Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([C:5]1[N:6]=[C:7]([CH2:10][N:11]2[N:15]=[C:14]([NH2:16])[CH:13]=[N:12]2)[S:8][CH:9]=1)([F:4])[CH3:3].[C:17]1([C:23]2[O:27][CH:26]=[N:25][C:24]=2[C:28](O)=[O:29])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[F:1][C:2]([C:5]1[N:6]=[C:7]([CH2:10][N:11]2[N:15]=[C:14]([NH:16][C:28]([C:24]3[N:25]=[CH:26][O:27][C:23]=3[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[O:29])[CH:13]=[N:12]2)[S:8][CH:9]=1)([F:4])[CH3:3]
Reactant: O=C(O)c1ncoc1-c1ccccc1
Reactant: CC(F)(F)c1csc(Cn2ncc(N)n2)n1
Product: CC(F)(F)c1csc(Cn2ncc(NC(=O)c3ncoc3-c3ccccc3)n2)n1

Procedure:
Following general procedure A, starting from 2-[4-(1,1-Difluoro-ethyl)-thiazol-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 5-phenyl-oxazole-4-carboxylic acid.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9](O)[C:10]3[CH2:16][CH2:15][N:14]([C:17]4[C:22]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:20]=[CH:19][N:18]=4)[CH2:13][CH2:12][C:11]=3[N:27]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:29]C([O-])(C)C.[K+].C(OC(C1C(=O)CCN([C:48]2[C:53]([C:54]([F:57])([F:56])[F:55])=[CH:52][CH:51]=[CH:50][N:49]=2)CC1)=O)C.Br.N1(C(=N)N)CCCCC1>CC(O)(C)C>[N:1]1([C:7]2[N:8]=[C:9]([NH:49][C:50]3[CH:51]=[CH:52][C:53]([C:54]([F:55])([F:56])[F:57])=[CH:48][CH:29]=3)[C:10]3[CH2:16][CH2:15][N:14]([C:17]4[C:22]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:20]=[CH:19][N:18]=4)[CH2:13][CH2:12][C:11]=3[N:27]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Oc1nc(N2CCCCC2)nc2c1CCN(c1ncccc1C(F)(F)F)CC2
Reactant: CCOC(=O)C1CCN(c2ncccc2C(F)(F)F)CCC1=O
Reactant: CC(C)(C)[O-]
Agent: Br
Agent: N=C(N)N1CCCCC1
Agent: [K+]
Solvent: CC(C)(C)O
Product: FC(F)(F)c1ccc(Nc2nc(N3CCCCC3)nc3c2CCN(c2ncccc2C(F)(F)F)CC3)cc1
Yield: 51 %

Procedure:
2-Piperidin-1-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ol. To solution of KOtBu (1.3 g, 5.77 mmol) in tBuOH (32 mL) was added 5-oxo-1-(3-trifluoromethyl-pyridin-2-yl)-azepane-4-carboxylic acid ethyl ester (Intermediate B; 1.27 g, 3.85 mmol), followed by piperidine-1-carboximidamide hydrobromide (1.2 g, 5.77 mmol). After heating at reflux for 24 h, the mixture was cooled and concentrated. The residue was dissolved in water and CH2Cl2. The aqueous layer was acidified to pH=7 with HOAc. The layers were separated and the aqueous layer was extracted with CH2Cl2. The combined organic layers were dried (Na2SO4) and concentrated. The residue was triturated with Et2O and filtered. The filtrate was concentrated and the residue was purified (FCC) to give the title compound (776.4 g, 51%—combined filtered and chromatographed).
Reaction SMILES: [Cl:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][CH2:7][NH:8][C:9]([C:11]2[CH:32]=[CH:31][C:14]([O:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25]CC)=[O:24])=[CH:18][C:17]=3[CH:28]3[CH2:30][CH2:29]3)=[CH:13][CH:12]=2)=[O:10])=[CH:4][CH:3]=1.[OH-].[Na+].O>O1CCOCC1.C(OCC)(=O)C.Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][NH:8][C:9]([C:11]2[CH:12]=[CH:13][C:14]([O:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][C:23]([OH:25])=[O:24])=[CH:18][C:17]=3[CH:28]3[CH2:29][CH2:30]3)=[CH:31][CH:32]=2)=[O:10])=[CH:33][CH:34]=1
Reactant: CCOC(=O)Cc1ccc(Oc2ccc(C(=O)NCCc3ccc(Cl)cc3)cc2)c(C2CC2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)Cc1ccc(Oc2ccc(C(=O)NCCc3ccc(Cl)cc3)cc2)c(C2CC2)c1
Reaction time: 3 h
Yield: 76.1 %

