Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[CH2:3][CH2:4][C:5](O)=[O:6].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[NH:40]1[CH2:44][CH2:43][C@@H:42]([C:45]2[O:49][N:48]=[C:47]([C:50]3[S:51][CH:52]=[CH:53][N:54]=3)[N:46]=2)[CH2:41]1>CN(C=O)C>[F:1][C:2]([F:9])([F:8])[CH2:3][CH2:4][C:5]([N:40]1[CH2:44][CH2:43][C@@H:42]([C:45]2[O:49][N:48]=[C:47]([C:50]3[S:51][CH:52]=[CH:53][N:54]=3)[N:46]=2)[CH2:41]1)=[O:6]
Reactant: O=C(O)CCC(F)(F)F
Reactant: c1csc(-c2noc([C@@H]3CCNC3)n2)n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CCC(F)(F)F)N1CC[C@@H](c2nc(-c3nccs3)no2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(R)—N—Boc-pyrrolidine-3-carboxylic acid (700 mg, 3.25 mmol, 1.1 equiv), HBTU (1.23 g, 1.1 equiv) and DIEA (1.53 mL, 3 equiv) were dissolved in DMF (15 mL). The solution was stirred 5 min and then 1,3-thiazole-2-amidoxime (5a) (422 mg, 2.95 mmol, 1 equiv) was added. The reaction mixture was stirred overnight at room temperature and then evaporated under reduced pressure. The residue was dissolved in AcOEt, washed twice with saturated aqueous NaHCO3, once with brine, then dried over MgSO4 and evaporated under reduced pressure. The residue was dissolved in 15 mL of DMF and then heated at 110° C. for 7 h. The solvent was removed under vacuum and the residue was dissolved in AcOEt. The organic layer was washed once with HCl 1N, once with saturated aqueous NaHCO3 and once with brine, then dried over MgSO4 and evaporated under reduced pressure. The obtained product was used in the next step without further purification. Boc intermediate was dissolved in dioxane (10 mL) and HCl 4N solution in dioxane (6 mL) was added. The reaction mixture was stirred overnight at room temperature and then the product was recovered by filtration and washed with petroleum ether to give 5-[(3R)-pyrrolidin-3-yl]-3-(1,3-thiazol-2-yl)-1,2,4-oxadiazole (yield 66% over two steps). 4,4,4-trifluorobutyric acid (1.3 equiv), EDCI (1.3 equiv), HOBt (0.4 equiv) and DIEA (4 equiv) were mixed in DMF (2 mL) for 5 minutes. 5-[(3R)-pyrrolidin-3-yl]-3-(1,3-thiazol-2-yl)-1,2,4-oxadiazole (0.62 mmol, 1 equiv) was added with 3 mL of DMF. The reaction mixture was stirred overnight at room temperature and then evaporated under reduced pressure and purified by preparative HPLC. Beige powder; Yield 33%; 1H NMR (CDCl3) δ 8.02-8.00 (m, 1H), 7.57-7.60 (m, 1H), 3.89-4.03 (m, 2H), 3.69-3.87 (m, 2H), 3.53-3.65 (m, 1H), 2.38-2.55 (m, 6H); 13C NMR (CDCl3) cis/trans isomer mixture (60 isomer A/40 isomer B); isomer A δ 180.31, 168.50, 163.98, 153.53, 144.99, 126.94 (q, J=276 Hz), 122.87, 49.24, 45.52, 35.03, 29.05 (q, J=29 Hz), 28.86, 27.07 (q, J=3 Hz); isomer B δ 179.84, 168.31, 163.98, 153.38, 144.94, 126.92 (q, J=276 Hz), 122.81, 49.43, 45.25, 36.82, 30.28, 29.05 (q, J=29 Hz), 27.24 (q, J=3 Hz). tR LCMS 4.6 min. Purity >99%; MS [M+H]+ m/z 347.
Reaction SMILES: [C:1]([S:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[N:24]([CH3:25])[C:15]2=[N:16][CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:19]=[C:14]2[N:13]=1)([CH3:4])([CH3:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:34])C=1.C(=O)([O-])O.[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)(Cl)Cl>[C:1]([S:5]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[N:24]([CH3:25])[C:15]2=[N:16][CH:17]=[C:18]([C:20]([F:22])([F:23])[F:21])[CH:19]=[C:14]2[N:13]=1)=[O:34])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cn1c(-c2ccccc2SC(C)(C)C)nc2cc(C(F)(F)F)cnc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Cn1c(-c2ccccc2S(=O)C(C)(C)C)nc2cc(C(F)(F)F)cnc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 36.3 %

