Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH2:5][NH:6][CH2:7][CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]1)[CH3:2].C(N(CC)CC)C.Br.[Br:26][C:27]1[CH:28]=[C:29]([CH2:34]Br)[C:30]([NH2:33])=[N:31][CH:32]=1>CN(C=O)C.O>[CH2:1]([O:3][C:4](=[O:17])[CH2:5][N:6]([CH2:34][C:29]1[C:30]([NH2:33])=[N:31][CH:32]=[C:27]([Br:26])[CH:28]=1)[CH2:7][CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]1)[CH3:2]
Reactant: CCOC(=O)CNCCCN1CCN(C)CC1
Reactant: Nc1ncc(Br)cc1CBr
Agent: Br
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CN(CCCN1CCN(C)CC1)Cc1cc(Br)cnc1N
Temperature: 25 °C
Reaction time: 72 h
Yield: 15.8 %

Procedure:
A solution of [3-(4-methyl-piperazin-1-yl)propylamino]acetic acid ethyl ester (1.80 g, 7.41 mmol) and triethylamine (2.3 mL, 16.4 mmol) in DMF (50 mL) was treated with 5-bromo-3-bromomethyl-pyridin-2-ylamine hydrobromide (2.57 g, 7.41 mmol). After stirring at room temperature for 3 d, the mixture was diluted with H2O (100 mL) and then extracted with EtOAc (4×100 mL). The combined organic layers were dried over Na2SO4, filtered and the solvent was removed in vacuo. Purification by flash column chromatography (silica gel, CH2Cl2/MeOH, 97:3 to 90:10) gave the title compound (0.50 g, 16%) as a colorless oil: MS (ESI) m/e 428 (M+H)+.
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[C:7]1([S:13][CH:14]([C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[CH:21][C:20]=2[O:29][CH3:30])[CH2:15][NH:16][CH:17]=[O:18])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>O.CO>[C:7]1([S:13]([CH:14]([C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[CH:21][C:20]=2[O:29][CH3:30])[CH2:15][NH:16][CH:17]=[O:18])=[O:2])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: COc1ccc2ccccc2c1C(CNC=O)Sc1ccccc1
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1ccc2ccccc2c1C(CNC=O)S(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 100 %

Procedure:
A concentrated solution of sodium metaperiodate (2139 mg. 10 mmol) in water is added dropwise at 0° C. under cooling to a solution of 1-(1-phenylthio-2-formylaminoethyl)-2-methoxy-naphthalene (3374 mg, 10 mmol) in methanol (100 ml). The reaction is then stirred at room temperature for 24 h. The solids are filtered off and washed several times with ethyl acetate (1000 ml). The filtrate and washings are combined and then evaporated under vacuum to yield crude title compound in about 100% yield (3534 mg ) which is used in the next step without further purification.
Reaction SMILES: [CH2:1](O)[CH:2]=[CH2:3].S(Cl)(Cl)=O.[Cl:9][C:10]1[N:11]=[CH:12][C:13]([NH:16][C:17](=[O:23])[CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[N:14][CH:15]=1>>[Cl:9][C:10]1[N:11]=[CH:12][C:13]([NH:16][C:17](=[O:23])[CH2:18][CH2:19][C:20]([O:22][CH2:3][CH:2]=[CH2:1])=[O:21])=[N:14][CH:15]=1
Reactant: O=C(O)CCC(=O)Nc1cnc(Cl)cn1
Reactant: C=CCO
Solvent: O=S(Cl)Cl
Product: C=CCOC(=O)CCC(=O)Nc1cnc(Cl)cn1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of prop-2-en-1-ol (2 mL) was added dropwise thionyl chloride (3 eq, 1.7 mmol). After 5 min, 4-[(5-chloropyrazin-2-yl)amino]-4-oxo-butanoic acid A6 (prepared as described before, 0.13 g, 0.57 mmol) was added to the solution. The reaction mixture was stirred overnight at room temperature. The reaction was stopped and the solution was partitioned between ethyl acetate and water. The aqueous layer was separated and extracted with ethyl acetate (2×). The combined organic layer was washed with a saturated solution of sodium hydrogenocarbonete and dried on magnesium sulfate, then concentrated under vacuum. The residue was first washed with cyclohexane and the solid obtained was purified by flash chromatography eluting with cyclohexane-ethyl acetate to give allyl 4-[(5-chloropyrazin-2-yl)amino]-4-oxo-butanoate A10 (37%). 1H NMR (400 MHz, CDCl3) 9.29 (s, 1H), 8.27 (s, 1H), 8.18 (bs, 1H), 5.92 (m, 1H), 5.29 (m, 2H), 4.62 (m, 2H), 2.80 (m, 4H).
Reaction SMILES: [CH3:1][N:2]([CH2:13][C:14]([O:16]C)=[O:15])[S:3]([C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=1)(=[O:5])=[O:4].O[Li].O>CO.C1COCC1.O>[CH3:1][N:2]([CH2:13][C:14]([OH:16])=[O:15])[S:3]([C:6]1[CH:7]=[CH:8][C:9]([CH3:12])=[CH:10][CH:11]=1)(=[O:4])=[O:5]
Reactant: COC(=O)CN(C)S(=O)(=O)c1ccc(C)cc1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1ccc(S(=O)(=O)N(C)CC(=O)O)cc1
Reaction time: 3 h