Procedure:
Ethyl 2-(4-(4-((4-chlorophenethyl)carbamoyl)phenoxy)-3-cyclopropylphenyl)acetate (70 mg, 0.146 mmol) was diluted with dioxane (1 mL) followed by the addition of NaOH (0.293 ml, 1.46 mmol) and water (300 μL). After stirring for 3 hours, the reaction was diluted with ethyl acetate and 2N HCl. The layers were separated and the organic layer was dried over MgSO4, filtered and concentrated to yield 2-(4-(4-((4-chlorophenethyl) carbamoyl)phenoxy)-3-cyclopropylphenyl)acetic acid (50 mg, 75.9% yield) as a white solid. 1H NMR (400 MHz, CD3Cl3, CD3OD) 7.65 (d, 2H), 7.30 (d, 2H), 7.15 (d, 2H), 7.10 (d, 1H), 6.90 (m, 4H), 3.65 (t, 2H), 3.60 (s, 2H), 2.90 (t, 2H), 2.05 (m, 1H), 0.80 (m, 2H), 0.62 (m, 2H).
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[C:7]([C:12]([OH:14])=[O:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][NH:3]1.S(=O)(=O)(O)O.[OH-].[Na+].[CH3:22]O>>[O:1]=[C:2]1[C:11]2[C:6](=[C:7]([C:12]([O:14][CH3:22])=[O:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][NH:3]1
Reactant: CO
Reactant: O=C(O)c1cccc2c(=O)[nH]cnc12
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: COC(=O)c1cccc2c(=O)[nH]cnc12
Temperature: 25 °C
Yield: 94 %

Procedure:
4-oxo-3,4-dihydroquinazoline-8-carboxylic acid (5.0 g, 26.3 mmol) was treated with a solution of sulfuric acid ((1.2 equivalents) in anhydrous MeOH (100 mL) under refluxing for 2 days. After cooling to rt, 2N NaOH solution was added to the reaction mixture to adjust pH˜8. After removal of MeOH, methyl ester was collected by filtration, and washing with water and ethyl acetate as pale yellow solid in 94% yield. 1HNMR (in DMSO): 3.84 (s, 3H), 7.42 (t, J=7.6 Hz, 1H), 7.85 (d, J=6.9 Hz, 1H), 8.16 (s, 1H), 8.20 (d, J=7.8 Hz, 1H). Mass: M+H+: 205.
Reaction SMILES: [ClH:1].Cl.[NH2:3][C:4]1[C:9]([NH2:10])=[CH:8][CH:7]=[C:6]([O:11][CH3:12])[N:5]=1.[CH2:13]([O:16][C:17]1[CH:25]=[C:24]([S:26][CH3:27])[CH:23]=[CH:22][C:18]=1[C:19](O)=O)[CH2:14][CH3:15]>>[ClH:1].[CH2:13]([O:16][C:17]1[CH:25]=[C:24]([S:26][CH3:27])[CH:23]=[CH:22][C:18]=1[C:19]1[NH:10][C:9]2[C:4]([N:3]=1)=[N:5][C:6]([O:11][CH3:12])=[CH:7][CH:8]=2)[CH2:14][CH3:15]
Reactant: CCCOc1cc(SC)ccc1C(=O)O
Reactant: COc1ccc(N)c(N)n1
Agent: Cl
Product: CCCOc1cc(SC)ccc1-c1nc2nc(OC)ccc2[nH]1