Procedure:
To a mixture of 2-(2-tert-butylsulfanylphenyl)-3-methyl-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine (0.87 g) and chloroform (12 ml), 3-chloroperbenzoic acid (purity: not less than 65%) (0.95 g) was added under ice-cooling, heated to room temperature, and stirred for 2 hours. Into the reaction mixture, saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium thiosulfate solution were poured, and extracted with chloroform. The organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to give 0.33 g of 2-(2-tert-butylsulfinylphenyl)-3-methyl-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine (hereinafter referred to as Present Compound 16) and 0.52 g of 2-(2-tert-butylsulfonylphenyl)-3-methyl-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine (hereinafter referred to as Present Compound 17).
Reaction SMILES: Cl[C:2](=[O:25])[CH2:3][CH2:4][C:5]1[CH:14]=[CH:13][C:12]([C:15]2[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=2)=[C:11]2[C:6]=1[CH:7]=[CH:8][CH:9]=[N:10]2.[CH3:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.N1C=CC=CC=1>O1CCOCC1>[CH3:26][N:27]1[CH2:32][CH2:31][N:30]([C:2](=[O:25])[CH2:3][CH2:4][C:5]2[CH:14]=[CH:13][C:12]([C:15]3[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=3)=[C:11]3[C:6]=2[CH:7]=[CH:8][CH:9]=[N:10]3)[CH2:29][CH2:28]1
Reactant: CN1CCNCC1
Reactant: COC(=O)c1ccc(-c2ccc(CCC(=O)Cl)c3cccnc23)cc1
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: COC(=O)c1ccc(-c2ccc(CCC(=O)N3CCN(C)CC3)c3cccnc23)cc1

Procedure:
A mixture of Example 201I (300 mg, 0.85 mmol), 1-methylpiperazine (111 mg, 1.11 mmol), and pyridine (74 mg, 0.94 mmol) in dioxane (4 mL) at room temperature was stirred for 75 minutes and purified by flash column chromatography on silica gel with 90:10:0.5 dichloromethane/methanol/concentrated ammonium hydroxide to provide the desired product.
Reaction SMILES: [CH3:1][C:2]1[CH2:11][S:10][C@@H:5]2[C@H:6](N)[C:7](=[O:8])[N:4]2[C:3]=1[C:12]([OH:14])=[O:13].C(O)C.[BrH:18].N([O-])=O.[Na+]>O>[Br:18][C@H:6]1[C:7](=[O:8])[N:4]2[C:3]([C:12]([OH:14])=[O:13])=[C:2]([CH3:1])[CH2:11][S:10][C@H:5]12
Reactant: CC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC1=C(C(=O)O)N2C(=O)[C@H](Br)[C@H]2SC1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 75.5 %

Procedure:
To an ice-cooled mixture of 7-ADCA (10.0 g, 0.4667 mol), ethanol (270 ml), water (83 ml) and hydrobromic acid (48%, 56.7 ml), sodium nitrite (4.67 g, 0.6769 mol) was added in small portions over 25 minutes and the mixture was stirred for 2.5 hours at ice-temperature. Ethanol was removed under reduced pressure and the residual mass was diluted with methylene chloride, washed with water. The aqueous washings were saturated with brine and re-extracted with methylene chloride. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated to give 9.8 g (75.5%) of 7α-bromo-3-methyl -3-cephem-4-carboxylic acid. This crude acid was directly used for the next step without further purification.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[CH:5][S:6][C:7]=1/[CH:8]=[CH:9]\[S:10][C:11]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[H-].[Na+].[CH2:32]([OH:35])[CH2:33][OH:34]>C1COCC1.[Cl-].[Na+].O>[OH:34][CH2:33][CH2:32][O:35][CH2:2][C:3]1[N:4]=[CH:5][S:6][C:7]=1/[CH:8]=[CH:9]\[S:10][C:11]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: OCCO
Reactant: ClCc1ncsc1/C=C\SC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: OCCOCc1ncsc1/C=C\SC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 50 °C
Reaction time: 37 h