Procedure:
Methyl ester 6 (2.60 g, 10.1 mmol) was dissolved in a 3:1:1 mixture of MeOH-THF—H2O. LiOH.H2O (0.53 g, 12.6 mmol) was added at room temperature and the reaction allowed to stir for 3 h. All solvents were evaporated, apart from water. The remaining aqueous solvent was diluted further and thoroughly washed with ethyl acetate. The aqueous basic aqueous layer was then acidified to pH 2 with 1 M HCl and the product extracted with ethyl acetate. The organic layers were then combined and dried over Na2SO4, filtered and concentrated to afford the title compound. (2.33 g, 95%): δH (400 MHz, CDCl3) 2.43 (s, 3H, CH3), 2.87 (s, 3H, CH3), 3.99 (s, 2H, CH2), 7.32 (d, J=8.0 Hz, 2H, CH), 7.69 (d, J=8.0 Hz, 2H, CH); δC (100 MHz, CDCl3) 21.4, 35.7, 50.6, 127.3, 129.6, 134.8, 143.7, 173.5; LRMS (ES+) calcd for [C10H13NO4S+H] 244.06. found 244.07 [M+H].
Reaction SMILES: [CH3:1][N:2]([C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1)[C:3]1[O:4][C:5]2[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:6]=2[N:7]=1.[N+](C1C=C(C(F)(F)F)C=CC=1O)([O-])=O.Br[CH:35]([CH3:43])[CH2:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C(C)C>[CH3:1][N:2]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH:35]([CH3:43])[CH2:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])=[CH:15][CH:14]=1)[C:3]1[O:4][C:5]2[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:6]=2[N:7]=1
Reactant: CN(c1ccc(O)cc1)c1nc2cc(Cl)ccc2o1
Reactant: CCOC(=O)CCC(C)Br
Agent: O=C([O-])[O-]
Agent: O=[N+]([O-])c1cc(C(F)(F)F)ccc1O
Agent: [K+]
Solvent: CC(=O)CC(C)C
Product: CCOC(=O)CCC(C)Oc1ccc(N(C)c2nc3cc(Cl)ccc3o2)cc1

Procedure:
A mixture of 4-[N-methyl-N-(5-chloro-2-benzoxazolyl)amino]phenol (1.0 g, 0.0039 mole; see Example 7 part (a), ethyl 4-bromovalerate (0.89 g, 0.0043 mole), anhydrous potassium carbonate (0.54 g) and methyl isobutyl ketone (15 ml) was heated under reflux for a period of 30 hours with further portions (0.05 g) of anhydrous potassium carbonate being added at 3 hour intervals. The reaction mixture was cooled, filtered and the filtrate was distilled under reduced pressure to remove the solvent. The residue (a red oil) was distilled under reduced pressure, bp 240°-260° C. at 0.04 mm Hg and the distillate was further purified by preparative thin layer chromatography on silica gel (eluent chloroform/ethanol 15:1) to give the title compound (0.47 g) as a red oil. The pmr and mass spectra of the compound were consistent with the assigned structure.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[S:30][CH:29]=[N:28][C:27]=2[C:31](O)=[O:32])=[CH:22][CH:21]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[C:16]([NH:18][C:31]([C:27]3[N:28]=[CH:29][S:30][C:26]=3[C:23]3[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=3)=[O:32])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3cc(N)cn3)o2)OCCO1
Reactant: O=C(O)c1ncsc1-c1ccc(F)cc1
Product: CC(=O)c1ccc(Cn2cc(NC(=O)c3ncsc3-c3ccc(F)cc3)cn2)o1