Procedure:
Prepared analogously to Example 5 from 2,3-diamino-6-methoxypyridine dihydrochloride and 2-propoxy-4-methylmercapto-benzoic acid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:9])=[CH:4][C:5](C)=[CH:6][CH:7]=1.N[C:11]1C(C)=CC=C(C)C=1.[OH2:19]>>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:11])[C:3]=1[CH3:9].[CH3:2][OH:19]
Reactant: Cc1ccc(N)c(C)c1
Reactant: Cc1ccc(C)c(N)c1
Reactant: O
Product: CO
Product: Cc1cccc(N)c1C

Procedure:
In accordance with the above, soil and water samples contaminated with 2,4 xylidine and 2,5 xylidine were cleaned. Spiked water samples were produced by adding specific amounts of 2,4 xylidine and 2,5 xylidine to deionized water. A soil containing 70 wt % sand, 10 wt % black earth, 10 wt % peat and 10 wt % water was produce and spiked with a xylidine/methanol solution. The methanol was thereafter evaporated by air drying at room temperature.
Reaction SMILES: [C:1]1(C2C=CC=CC=2)[C:2]([C:7]([CH2:9][CH2:10][C:11]2[C:16]3[NH:17][C:18](=[O:20])[O:19][C:15]=3[CH:14]=[C:13]([C:21]#[N:22])[CH:12]=2)=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.C(N)(=N)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(=O)([O-])[O-].[NH4+:42].[NH4+]>>[C:5]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:4]=[CH:3][C:2]([C:7]([CH2:9][CH2:10][C:11]2[C:16]3[NH:17][C:18](=[O:20])[O:19][C:15]=3[CH:14]=[C:13]([C:21](=[NH:22])[NH2:42])[CH:12]=2)=[O:8])=[CH:1][CH:6]=1
Reactant: [NH4+]
Reactant: N#Cc1cc(CCC(=O)c2ccccc2-c2ccccc2)c2[nH]c(=O)oc2c1
Reactant: N=C(N)c1ccccc1
Agent: O=C([O-])[O-]
Product: N=C(N)c1cc(CCC(=O)c2ccc(-c3ccccc3)cc2)c2[nH]c(=O)oc2c1

Procedure:
6-Cyanobenzoxazolinone (5.0 mmol, 0.80 g) was synthesized as previously described and added to a solution of 3-[1,1′]-biphenyl-1,2-propen-3-one (5.0 mmol, 1.04 g) and triethylamine (10.00 mmol, 1.39 mL) in 40 mL acetonitrile. The reaction mixture was warmed from ambient temperature to 77° C. for 2h. The reaction mixture was concentrated and placed under high vaccum to give the crude product. The crude material was used directly. LRMS: m/z 386 (M+NH4,100). The 1N-[[1,1′]-biphenylcarbonyl]ethyl-6-cyanobenzoxazolinone was converted to its corresponding benzamidine via the Pinner synthesis and amidination with ammonium carbonate to give crude 1N-[4-biphenylcarbonyl]ethyl-6-amidinobenzoxazolinone. The crude product was purified by standard reverse phase HPLC. LRMS: m/z 386(M+H,100). HRMS: calcd for C23H20N3O3, 386.150467; found, 386.150040.
Reaction SMILES: Br[C:2]1[C:3]2[S:9][CH:8]=[C:7]([Br:10])[C:4]=2[S:5][CH:6]=1.[CH3:11][O:12][C:13](=[O:46])[NH:14][C@H:15]([C:19]([N:21]1[CH2:25][CH2:24][CH2:23][C@H:22]1[C:26]1[NH:27][C:28]([C:31]2[CH:36]=[CH:35][C:34](B3OC(C)(C)C(C)(C)O3)=[CH:33][CH:32]=2)=[CH:29][N:30]=1)=[O:20])[CH:16]([CH3:18])[CH3:17].C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C>CN(C=O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:11][O:12][C:13](=[O:46])[NH:14][C@H:15]([C:19]([N:21]1[CH2:25][CH2:24][CH2:23][C@H:22]1[C:26]1[NH:30][CH:29]=[C:28]([C:31]2[CH:32]=[CH:33][C:34]([C:2]3[C:3]4[S:9][CH:8]=[C:7]([Br:10])[C:4]=4[S:5][CH:6]=3)=[CH:35][CH:36]=2)[N:27]=1)=[O:20])[CH:16]([CH3:18])[CH3:17]
Reactant: Brc1csc2c(Br)csc12
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)[nH]1)C(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc(-c2ccc(-c3csc4c(Br)csc34)cc2)c[nH]1)C(C)C
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 74 %