Procedure:
4-Chloromethyl-5-((Z)-2-tritylthioethen-1-yl)thiazole (5.57 g) was suspended in 100 ml of THF and 30 ml of ethylene glycol, 1.5 g of sodium hydride was added to the suspension, and the mixture was stirred at 50° C. for 37 hr. Brine was added to the reaction solution, and the mixture was extracted twice with ethyl acetate. The organic layers were combined, were washed twice with brine, were dried over anhydrous magnesium sulfate, were filtered, and were concentrated under the reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate) to give 4.87 g of the title compound.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[CH:6][CH:5]=[CH:4]1)[CH3:2].[Cl-].[CH3:9][O:10][C:11]1[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=1[CH:13]=[N+:14]([CH3:16])[CH3:15]>>[CH2:1]([N:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[CH:13]([N:14]([CH3:15])[CH3:16])[C:12]1[CH:17]=[CH:18][CH:19]=[CH:20][C:11]=1[O:10][CH3:9])[CH3:2]
Reactant: CCn1cccc1
Reactant: COc1ccccc1C=[N+](C)C
Agent: [Cl-]
Product: CCn1cccc1C(c1ccccc1OC)N(C)C

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 1-ethyl-1H-pyrrole and (2-methoxy-benzylidene)-dimethyl-ammonium chloride.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:6]=[C:7]([C:11]2[NH:40][C:14]3=[N:15][CH:16]=[CH:17][C:18]([C:19]4[C:20]([C:28]5[CH:33]=[CH:32][C:31]([NH:34][C:35](=[O:39])[N:36]([CH3:38])[CH3:37])=[CH:30][CH:29]=5)=[N:21][N:22]([CH2:24][CH2:25][NH:26][CH3:27])[CH:23]=4)=[C:13]3[CH:12]=2)[CH:8]=[CH:9][CH:10]=1)[CH3:3].[OH-].[Na+].CC(O[C:47]([CH3:49])=[O:48])=O>CO.O>[CH3:37][N:36]([CH3:38])[C:35]([NH:34][C:31]1[CH:30]=[CH:29][C:28]([C:20]2[C:19]([C:18]3[CH:17]=[CH:16][N:15]=[C:14]4[NH:40][C:11]([C:7]5[CH:8]=[CH:9][CH:10]=[C:5]([CH2:4][N:2]([CH3:1])[CH3:3])[CH:6]=5)=[CH:12][C:13]=34)=[CH:23][N:22]([CH2:24][CH2:25][N:26]([CH3:27])[C:47](=[O:48])[CH3:49])[N:21]=2)=[CH:33][CH:32]=1)=[O:39]
Reactant: CC(=O)OC(C)=O
Reactant: CNCCn1cc(-c2ccnc3[nH]c(-c4cccc(CN(C)C)c4)cc23)c(-c2ccc(NC(=O)N(C)C)cc2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(=O)N(C)CCn1cc(-c2ccnc3[nH]c(-c4cccc(CN(C)C)c4)cc23)c(-c2ccc(NC(=O)N(C)C)cc2)n1
Temperature: 25 °C
Yield: 90 %