Procedure:
Following general procedure B followed by either C or D, 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-4-ylamine and 5-(4-fluoro-phenyl)-thiazole-4-carboxylic acid. LC-MS-conditions 02: tR=0.95 min; [M+H]+=410.92.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([CH2:9][C:10]2[CH:11]=[N:12][C:13]([CH3:16])=[CH:14][CH:15]=2)=[CH:4][N:3]=1.[Na].[CH2:18]([OH:21])[CH:19]=[CH2:20]>O1CCCC1>[Cl:1][C:2]1[N:7]=[C:6]([O:21][CH2:18][CH:19]=[CH2:20])[C:5]([CH2:9][C:10]2[CH:11]=[N:12][C:13]([CH3:16])=[CH:14][CH:15]=2)=[CH:4][N:3]=1
Reactant: C=CCO
Reactant: Cc1ccc(Cc2cnc(Cl)nc2Cl)cn1
Agent: [Na]
Solvent: C1CCOC1
Product: C=CCOc1nc(Cl)ncc1Cc1ccc(C)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88 %

Procedure:
To a stirred solution of 118.0 g (0.465 mol) of 2,4-dichloro-5-[(6-methyl-3-pyridinyl)methyl]pyrimidine from Example 1 in 200 ml of allyl alcohol and 300 ml of tetrahydrofuran at 0°-5° was added dropwise over 2 hours a solution of the sodium salt of allyl alcohol [generated from 22.4 g (0.465) of sodium hydride (50% oil dispersion) and 200 ml of allyl alcohol]. The mixture was stirred 30 minutes at 5°, warmed to room temperature and concentrated. The resulting oil was dissolved in 1 L of methylene chloride, washed with water, dried over sodium sulfate, filtered, and concentrated to give 112.0 g (0.0409 mol, 88%) of 2-chloro-4-allyloxy-5[(6-methyl-3-pyridinyl)methyl]pyrimidine as crystals: IR(Nujol) 2850, 2650, 1655, 1580, 1560 cm-1 ; 1H NMR(D6 -DMSO/CDCl3) δ 2.45 (s, 3H), 3.85 (s, 2H), 4.90 (dd, 2H), 5.25 (dd, 1H), 5.34 (dd, 1H), 6.00 (m, 1H), 7.10 (d, 1H), 7.48 (dd, 1H), 8.30 (s, 1H), 8.35 (d, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].C[Al](C)C.C1(C)C=CC=CC=1.[Cl:20][C:21]1[C:26]([CH2:27][CH2:28][C:29](OC)=[O:30])=[C:25]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[Cl:39])[CH:24]=[C:23]([Cl:40])[N:22]=1.Cl>ClCCl.O>[Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][C:29](=[O:30])[CH2:28][CH2:27][C:26]1[C:21]([Cl:20])=[N:22][C:23]([Cl:40])=[CH:24][C:25]=1[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[Cl:39]
Reactant: Nc1ccccc1Cl
Reactant: COC(=O)CCc1c(-c2ccccc2Cl)cc(Cl)nc1Cl
Agent: C[Al](C)C
Agent: Cl
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(CCc1c(-c2ccccc2Cl)cc(Cl)nc1Cl)Nc1ccccc1Cl
Reaction time: 17 h
Yield: 85 %