Procedure:
To a degassed mixture of 3,6-dibromo-thieno[3,2-b]thiophene (0.335 mmol), compound 8 (0.335 mmol), and sodium carbonate (1.34 mmol) in a mixture of DMF and water (10 mL/1 mL) was added Pd(PPh3)4 (0.335 mmol). The reaction mixture was heated for 1 hr at 80° C. Ethyl acetate and water were then added and the mixture was vigorously stirred for 10 min. The layers were partitioned into a phase separator. The organic layer was separated, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (eluent: DCM to DCM/MeOH 9/1) to give compound A155 as a green gum in 74% yield. 1H NMR (DMSO-d6, 400 MHz) δ (ppm) 0.85 (d, J=6.61 Hz, 3H), 0.90 (d, J=6.61 Hz, 3H), 1.92-2.19 (m, 5H), 3.53 (s, 3H), 3.77-3.84 (m, 2H), 4.06 (t, J=8.34 Hz, 1H), 5.07-5.09 (m, 1H), 7.28 (d, J=8.32 Hz, 1H), 7.54 (d, J=1.97 Hz, 1H), 7.70-7.76 (m, 2H), 7.84-7.93 (m, 3H), 8.08-8.14 (m, 1H), 11.81 (s, 1H); MS (ESI, EI+) m/z=587-589 (MH+).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[C:6]([C:10]1[CH:11]=[C:12]([NH:31][C:32]([NH:34][C@@H:35]2[C:44]3[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=3)[C@H:38]([O:45][C:46]3[CH:47]=[CH:48][C:49]4[N:50]([C:52]([N:55]5[CH2:60][CH2:59][CH2:58][CH2:57][CH2:56]5)=[N:53][N:54]=4)[CH:51]=3)[CH2:37][CH2:36]2)=[O:33])[N:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][CH2:23][O:24]C3CCCCO3)[CH:16]=2)[N:14]=1)([CH3:9])([CH3:8])[CH3:7].CCN(C(C)C)C(C)C>C(Cl)Cl>[C:6]([C:10]1[CH:11]=[C:12]([NH:31][C:32]([NH:34][C@@H:35]2[C:44]3[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=3)[C@H:38]([O:45][C:46]3[CH:47]=[CH:48][C:49]4[N:50]([C:52]([N:55]5[CH2:60][CH2:59][CH2:58][CH2:57][CH2:56]5)=[N:53][N:54]=4)[CH:51]=3)[CH2:37][CH2:36]2)=[O:33])[N:13]([C:15]2[CH:16]=[C:17]([CH:18]=[CH:19][CH:20]=2)[O:21][CH2:22][CH2:23][O:24][S:2]([CH3:1])(=[O:4])=[O:3])[N:14]=1)([CH3:9])([CH3:7])[CH3:8]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)c1cc(NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCCCC5)n4c3)c3ccccc32)n(-c2cccc(OCCOC3CCCCO3)c2)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)c1cc(NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCCCC5)n4c3)c3ccccc32)n(-c2cccc(OCCOS(C)(=O)=O)c2)n1
Temperature: 0 °C
Yield: 100 %