Procedure:
To N′-(4-{4-(2-{3-[(dimethylamino)methyl]phenyl}-1H-pyrrolo[2,3-b]pyridin-4-yl)-1-[2-(methylamino)ethyl]-1H-pyrazol-3-yl}phenyl)-N,N-dimethylurea 3TFA (300 mg, 0.34 mMol) in MeOH (10 mL) was added with stirring at RT, aq. 1 N NaOH and Ac2O (40 uL, 0.42 mMol). After stirring for 30 min. the reaction was diluted with water, basified with aq. 1 N NaOH (0.4 mL), extracted with (9:1) CHCl3/iPrOH, dried (Na2SO4), filtered, and evaporated to dryness under vacuum. Trituration with (1:1) Et2O and petroleum ether, filtration and drying under vacuum gave the title compound (177 mg, 90%) as an off-white solid. ESMS [M+H]+: 579.7.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH2:11])[CH:9]=2)[NH:4][N:3]=1.N1C=CC=CC=1.[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:20]=1[S:26](Cl)(=[O:28])=[O:27]>O1CCCC1>[NH2:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH:11][S:26]([C:20]3[C:21]([Cl:25])=[CH:22][CH:23]=[CH:24][C:19]=3[Cl:18])(=[O:28])=[O:27])[CH:9]=2)[NH:4][N:3]=1
Reactant: Nc1ccc2[nH]nc(N)c2c1
Reactant: O=S(=O)(Cl)c1c(Cl)cccc1Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: Nc1n[nH]c2ccc(NS(=O)(=O)c3c(Cl)cccc3Cl)cc12
Yield: 18.6 %

Procedure:
N-(3-Amino-1H-indazol-5-yl)-2,6-dichlorobenzenesulfonamide can be obtained as described in Example 39 from 0.8 g of 3,5-diamino-1H-indazole, 8 ml of pyridine, 8 ml of tetrahydrofuran and 1.29 g of 2,6-dichlorobenzenesulfonyl chloride. 350 mg of N-(3-amino-1H-indazol-5-yl)-2,6-dichlorobenzenesulfonamide are thus obtained in the form of a pale yellow solid melting at 250° C. (analysis C13H10Cl2N4O2S % calculated C, 43.71; H, 2.82; Cl, 19.85; N, 15.68; O, 8.96; S, 8.98. % found C, 43.39; H, 2.92; Cl, 19.45; N, 15.31; S, 8.73).
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C.[N:21]1[CH:26]=[CH:25][C:24]([C:27]2[S:28][CH:29]=[C:30]([NH:32][C:33]([NH:35][C:36]3[CH:41]=[CH:40][CH:39]=[C:38]([CH3:42])[N:37]=3)=[O:34])[N:31]=2)=[CH:23][CH:22]=1>C(Cl)(Cl)(Cl)Cl>[Br:8][C:29]1[S:28][C:27]([C:24]2[CH:25]=[CH:26][N:21]=[CH:22][CH:23]=2)=[N:31][C:30]=1[NH:32][C:33]([NH:35][C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([CH3:42])[N:37]=1)=[O:34]
Reactant: Cc1cccc(NC(=O)Nc2csc(-c3ccncc3)n2)n1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1cccc(NC(=O)Nc2nc(-c3ccncc3)sc2Br)n1
Temperature: 25 °C

Procedure:
NBS (686 mg, 3.85 mmol) and AIBN (158 mg, 0.96 mmol) were added to a heterogeneous solution of 1-((2-pyridin-4-yl)thiazol-4-yl)-3-(6-methylpyridin-2-yl)urea (600 mg, 1.93 mmol, Example. 6) in CCl4 (25 mL) and the resulting mixture was heated at reflux for 2 h. After cooling to RT, a precipitate formed and was collected, rinsing with hexane to give a white solid. MS m/z: 392.0 (M+2H). Calc'd for C15H12BrN5OS-390.26.
Reaction SMILES: Cl[C:2](=[O:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[Cl-].[Al+3].[Cl-].[Cl-].[Br:13][C:14]1[CH:18]=[C:17]([CH3:19])[S:16][C:15]=1[CH3:20].O>ClCCl>[Br:13][C:14]1[C:18]([C:2](=[O:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4])=[C:17]([CH3:19])[S:16][C:15]=1[CH3:20]
Reactant: CCOC(=O)C(=O)Cl
Reactant: Cc1cc(Br)c(C)s1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)C(=O)c1c(C)sc(C)c1Br
Reaction time: 3 h
Yield: 53.9 %