Procedure:
2-Chloroaniline (0.87 ml, 8.21 mmol) in dichloromethane (80 ml) was treated with 2M trimethylaluminium in toluene (4.1 ml, 8.2 mmol) at 0-5° under nitrogen. After stirring for 15 min. a solution of methyl 3-[2,6-dichloro-4-(2-chlorophenyl)-3-pyridinyl]propanoate (1.40 g, 4.063 mmol) in dichloromethane (40 ml) was added and the solution stirred at 21° for 17 h. Water (15 ml) was added (very slowly at first), followed by sufficient 2M hydrochloric acid to dissolve all the precipitated aluminium salts. The organic phase was separated and the aqueous phase further extracted with dichloromethane (50 ml). The combined organic extracts passed through a hydrophobic frit, evaporated in vacuo, and the oily residue purified by column chromatography over silica (70 g) eluting with cyclohexane-ethyl acetate (100:0-65:35) to afford the title compound as a gum (1.52 g, 85%).
Reaction SMILES: [CH3:1][C:2]([OH:19])([CH2:4][CH2:5][Si:6]([Si:15]([CH3:18])([CH3:17])[CH3:16])([Si:11]([CH3:14])([CH3:13])[CH3:12])[Si:7]([CH3:10])([CH3:9])[CH3:8])[CH3:3].O1CCCC1.C(N(CC)CC)C.[C:32](Cl)(=[O:36])[C:33]([CH3:35])=[CH2:34]>C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C.CCCCC>[CH3:35][C:33](=[CH2:34])[C:32]([O:19][C:2]([CH3:1])([CH2:4][CH2:5][Si:6]([Si:15]([CH3:16])([CH3:18])[CH3:17])([Si:7]([CH3:10])([CH3:9])[CH3:8])[Si:11]([CH3:14])([CH3:13])[CH3:12])[CH3:3])=[O:36]
Reactant: C=C(C)C(=O)Cl
Reactant: CC(C)(O)CC[Si]([Si](C)(C)C)([Si](C)(C)C)[Si](C)(C)C
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Solvent: CCN(CC)CC
Solvent: CCCCC
Solvent: C1CCOC1
Product: C=C(C)C(=O)OC(C)(C)CC[Si]([Si](C)(C)C)([Si](C)(C)C)[Si](C)(C)C
Yield: 67.5 %

Procedure:
A dried reaction flask equipped for magnetic stirring was flushed with nitrogen and charged with 2,6,6-trimethyl-5,5-bis(trimethylsilyl)-5,6-disilaheptan-2-ol (53.6 g, 160 mmol, prepared as described in Example 1) and dry tetrahydrofuran (400 mL). Triethylamine (78.1 mL, 56.7 g, 560 mmol) and methacryloyl chloride (54.7 mL, 58.5 g, 560 mmol) were added, and the reaction mixture was stirred at room temperature for 24 hours. Analysis of the reaction mixture by gas chromatography indicated the clean formation of a single product. Pentane (500 mL) was added, precipitated triethylamine hydrochloride was separated by filtration, and the filtrate was concentrated under reduced pressure. The turbid concentrate was dissolved in pentane (500 mL), the resultant solution was filtered and concentrated under reduced pressure, and 2,6-di-tert-butyl-4-methylphenol (0.50 g, 2.3 mmol) was added to the concentrate. The concentrate was distilled under vacuum (bp 120-130° C. at 0.05 mm) to afford the title compound (43.5 g, 67%) as a clear, colorless liquid. The distilled product was characterized by the following NMR data: 1H NMR (CDCl3) δ 0.13 (s, 27 H), 0.70-0.80 (m, 2 H), 1.43 (s, 6 H), 1.75-1.85 (m, 2 H), 1.87 (s, 3 H), 5.43 (m, 1 H), 5.96 (m, 1 H); 13C NMR (CDCl3) δ 0.78 (1 C), 0.99 (9 C), 18.30 (1 C), 25.19 (2 C), 40.25 (1 C), 82.83 (1 C), 123.89 (1 C), 137.85 (1 C), 166.36 (1 C); 29Si NMR (CDCl3) δ −81.26 (1 Si), −12.80 (3 Si).
Reaction SMILES: Cl.[C:2]1([N:8]([CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])[C:9]([C:11]2[CH:33]=[CH:32][C:14]3[N:15]([CH3:31])[C:16]([CH2:18][NH:19][C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:28])[NH2:27])=[CH:22][C:21]=4[O:29][CH3:30])=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:42]([O:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])=[O:43]>ClCCl.C(O)C>[C:2]1([N:8]([CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])[C:9]([C:11]2[CH:33]=[CH:32][C:14]3[N:15]([CH3:31])[C:16]([CH2:18][NH:19][C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:27])[NH:28][C:42]([O:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])=[O:43])=[CH:22][C:21]=4[O:29][CH3:30])=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1OC)n2C)c1ccccc1
Reactant: CCCCCCCOC(=O)Cl
Agent: Cl
Solvent: CCO
Solvent: ClCCl
Product: CCCCCCCOC(=O)NC(=N)c1ccc(NCc2nc3cc(C(=O)N(CCC(=O)OCC)c4ccccc4)ccc3n2C)c(OC)c1
Yield: 68 %