Procedure:
Methane sulfonylchloride (46.0 μL, 0.59 mmol) was added to an ice cold solution of Example 39 (187 mg, 0.28 mmol) and DIPEA (122 μL, 0.70 mmol) in DCM (3.0 mL). After 2.5 h the reaction was partitioned between DCM and water. The aqueous layer was then extracted with DCM (3×). The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated in vacuo to give the title compound (208 mg, 99%). LCMS (Method 2): Rt 3.38 min, m/z 743 [MH+].
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH3:15])=[CH:10][CH:9]=1)=[O:7].[Br:16]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C1(C)C=CC=CC=1.C(Cl)(Cl)(Cl)Cl>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([C:8]1[CH:9]=[CH:10][C:11]([CH:14]([Br:16])[CH3:15])=[CH:12][CH:13]=1)=[O:7]
Reactant: CCc1ccc(C(=O)c2cccs2)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: CC(Br)c1ccc(C(=O)c2cccs2)cc1

Procedure:
A mixture of 23.5 parts of p-ethylphenyl 2-thienyl ketone, 19.5 parts of N-bromosuccinimide, 220 parts of carbon tetrachloride, 1.1 parts of benzoyl peroxide and one drop of toluene is stirred and refluxed for 2 hours. The precipitated succinimide is filtered off and the carbon tetrachloride filtrate is dried and evaporated. The oily residue solidifies on cooling. The solid product is dissolved in 2-propanol and the product is allowed to crystallize. It is filtered off and dried in vacuo, yielding α-bromo-α-methyl-p-tolyl 2-thienyl ketone; mp. 71.1° C.
Reaction SMILES: [CH2:1]([N:3]1[C:7](=[O:8])[CH2:6][S:5][C:4]1=[N:9][OH:10])[CH3:2].[CH3:11][N:12]([S:16][C:17]([Cl:20])([Cl:19])[Cl:18])[C:13](F)=[O:14].C(N(CC)CC)C>O1CCOCC1.O>[CH2:1]([N:3]1[C:7](=[O:8])[CH2:6][S:5][C:4]1=[N:9][O:10][C:13](=[O:14])[N:12]([CH3:11])[S:16][C:17]([Cl:20])([Cl:19])[Cl:18])[CH3:2]
Reactant: CCN1C(=O)CSC1=NO
Reactant: CN(SC(Cl)(Cl)Cl)C(=O)F
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1COCCO1
Product: CCN1C(=O)CSC1=NOC(=O)N(C)SC(Cl)(Cl)Cl
Reaction time: 0.42 h

Procedure:
To a solution of 1.74 g, 3-ethyl-2-oximino-4-thiazolidinone in 25 ml of dioxane cooled to 20°C was added to a solution 2.53 g of N-methyl-N-(trichloromethanesulfenyl) carbamyl fluoride in 25 ml dioxane. To this mixture was added dropwise with external cooling 1.37 g of triethylamine. After stirring for 25 minutes the solution was diluted with 150 ml of water. The solid product was filtered off, dissolved in ethylacetate, dried and concentrated. Crystallized from acetone. Weight 2.8 g., m.p. 126°-128°C.
Reaction SMILES: N1C=CC=CC=1.Cl[C:8]([C:10]1[CH:11]=[CH:12][C:13]([NH:20][C:21](=[O:26])[C:22]([F:25])([F:24])[F:23])=[C:14]([CH:19]=1)[C:15]([O:17][CH3:18])=[O:16])=[O:9].[CH2:27]([O:34][C:35]1[C:43]2[N:39]([CH:40]=[C:41]([CH3:46])[C:42]=2[O:44][CH3:45])[CH:38]=[CH:37][CH:36]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>ClCCl.C(O)C>[CH2:27]([O:34][C:35]1[C:43]2[N:39]([C:40]([C:8]([C:10]3[CH:11]=[CH:12][C:13]([NH:20][C:21](=[O:26])[C:22]([F:25])([F:24])[F:23])=[C:14]([CH:19]=3)[C:15]([O:17][CH3:18])=[O:16])=[O:9])=[C:41]([CH3:46])[C:42]=2[O:44][CH3:45])[CH:38]=[CH:37][CH:36]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: COC(=O)c1cc(C(=O)Cl)ccc1NC(=O)C(F)(F)F
Reactant: COc1c(C)cn2cccc(OCc3ccccc3)c12
Solvent: CCO
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1cc(C(=O)c2c(C)c(OC)c3c(OCc4ccccc4)cccn23)ccc1NC(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 61.9 %