Procedure:
Under a nitrogen atmosphere, ethyl chlorooxoacetate (1.04 mL, 9.27 mmol) and aluminum chloride (per 3 portions) (2.47 g, 18.54 mmol) was added successively at −5° C. to a solution of 3-bromo-2,5-dimethylthiophene (28b) (886 mg, 4.64 mmol) in dichloromethane (20 mL). After 3 hours at −5° C., the reaction mixture was slowly hydrolyzed at 0° C. with water. The organic layer was separated, washed with water, brine, dried over sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 95/5) to give the desired keto-ester (28c) (725 mg, 2.50 mmol, 50%).
Reaction SMILES: [H-].[Li+].[CH2:3]([P:7](=[O:14])([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10])[C:4]([CH3:6])=[O:5].[Cl:15][C:16]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:17]=1[O:18][CH2:19][CH2:20][CH2:21][CH2:22]I>>[C:4]([CH:3]([P:7](=[O:14])([O:8][CH2:9][CH3:10])[O:11][CH2:12][CH3:13])[CH2:22][CH2:21][CH2:20][CH2:19][O:18][C:17]1[CH:24]=[CH:25][C:26]([O:28][CH3:29])=[CH:27][C:16]=1[Cl:15])(=[O:5])[CH3:6]
Reactant: CCOP(=O)(CC(C)=O)OCC
Reactant: COc1ccc(OCCCCI)c(Cl)c1
Agent: [H-]
Agent: [Li+]
Product: CCOP(=O)(OCC)C(CCCCOc1ccc(OC)cc1Cl)C(C)=O
Yield: 15.9 %

Procedure:
[II; Ar is 2-Cl-4-CH3OC6H3, Y is O(CH2)4, R is C2H5, R' is CH3CO] was prepared from 0.79 g of lithium hydride, 19.4 g of diethyl acetonylphosphonate and 34.0 g of 4-(2-chloro-4-methoxyphenoxy)butyl iodide according to the procedure of Example 2(b). The product was chromatographed on Florisil to give 6.45 g of diethyl [1-acetyl-5-(2-chloro-4-methoxyphenoxy)pentyl]phosphonate as a yellow oil; MIC vs. herpes simplex type 2=12 mcg/ml. The NMR spectrum was consistent with the assigned structure.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]([OH:15])=O.[NH:16]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[N:18]=[C:17]1[C:25]1[C:29]([NH2:30])=[CH:28][NH:27][N:26]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CS(C)=O>[NH:18]1[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[N:16]=[C:17]1[C:25]1[C:29]([NH:30][C:13]([C:3]2[C:4]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)=[N:5][O:6][C:2]=2[CH3:1])=[O:15])=[CH:28][NH:27][N:26]=1
Reactant: Cc1onc(-c2ccccc2)c1C(=O)O
Reactant: Nc1c[nH]nc1-c1nc2ccccc2[nH]1
Agent: On1nnc2ccccc21
Solvent: CS(C)=O
Solvent: ClCCCl
Product: Cc1onc(-c2ccccc2)c1C(=O)Nc1c[nH]nc1-c1nc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 24 h
Yield: 15.6 %

Procedure:
A mixture of 5-methyl-3-phenylisoxazole-4-carboxylic acid (57 mg, 0.28 mmol), 3-(1H-benzimidazol-2-yl)-1H-pyrazol-4-ylamine (50 mg, 0.25 mmol), EDC (58 mg, 0.30 mmol) and HOBt (41 mg, 0.30 mmol) in DMSO (2 ml) was stirred at ambient temperature for 24 h. The reaction mixture was partitioned between EtOAc and water and the organic portion dried (MgSO4), filtered and reduced in vacuo. The residue was purified by flash column chromatography [SiO2, EtOAc-petrol (1:2, 1:1, 2:1)] affording 5-methyl-3-phenyl-isoxazole-4-carboxylic acid [3-(1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]-amide as a cream solid (15 mg, 16%). (LC/MS: Rt 3.73, [M+H]+ 385.14).
Reaction SMILES: [H-].[Na+].[CH3:3][CH2:4][O:5][C:6](/[CH:8]=[CH:9]/[CH2:10]P(OCC)(OCC)=O)=[O:7].[CH3:19][O:20][CH2:21][CH2:22][O:23][CH2:24][O:25][C:26]1[C:33]([CH3:34])=[CH:32][C:29]([CH:30]=O)=[CH:28][C:27]=1[CH3:35]>O1CCCC1>[CH3:19][O:20][CH2:21][CH2:22][O:23][CH2:24][O:25][C:26]1[C:33]([CH3:34])=[CH:32][C:29](/[CH:30]=[CH:10]/[CH:9]=[CH:8]/[C:6]([O:5][CH2:4][CH3:3])=[O:7])=[CH:28][C:27]=1[CH3:35]
Reactant: CCOC(=O)/C=C/CP(=O)(OCC)OCC
Reactant: COCCOCOc1c(C)cc(C=O)cc1C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)/C=C/C=C/c1cc(C)c(OCOCCOC)c(C)c1
Reaction time: 0.5 h
Yield: 75.2 %