Procedure:
Prepared analogously to Example 90 from 1-methyl-2-[N-(4-amidino-2-methoxy-phenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide-hydrochloride and n-heptyl chloroformate. Yield: 68% of theory, C37H46N6O6 (670.8) Rf value: 0.56 (silica gel; dichloromethane/ethanol=9:1) ##EQU141##
Reaction SMILES: C([O:3][C:4](=[O:17])[CH:5]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.[C:18](OC(=O)C)(=O)C.OS(O)(=O)=O.CC(C)=O>O>[CH3:10][C:9]1([CH3:18])[O:8][C:6](=[O:7])[CH:5]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:4](=[O:3])[O:17]1
Reactant: CCOC(=O)C(C(=O)OCC)c1ccccc1
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(C)=O
Product: CC1(C)OC(=O)C(c2ccccc2)C(=O)O1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 11.8 g (50 mmol) of phenylmalonic acid diethyl ester in 23 ml. of acetic anhydride there are added 0.5 ml. of concentrated H2SO4 and 20 ml. of acetone. The mixture is stirred at 25° C for 8 hours, water (250 ml.) is then added thereto and the mixture is stirred for 30 minutes. The obtained precipitate is washed with 250 ml. of water up to pH 6.5, dried under reduced pressure and dissolved in 100 ml. of chloroform. The organic solution is dried over anhydrous sodium sulfate, most of the solvent is evaporated under reduced pressure and 100 ml. of petroleum ether (50°-70° C) is added thereto. The suspension is stirred for 30 minutes and filtered. The precipitate is washed with 20 ml. of petroleum ether (50°-70° C) and dried over P2O5 under reduced pressure to yield 2.2-dimethyl-5-phenyl-1.3-dioxane-4.6-dione with the same characteristics as the compound described by P. J. Scheuer in J.A.C.S. 80, 4933-38 (1958).
Reaction SMILES: Cl[C:2]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]3[N:25](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:24]=[N:23][N:22]=3)=[CH:11][CH:10]=2)[C:6](=[O:45])[N:5]([CH2:46][CH2:47][CH3:48])[C:4](=[O:49])[CH:3]=1.[CH2:50]([SH:54])[CH2:51][CH2:52][CH3:53].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:50]([S:54][C:2]1[N:7]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]3[NH:22][N:23]=[N:24][N:25]=3)=[CH:13][CH:14]=2)[C:6](=[O:45])[N:5]([CH2:46][CH2:47][CH3:48])[C:4](=[O:49])[CH:3]=1)[CH2:51][CH2:52][CH3:53]
Reactant: CCCn1c(=O)cc(Cl)n(Cc2ccc(-c3ccccc3-c3nnnn3C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2)c1=O
Reactant: CCCCS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCCSc1cc(=O)n(CCC)c(=O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Yield: 55 %

Procedure:
A mixture of 6-chloro-3-propyl-1-[[2'-(N-trityltetrazol-5-yl)biphenyl-4-yl]methyl]pyrimidine-2,4(1H,3H)-dione (0.5 g), butylmercaptan (0.1 ml) and potassium carbonate (0.13 g) in acetonitrile (10 ml) was heated under reflux for 3 hours with stirring. The insoluble material was removed from the reaction mixture by filtration and the filtrate was concentrated to dryness. The resulting residue was dissolved in methanol (15 ml) and then 1N hydrochloric acid (1.5 ml) was added to the solution, followed by stirring at room temperature for 3 hours. The reaction mixture was concentrated to dryness and then the residue was extracted with methylene chloride-water. The organic layer was washed with water, dried, and evaporated to dryness. The resulting residue was purified by column chromatography on silica gel to give colorless powders (0.2 g, 55%).
Reaction SMILES: [NH2:1][C@H:2]([CH2:5][CH:6]([CH3:8])[CH3:7])[CH2:3][OH:4].C(N(CC)CC)C.Cl[C:17](Cl)([O:19]C(=O)OC(Cl)(Cl)Cl)Cl.[NH4+].[Cl-]>C(Cl)Cl>[CH2:5]([C@@H:2]1[CH2:3][O:4][C:17](=[O:19])[NH:1]1)[CH:6]([CH3:8])[CH3:7]
Reactant: CC(C)C[C@@H](N)CO
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)C[C@@H]1COC(=O)N1
Temperature: 4 °C
Reaction time: 0.25 h
Yield: 264.9 %