Procedure:
4.4 ml (54.3 mmol) of pyridine and then 15.0 g (48.4 mmol) of methyl 5-(chlorocarbonyl)-2-[(trifluoro-acetyl)amino]benzoate (described in Patent Application WO2003084956) are added, under argon, to the solution of 13.2 g (49.4 mmol) of 8-(benzyloxy)-1-methoxy-2-methylindolizine in 165 ml of dichloromethane. The reaction medium is stirred at ambient temperature for 3 hours. This is diluted with dichloromethane and this organic solution is washed with a saturated aqueous solution of sodium bicarbonate and then a saturated aqueous solution of sodium chloride, and dried over sodium sulphate. After concentration under reduced pressure, the solid obtained is taken up in ethanol, filtered and washed with ethanol, to give 16.2 g (61%) of an orange powder.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:21]=O)[C:5]([N:8]([CH2:17][CH:18]([CH3:20])[CH3:19])[CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[N:6][CH:7]=1.C[O-].[Na+].O>C(=O)(OC)OC.CO>[Br:1][C:2]1[CH:7]=[N:6][C:5]2[N:8]([CH2:17][CH:18]([CH3:20])[CH3:19])[CH2:9][CH2:10][CH2:11][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:21][C:4]=2[CH:3]=1
Reactant: COC(=O)CCCCN(CC(C)C)c1ncc(Br)cc1C=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: COC(=O)OC
Product: COC(=O)C1=Cc2cc(Br)cnc2N(CC(C)C)CCC1
Temperature: 65 °C
Yield: 92.7 %

Procedure:
To a solution of methyl 5-[(5-bromo-3-formylpyridin-2-yl)(isobutyl)amino]pentanoate (840 mg) in dimethyl carbonate (20 ml) was added a 28% sodium methoxide solution in methanol (874 mg), and the mixture was heated at 65° C. for 3 hours under a nitrogen atmosphere. The mixture was returned to room temperature, water was added, and then the resulting mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to obtain the residue, and then the obtained residue was washed with hexane-ethyl acetate to give methyl 3-bromo-10-isobutyl-7,8,9,10-tetrahydropyrido[2,3-b]azocine-6-carboxylate (741 mg) as yellow crystals.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7](Cl)=[O:8])([O-:3])=[O:2].[CH2:13]([NH2:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(OCC)(=O)C>[C:14]1([CH2:13][NH:20][C:7](=[O:8])[C:6]2[CH:10]=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NCc1ccccc1
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Solvent: CCOC(C)=O
Product: O=C(NCc1ccccc1)c1cccc([N+](=O)[O-])c1
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
A sample of m-nitrobenzoyl chloride, 7.4 g in 300 ml of ethyl acetate was treated with 11 ml of benzyl amine. After 30 minutes, the mix was washed with 100 ml of water. The ethyl acetate layer was concentrated hot to 100 ml and diluted with heptane until solids formed, and then the mix was stirred overnight and allowed to cool to 20° C. The solids were then collected to give N-phenylmethyl-3-nitrobenzamide. m.s. (M+H)+ =257
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[CH2:7][C@@H:8]([CH2:15][OH:16])[CH2:9][C@H:10]([CH3:14])[CH2:11][CH2:12][CH3:13])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[S:25](Cl)([C:28]1[CH:34]=[CH:33][C:31]([CH3:32])=[CH:30][CH:29]=1)(=[O:27])=[O:26].Cl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:1]([O:5][C:6](=[O:17])[CH2:7][C@@H:8]([CH2:15][O:16][S:25]([C:28]1[CH:34]=[CH:33][C:31]([CH3:32])=[CH:30][CH:29]=1)(=[O:27])=[O:26])[CH2:9][C@H:10]([CH3:14])[CH2:11][CH2:12][CH3:13])([CH3:3])([CH3:2])[CH3:4]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCC[C@@H](C)C[C@H](CO)CC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC[C@@H](C)C[C@H](COS(=O)(=O)c1ccc(C)cc1)CC(=O)OC(C)(C)C
Yield: 91.1 %