Procedure:
To a stirred suspension of 60% sodium hydride (1.01 g) in dry tetrahydrofuran (60 ml), 80% triethyl 4-phosphonocrotonate (6.57 g) was added dropwise below 10° C. under an inert atmosphere. After being stirred for 30 minutes, a solution of 4-[(2-methoxyethoxy)methoxy]-3,5-dimethylbenzaldehyde (5.0 g) in dry tetrahydrofuran (50 ml) was added thereto below 10° C. After stirring for 2 hours, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (100 ml), washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. The solvent was distilled off and the residue was subjected to column chromatography on silica gel (130 g) and eluted with a mixture of n-hexane and ethyl acetate (7:3 V/V). The fractions containing the object compound were combined and concentrated under reduced pressure to give a syrup of ethyl 5-[4-{(2-methoxyethoxy)methoxy}-3,5-dimethylphenyl]-(2E,4E)-2,4-pentadienoate (5.28 g).
Reaction SMILES: [NH2:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@H:5]([OH:12])[CH2:4][CH2:3]1.[H-].[Na+].[CH2:15]1[C:17]2([CH2:22][CH2:21][CH2:20][CH2:19][N:18]2[C:23]2[N:27]3[CH:28]=[C:29](F)[CH:30]=[CH:31][C:26]3=[N:25][N:24]=2)[CH2:16]1.O>CN(C=O)C>[CH2:16]1[C:17]2([CH2:22][CH2:21][CH2:20][CH2:19][N:18]2[C:23]2[N:27]3[CH:28]=[C:29]([O:12][C@H:5]4[C:6]5[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=5)[C@@H:2]([NH2:1])[CH2:3][CH2:4]4)[CH:30]=[CH:31][C:26]3=[N:25][N:24]=2)[CH2:15]1
Reactant: Fc1ccc2nnc(N3CCCCC34CC4)n2c1
Reactant: N[C@H]1CC[C@@H](O)c2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N[C@H]1CC[C@@H](Oc2ccc3nnc(N4CCCCC45CC5)n3c2)c2ccccc21
Temperature: 60 °C
Reaction time: 1 h
Yield: 62.9 %

Procedure:
To an opaque brown solution of Intermediate A (371 mg, 2.28 mmol) in dry DMF (5 mL) under N2 was added sodium hydride (60% dispersion in mineral oil, 273 mg, 6.83 mmol) and the resulting mixture stirred at RT for 30 min. (CARE: gas evolution) A solution of Intermediate 148c (448 mg, 1.82 mmol) in dry DMF (5 mL) was added and the resulting dark brown solution stirred at 60° C. for 1 h. The solution was cooled to RT, then water (0.2 mL) added (CARE: gas evolution) and the mixture concentrated in vacuo. The residue was redissolved in MeOH (10 mL), applied to an SCX-2 cartridge (25 g) and washed with MeOH (100 mL). The product was eluted with 2M NH3 in MeOH (75 mL); concentration in vacuo left a dark brown gum. Flash chromatography (silica 40 g, 4-7% [2M NH3 in MeOH] in DCM) gave the title compound as a pale brown foam (446 mg, 63%). LCMS (Method 3): Rt 2.31 min, m/z 390 [MH+].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8]O)[CH:5]=[N:6][CH:7]=1.P(Br)(Br)[Br:11].CCN(CC)CC>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]([CH2:8][Br:11])[CH:3]=1
Reactant: OCc1cncc(Br)c1
Reactant: BrP(Br)Br
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: BrCc1cncc(Br)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 68.5 %