Procedure:
To a cooled (4° C.) solution of (R)-2-amino-4-methylpentan-1-ol (2.98 g, 25.4 mmol) and triethylamine (7.6 mL, 54 mmol, 2.1 equiv) in CH2Cl2 (80 mL) was added dropwise a solution of triphosgene (2.52 g, 8.49 mmol, 0.334 equiv) in 10 ml of CH2Cl2 over 30 min. The reaction mixture was stirred at 4° C. for 15 min, warmed up to room temperature and stirred for an additional 1 h. The mixture was treated with saturated NH4Cl (25 mL), followed by CH2Cl2 (50 mL) and the resulting mixture was stirred for 20 min. The layers were separated and the organic layer was washed with water. The combined aqueous layers were extracted with CH2Cl2 (50 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated to give (R)-4-isobutyloxazolidin-2-one (3.22 g) in 88% yield. The crude product was used for the next reaction without purification. 1H NMR (400 MHz, CD3OD) δ 4.53-4.47 (m, 1H), 4.00-3.92 (m, 2H), 1.67 (ddq, J=13, 8.0, 6.5 Hz, 1H), 1.56-1.48 (m, 1H), 1.40-1.32 (m, 1H), 0.95 (d, J=6.1 Hz, 3H), 0.93 (d, J=6.1 Hz, 3H).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-])=O)[N:4]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)[N:3]=1.[NH4+].[Cl-]>[Zn].CO>[F:24][C:21]([F:22])([F:23])[C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][CH:18]=1)[CH2:14][N:4]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([NH2:11])[C:10]=2[CH:2]=[N:3]1
Reactant: O=[N+]([O-])c1cccc2c1c(I)nn2Cc1cccc(C(F)(F)F)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Product: Nc1cccc2c1cnn2Cc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 34 %

Procedure:
To a round bottom flask was added 3-iodo-4-nitro-1-(3-(trifluoromethyl)benzyl)-1H-indazole (0.540 g, 1.21 mmol) and MeOH (12 mL). Zinc dust (0.395 g, 6.04 mmol) was added followed by saturated aqueous NH4Cl (12 mL). The mixture was stirred vigorously at ambient temperature for 2 hours. The reaction mixture was filtered and the solids were washed with EtOAc (30 mL). Saturated aqueous NH4OAc (25 mL) was added to the filtrate and the mixture was concentrated to remove organic solvents. The aqueous phase was then extracted with EtOAc (3×20 mL). The combined organic extracts were washed with a saturated aqueous NaHCO3 solution and brine, dried over Na2SO4, filtered and concentrated. The crude residue was purified by 1 mm preparative TLC using 5% MeOH/CH2Cl2 to afford 0.120 g (34%) of the product as a dark yellow/orange oil.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:18])([F:17])[C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11]2[NH:12][O:13][C:14](=[O:16])[N:15]=2)[CH:6]=1.Br[CH2:20][C:21]#[N:22].[Cl-].[NH4+]>CN(C)C=O>[C:21]([CH2:20][N:15]1[C:14](=[O:16])[O:13][N:12]=[C:11]1[C:7]1[CH:6]=[C:5]([C:4]([F:3])([F:17])[F:18])[CH:10]=[CH:9][N:8]=1)#[N:22]
Reactant: O=c1nc(-c2cc(C(F)(F)F)ccn2)[nH]o1
Reactant: N#CCBr
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: N#CCn1c(-c2cc(C(F)(F)F)ccn2)noc1=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 72.7 %