Procedure:
To alcohol 103 (1.98 g, 8.1 mmol) in CH2Cl2 (40 mL) at room temperature was added triethylamine (2.4 g, 0.024 mol), DMAP (20 mg) and tosyl chloride (2.3 g, 0.012 mol). After 14 hours 1N HCl was added and the two layers separated. The aqueous phase was extracted with ether and the combined organic phases dried (MgSO4) and concentrated. Flash chromatography (95% hexane/EtOAc) gave tosylate 104 as an oil (2.94 g, 91%). 13C NMR (100 MHz; CDCl3) 171.60, 144.92, 133.07, 130.02, 128.12, 80.80, 72.15, 39.73, 38.09, 37.89, 32.67, 29.71, 28.22, 21.83, 20.10, 19.54, 14.49.
Reaction SMILES: [O:1]=[C:2]1[CH2:5][C@@H:4]([CH2:6][CH:7]2[O:11][CH2:10]O[O:8]2)[N:3]1C(=O)C(OC)=O.[CH3:18]SC>CO.ClCCl>[CH3:10][O:11][CH:7]([O:8][CH3:18])[CH2:6][C@H:4]1[NH:3][C:2](=[O:1])[CH2:5]1.[O:8]=[CH:7][CH2:6][C@H:4]1[NH:3][C:2](=[O:1])[CH2:5]1
Reactant: CSC
Reactant: COC(=O)C(=O)N1C(=O)C[C@H]1CC1OCOO1
Solvent: CO
Solvent: ClCCl
Product: COC(C[C@@H]1CC(=O)N1)OC
Product: O=CC[C@@H]1CC(=O)N1
Temperature: 5 °C
Reaction time: 15 h

Procedure:
A solution of methyl [(4R)-2-oxo-4-(1,2,4-trioxolan-3-ylmethyl)azetidin-1-yl]glyoxylate (320 mg) and dimethyl sulfide (2 ml) in a mixture of methanol (10 ml) and dichloromethane (9 ml) was stirred at 5° C. for six hours, at room temperature for 15 hours, and at 55° C. for four hours. The resultant solution was concentrated and the residue was dissolved in a mixture of dimethyl sulfide (2 ml) and methanol (15 ml). Silica gel (100 mg) was added and the mixture was stirred at room temperature for four days, at 50° C. for eight hours, and at 60° C. for seven hours. After evaporation of the solvent, the residue was chromatographed on silica gel (7 g) eluting with 2-5% methanol in dichloromethane to give (4R)-4-(2,2-dimethoxyethyl)-2-oxo-azetidine (57 mg) as an impure oil and (4R)-4-(2-oxoethyl)-2-oxoazetidine (31 mg). Further purification of the impure oil on silica gel (4 g) eluting with 0.5-2% methanol in dichloromethane afforded the pure oil (31 mg) of the former compound.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.Br[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[O:20][N:19]=[C:18]([CH3:21])[CH:17]=1.[OH-].[K+]>C(#N)C>[CH3:21][C:18]1[CH:17]=[C:16]([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][O:1][C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)[O:20][N:19]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: Cc1cc(CCCCCBr)on1
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Product: Cc1cc(CCCCCOc2ccc(C=O)cc2)on1
Yield: 67 %