Procedure:
(5-Bromopyridin-3-yl)methanol (1.41 g; 7.5 mmol) is dissolved in 20 mL DCM and the flask is flushed with argon and cooled to 0° C. Phosphorus tribromide (0.70 mL; 7.5 mmol) is added dropwise via a syringe and reaction mixture is stirred at RT for 2 h. NEt3 (1 mL) is added by syringe and the reaction mixture is stirred for 1 h. The mixture is cooled to 0° C. and quenched with the slow addition of 5 mL water, followed by the addition of 2M K2CO3 until mixture is neutral (pH=˜7). The mixture is partitioned between water and EtOAc, the aqueous phase is washed three times with EtOAc and the organic layers are combined, dried over anhydrous sodium sulfate, filtered and deposited on silica. Purification by column chromatography on silica gel (pre-washed with 1% NEt3) using a solvent gradient of hexanes to EtOAc led to the isolation of the desired product as white crystals (1.29 g, 69% yield).
Reaction SMILES: O[N:2]1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.O.N.[Cl:25][C:26]1[S:27][CH:28]=[C:29]([C:31]([OH:33])=O)[N:30]=1>O.ClCCl>[Cl:25][C:26]1[S:27][CH:28]=[C:29]([C:31]([NH2:2])=[O:33])[N:30]=1
Reactant: O=C(O)c1csc(Cl)n1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Solvent: ClCCl
Solvent: O
Product: NC(=O)c1csc(Cl)n1
Temperature: 25 °C
Reaction time: 46 h
Yield: 95.5 %

Procedure:
1-hydroxybenzotriazole (0.56 g, 3.7 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (WSC) (0.7 g, 3.7 mmol) and ammonia water (28%, 0.5 ml)) were added to a dichloromethane solution (10 ml) of 2-chlorothiazole-4-carboxylic acid (0.5 g, 3.06 mmol) and the mixture was stirred at room temperature for 46 hours. Water was added to the reaction solution, which was then extracted with ethyl acetate. The extraction solution with ethyl acetate was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=3:5→ethyl acetate). The purified product was concentrated to dryness under reduced pressure to obtain 2-chlorothiazole-4-carboxamide (475 mg) as white powder.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[CH3:20][O:21][CH2:22][C@H:23](O)[CH2:24][CH3:25].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.C1(C)C=CC=CC=1>C1COCC1>[CH3:20][O:21][CH2:22][C@@H:23]([O:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])[CH2:24][CH3:25]
Reactant: CC[C@@H](O)COC
Reactant: COC(=O)c1cc(O)cc(OCc2ccccc2)c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC[C@@H](COC)Oc1cc(OCc2ccccc2)cc(C(=O)OC)c1
Temperature: 10 °C
Reaction time: 16 h
Yield: 68.6 %

Procedure:
A stirred solution of methyl 3-hydroxy-5-{[phenylmethyl]oxy}benzoate (7.5 g, 29 mmol), (R)-1-methoxy-butan-2-ol (3.76 g, 36.25 mmol) and triphenylphosphine (9.5 g, 36.25 mmol) in dry THF (75 mL) was cooled in an ice-bath and a solution of 40% DEAD in toluene (15.8 mL, 36.25 mmol) was added dropwise over 30 minutes. The reaction mixture was allowed to warm slowly to 10° C. and stirred for 16 hours. The THF was evaporated. The residue was dissolved in 30% ethyl acetate in isohexane and cooled in ice. The resultant precipitate was removed by filtration and washed with 10% ethyl acetate in isohexane. The filtrate was evaporated and purified by column chromatography, eluting with 10% ethyl acetate in isohexane, to give the title compound as a colourless oil (6.85 g).