
Temperature: 65 °C

Procedure:
To a solution of 1.7 g of 2(2-(4,4-dimethyl-oxazolin-2-yl)-benzyl)-4,6-dichloropyrimidine in 100 ml of methanol are added 2.18 g of 25% methanolic NaOCH3 and the mixture heated for 10 hrs at 65° C. with stirring. The temperature is lowered to 60° and stirring continued overnight. The solvent is stripped and the residue taken up in 80 ml of toluene and 50 ml of water. The toluene layer was separated and washed with 50 ml of water, separated and concentrated to give the title compound as a yellow oil.
Reaction SMILES: [I:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.[H-].[Na+].[H][H].[CH3:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17]Cl)=[CH:15][CH:14]=1>CN(C=O)C>[I:1][C:2]1[CH:3]=[N:4][N:5]([CH2:17][C:16]2[CH:19]=[CH:20][C:13]([O:12][CH3:11])=[CH:14][CH:15]=2)[CH:6]=1
Reactant: [H][H]
Reactant: Ic1cn[nH]c1
Reactant: COc1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(Cn2cc(I)cn2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.1 %

Procedure:
To a stirred solution of 4-iodo-1H-pyrazole (1.50 g, 7.73 mmol) in dry DMF (15 mL) at 0° C. was added sodium hydride (9.28 mmol, 60% dispersion in mineral oil) and the reaction mixture was allowed to warm to room temperature. After the evolution of hydrogen had ceased, 4-methoxy-benzyl chloride (1.06 mL, 7.80 mmol) was added and the reaction was stirred for 2 h and then quenched with water (50 mL) and extracted with diethyl ether (100 mL). The organic layer was washed with water (3×30 mL) and brine, dried over magnesium sulphate and the solvent removed under vacuum. The crude residue was washed with small portions of hexane and dried in vacuo, providing the product as a white solid (2.26 g, 93% yield). 1H-NMR (CDCl3) δ 7.51 (s, 1H), 7.34 (s, 1H), 7.17 (d, J=8.5 Hz, 2H), 6.87 (d, J=8.5 Hz, 2H), 5.21 (s, 2H), 3.78 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([S:11][CH:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:3]=1.[C:25]([O:28][CH2:29][CH:30]([CH2:34][O:35][C:36](=[O:38])[CH3:37])[CH2:31][CH2:32]I)(=[O:27])[CH3:26].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:25]([O:28][CH2:29][CH:30]([CH2:34][O:35][C:36](=[O:38])[CH3:37])[CH2:31][CH2:32][N:8]1[CH:7]=[N:6][C:5]2[C:9]1=[N:10][C:2]([NH2:1])=[N:3][C:4]=2[S:11][CH:12]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(=[O:27])[CH3:26]
Reactant: CC(=O)OCC(CCI)COC(C)=O
Reactant: Nc1nc(SC(c2ccccc2)c2ccccc2)c2[nH]cnc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)OCC(CCn1cnc2c(SC(c3ccccc3)c3ccccc3)nc(N)nc21)COC(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.1 %

Procedure:
A mixture of 2-amino-6-[(diphenylmethyl)thio]purine (6.7 g), 2-acetoxymethyl-4-iodobut-1-yl acetate (7.0 g) and anhydrous potassium carbonate (4.14 g) in N,N-dimethylformamide (100 cm3) was stirred at ambient temperature overnight. The reaction mixture was filtered and the residue washed with N,N-dimethylformamide (100 cm3). Evaporation of the filtrate gave a pale coloured oil. Purification via column chromatography on silica (450 g) [eluant 3% methanol-dichloromethane] gave the title compound 9.3 g (89%) as a viscous gum and 1.1 g (10.5%) of 7-(4-acetoxy-3-acetoxymethylbut-1-yl)-2-amino-6-(diphenylmethyl)thio]purine.
Reaction SMILES: [O:1]=[S:2]1(=[O:25])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][N:5]([C:13]2[CH:22]=[C:21]([NH2:23])[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH3:24])[CH:19]=3)[N:14]=2)[CH2:4][CH2:3]1.C(N(CC)CC)C.[Br:33][C:34]([CH3:39])([CH3:38])[C:35](Cl)=[O:36]>C(Cl)(Cl)Cl>[Br:33][C:34]([CH3:39])([CH3:38])[C:35]([NH:23][C:21]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([CH3:24])[CH:19]=2)[N:14]=[C:13]([N:5]2[CH2:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[S:2](=[O:1])(=[O:25])[CH2:3][CH2:4]2)[CH:22]=1)=[O:36]
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(N)c2c1
Reactant: CC(C)(Br)C(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NC(=O)C(C)(C)Br)c2c1
Temperature: 110 °C
Yield: 63.3 %

Procedure:
To a solution of 2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine (200 mg, 0.566 mmol) in chloroform (10 mL) was added triethylamine (0.124 mL), followed by 2-bromo-2-methylpropionyl chloride (286 mg, 1.30 mmol). The resulting mixture was heated at 110° C. for 2 hours under microwave irradiation. After being cooled to room temperature, the mixture was concentrated in vacuo. The residue was diluted with ethyl acetate (35 mL), washed with brine and dried over sodium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography to afford 180 mg of the title compound as a light solid (yield was 63%).