Procedure:
A solution of 7.2 g 4-hydroxybenzaldehyde, 14.6 g 5-(5-bromopentyl)-3-methylisoxazole, 4 g potassium hydroxide in 100 ml acetonitrile was heated at reflux for 1.5 hours. The reaction mixture was cooled and filtered, the solvent removed, and the residue recrystallized from isopropyl acetate-hexane to give 10.8 g 4-[5(3-methyl-5-isoxazolyl)pentyloxy]benzaldehyde as a pale-yellow powder.
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH2:12][C:13]2[CH2:17][CH2:16][O:15][N:14]=2)=[C:10]([CH:18]=[S:19](=[O:21])=[O:20])[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[OH-].[Li+].Cl>O1CCCC1.C(OCC)C>[Cl:1][C:2]1[C:11]([CH2:12][C:13]2[CH2:17][CH2:16][O:15][N:14]=2)=[C:10]([CH:18]=[S:19](=[O:20])=[O:21])[CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1ccc(C=S(=O)=O)c(CC2=NOCC2)c1Cl
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C(O)c1ccc(C=S(=O)=O)c(CC2=NOCC2)c1Cl

Procedure:
At 5° C., a solution of 2.3 g (7 mmol) of methyl 2-chloro-3-(4,5-dihydro-3-isoxazolylmethyl)-4-sulfonylmethylbenzoate in 40 ml of tetrahydrofuran is treated with 0.3 g (13 mmol) of lithium hydroxide. The reaction mixture is taken up in 300 ml of diethyl ether and adjusted to pH 1 using 10% strength aqueous hydrochloric acid. The aqueous phase is extracted with diethyl ether. The combined organic phases are dried over sodium sulfate, filtered and freed from the solvent under reduced pressure. Yield: 1.7 g; 1H NMR, δ [ppm], DMSO-d6; 3.0 (t), 3.3 (s), 4.2 (t), 4.3 (s), 7.8 (d), 8.1 (d).
Reaction SMILES: [N:1]1[C:2]([CH2:10][OH:11])=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.[CH:12]([Si:15](Cl)([CH:19]([CH3:21])[CH3:20])[CH:16]([CH3:18])[CH3:17])([CH3:14])[CH3:13].O>ClCCl>[CH:12]([Si:15]([CH:19]([CH3:21])[CH3:20])([CH:16]([CH3:18])[CH3:17])[O:11][CH2:10][C:2]1[N:1]=[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][N:4]2[CH:3]=1)([CH3:14])[CH3:13]
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: OCc1cn2ccccc2n1
Solvent: ClCCl
Solvent: O
Product: CC(C)[Si](OCc1cn2ccccc2n1)(C(C)C)C(C)C
Yield: 92.8 %

Procedure:
1 g (6.55 mmol) of imidazo[1,2-a]pyridin-2-ylmethanol were solubilised in 25 ml of dichloromethane with magnetic stirring and then 2.145 ml (9.82 mmol) of triisopropylsilyl chloride were slowly added. The mixture was stirred at r.t. for 1 h before being treated with 100 ml of water. The aqueous phase was extracted with 3×50 ml of dichloromethane. The combined organic phases were washed with 100 ml of a saturated NaCl aqueous solution, dried on Na2SO4 which was then removed by filtration. The obtained filtrate was concentrated in vacuo. The crude residue was purified by flash chromatography on a silica gel cartridge (eluent: dichloromethane 100% and then ethyl acetate 100%). 1.85 g (yield=92%) of 2-(((triisopropylsilyl)oxy)methyl)imidazo[1,2-a]pyridine were obtained as a colourless oil. LC-MS: m/z=305 (MH+); UV purity at 254 nm=99%. 1H NMR (300 MHz, DMSO) δ 8.57-8.50 (m, 1H), 7.81 (s, 1H), 7.46 (dd, J=9.1, 0.6 Hz, 1H), 7.19 (ddd, J=9.1, 6.7, 1.3 Hz, 1H), 6.84 (td, J=6.8, 1.1 Hz, 1H), 4.88 (d, J=0.6 Hz, 2H), 1.23-1.11 (m, 3H), 1.11-1.02 (m, 18H).