Procedure:
Into 2 ml of N,N-dimethylformamide was suspended 0.04 g of sodium hydride (60% oily), and 0.2 g of 3-(4-trifluoromethylpyridin-2-yl)-1,2,4-oxadiazol-5-one was added at room temperature. After stirring for 10 minutes, 0.16 g of bromoacetonitrile was added, and the mixture was stirred for 2 hours. After stirring at 60° C. for 6 hours, the reaction solution was allowed to cool to room temperature, and poured into an aqueous saturated ammonium chloride solution, followed by extraction with tert-butyl=methyl=ether three times. The organic layers were combined, washed with an aqueous saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 0.17 g of 4-cyanomethyl-3-(4-trifluoromethylpyridin-2-yl)-1,2,4-oxadiazol-5-one (present compound (6)).
Reaction SMILES: [N:1]1[N:5]2[C:6]([CH:10](O)[CH3:11])=[CH:7][CH:8]=[N:9][C:4]2=[N:3][CH:2]=1.S(Cl)([Cl:15])=O>ClCCl>[Cl:15][CH:10]([C:6]1[N:5]2[N:1]=[CH:2][N:3]=[C:4]2[N:9]=[CH:8][CH:7]=1)[CH3:11]
Reactant: O=S(Cl)Cl
Reactant: CC(O)c1ccnc2ncnn12
Solvent: ClCCl
Product: CC(Cl)c1ccnc2ncnn12
Reaction time: 2 h

Procedure:
A solution of 1-(1,2,4-triazolo[1,5-a]pyrimidin-7-yl)ethanol (1 g, prepared in an similiar manner to that described above) in dichloromethane (30 ml) was added dropwise over 30 minutes to a solution of thionyl chloride (0.5 ml) in dichloromethane (50 ml), heated under reflux, and the heating was continued for a further 2 hours. Further thionyl chloride (0.5 ml) was added and the heating continued overnight. The dichloromethane was removed by distillation and the residue dissolved in further dichloromethane (50 ml). The solution was washed with a mixture of water (20 ml) with 1M sodium bicarbonate (3 ml), and the aqueous washings were extracted with dichloromethane (20 ml). The dichloromethane solutions were combined, washed with brine (40 ml), dried over magnesium sulphate and the solvent was evaporated to give, as a light brown solid, 7-(1-chloroethyl)-1,2,4-triazolo[1,5-a]pyrimidine. Yield 1.00 g.
Reaction SMILES: [C:1]([N:8]1[CH2:12][C@@H:11]([N:13]=[N+]=[N-])[CH2:10][C@@H:9]1[CH2:16][CH:17]=[CH2:18])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CP(C)C.O>C1COCC1>[C:1]([N:8]1[CH2:12][C@H:11]([NH2:13])[CH2:10][C@@H:9]1[CH2:16][CH:17]=[CH2:18])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: C=CC[C@H]1C[C@H](N=[N+]=[N-])CN1C(=O)OC(C)(C)C
Agent: CP(C)C
Solvent: C1CCOC1
Solvent: O
Product: C=CC[C@H]1C[C@@H](N)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 5 h
Yield: 69.5 %

Procedure:
To a solution of (2S,4R)-1-Boc-2-allyl-4-azidopyrrolidine (450 mg, 1.78 mmol) prepared in Step B in THF was added dropwise trimethylphosphine (135 mg, 1.78 mmol). After the reaction mixture was stirred at rt for 5 h, water (0.03 ml) was added, and stirred for additional 20 min. The reaction mixture was concentrated in vacuo, extracted with EtOAc, washed with water and brine, and concentrated in vacuo. The residue was purified by column chromatography(eluent, MeOH/DCM=1/9) to give the title compound (280 mg, 70%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][CH3:9])=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[NH3:11]>>[Cl:1][C:2]1[N:3]=[CH:4][N:5]=[C:6]([NH2:11])[C:7]=1[NH:8][CH3:9]
Reactant: N
Reactant: CNc1c(Cl)ncnc1Cl
Product: CNc1c(N)ncnc1Cl
Yield: 76.78 %

Procedure:
Combine 4,6-dichloro-N-methylpyrimidin-5-amine (0.6 g; 0.0034 mol), and liquid ammonia (6 mL) and stir at 80° C. for 4 h. Extract with EA and evaporate to give the title compound (0.41 g; 76.78%).