Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[S:41][C:6]2[N:7]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[C:35]4[NH:39][C:38](=[O:40])[O:37][N:36]=4)=[CH:25][CH:24]=3)[C:8](=[O:21])[N:9]([CH2:12][C:13](=O)[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:10](=O)[C:5]=2[CH:4]=1)[CH3:2].Cl.[NH2:43][O:44][CH2:45]C=C.N1C=CC=CC=1.Cl.[OH2:55]>C(Cl)(Cl)Cl.C(O)C>[CH2:1]([C:3]1[S:41][C:6]2[N:7]([CH2:22][C:23]3[CH:24]=[CH:25][C:26]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[C:35]4[NH:39][C:38](=[O:40])[O:37][N:36]=4)=[CH:27][CH:28]=3)[C:8](=[O:21])[N:9]([CH2:12][C:13](=[N:43][O:44][CH3:45])[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:10](=[O:55])[C:5]=2[CH:4]=1)[CH3:2]
Reactant: C=CCON
Reactant: O
Reactant: CCc1cc2c(=O)n(CC(=O)c3ccccc3)c(=O)n(Cc3ccc(-c4ccccc4-c4noc(=O)[nH]4)cc3)c2s1
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CCc1cc2c(=O)n(CC(=NOC)c3ccccc3)c(=O)n(Cc3ccc(-c4ccccc4-c4noc(=O)[nH]4)cc3)c2s1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
A mixture of 6-ethyl-1-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-3-(2-oxo-2-phenylethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (0.3 g), 3-(aminooxy)prop-1-ene hydrochloride (0.05 g), pyridine (10 mL) and ethanol (10 mL) was stirred at 100° C. for 16 hr. To the reaction mixture were added chloroform and water, and the mixture was adjusted to pH 4 with 1N hydrochloric acid. The chloroform layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a stereoisomer mixture (0.22 g, 74%).
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:10]=[CH:9][C:7](=[O:8])[NH:6][C:4]1=[O:5].[CH2:11](Br)[CH:12]=[CH2:13]>CN(C=O)C>[CH2:13]([N:3]1[CH:10]=[CH:9][C:7](=[O:8])[NH:6][C:4]1=[O:5])[CH:12]=[CH2:11]
Reactant: O=c1cc[nH]c(=O)[nH]1
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCn1ccc(=O)[nH]c1=O
Temperature: 70 °C
Reaction time: 2 h
Yield: 38.9 %

Procedure:
2.5 g (104 mmol, 80% suspension) of NaH was added to a suspension of 10.5 g (93 mmol) uracil in 100 ml DMF and the reaction allowed to continue for 2 hours at room temperature. After 2 hours 10.73 mL (15 g, 123 mmol) allylbromide was added and the mixture heated for 2 hours at 70° C. The solvent was removed under reduced pressure and the residue treated with methylene chloride. The residue from the methylene chloride extract was a mixture of mono-allyl- and di-allyl-uracil. 5.5 g (39%) of 1-allyluracil was isolated by preparative column chromatography, using chlormoform/methanol 40:1 as eluant (m.p. 108–109° C., Lit. 105–109° C., Beilstein).
Reaction SMILES: [C:1]([C:5]1[S:9]/[C:8](=[N:10]\[C:11](=[O:21])[C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=2[O:19][CH3:20])/[N:7]([CH2:22][C@H:23]([NH:25]C(=O)OC(C)(C)C)[CH3:24])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl>CO.O1CCOCC1>[NH2:25][C@H:23]([CH3:24])[CH2:22][N:7]1[CH:6]=[C:5]([C:1]([CH3:3])([CH3:4])[CH3:2])[S:9]/[C:8]/1=[N:10]\[C:11](=[O:21])[C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=1[O:19][CH3:20]
Reactant: COc1ccc(Cl)cc1C(=O)/N=c1\sc(C(C)(C)C)cn1C[C@@H](C)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: COc1ccc(Cl)cc1C(=O)/N=c1\sc(C(C)(C)C)cn1C[C@@H](C)N
Reaction time: 24 h
Yield: 53.7 %

Procedure:
In a 20 mL vial, to a solution of Example 59B (75 mg, 0.156 mmol) in MeOH (1 mL) was added a solution of hydrogen chloride (0.039 mL, 0.156 mmol) in dioxane and the mixture was stirred for 24 hr. The reaction was concentrated and the residue was purified by preparative HPLC on a Waters Symmetry C8 column (25 mm×100 mm, 7 μm particle size) using a gradient of 10-100% acetonitrile (A) and 10 mM ammonium acetate in water (B), at a flow rate of 2.0 mL/min (0-0.1 min 10% A, 0.1-2.6 min 10-100% A, 2.6-2.9 min 100% A, 2.9-3.0 min 100-10% A. 0.5 min post-run delay) to obtain the title compound (32 mg, 59%). 1H NMR (300 MHz, METHANOL-d4) δ ppm 1.26 (d, J=6.78 Hz, 3H) 1.40 (s, 9H) 3.64-3.73 (m, 1H) 3.86 (s, 3H) 4.26-4.31 (m, 2H) 7.09 (d, J=8.82 Hz, 1H) 7.18 (s, 1H) 7.41 (dd, J=8.82, 2.71 Hz, 1H) 7.74 (d, J=2.71 Hz, 1H); MS (DCI) m/z 382 (M+H)+.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[C:29]4[C:24](=[CH:25][CH:26]=[C:27]([C:30]#[C:31][CH2:32]OS(C)(=O)=O)[CH:28]=4)[N:23]=[CH:22][N:21]=3)[CH2:16][CH2:15]2)=[O:13])=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[CH2:38]([NH:40][CH2:41][CH3:42])[CH3:39]>CC#N>[CH:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12]([N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[C:29]4[C:24](=[CH:25][CH:26]=[C:27]([C:30]#[C:31][CH2:32][N:40]([CH2:41][CH3:42])[CH2:38][CH3:39])[CH:28]=4)[N:23]=[CH:22][N:21]=3)[CH2:16][CH2:15]2)=[O:13])=[CH:9][CH:10]=1)([CH3:3])[CH3:2]
Reactant: CCNCC
Reactant: CC(C)Oc1ccc(NC(=O)N2CCC(c3ncnc4ccc(C#CCOS(C)(=O)=O)cc34)CC2)cc1
Solvent: CC#N
Product: CCN(CC)CC#Cc1ccc2ncnc(C3CCN(C(=O)Nc4ccc(OC(C)C)cc4)CC3)c2c1
Temperature: 25 °C
Yield: 78.9 %

Procedure:
A solution of methanesulfonic acid 3-{4-[1-(4-isopropoxy-phenylcarbamoyl)-piperidin-4-yl]-quinazolin-6-yl}-prop-2-ynyl ester (180.0 mg, 345 μmol), as prepared in the previous step, in CH3CN (0.5 mL) was treated with diethylamine (79 μL, 759 μmol) very rapidly by syringe in 1 portion with stirring at rt, and the pale yellow solution was allowed to stir at rt for 2 h. Purification of the crude reaction with a flash silica column (1:2 hex/acetone) afforded the title compound as an off-white foam (136 mg, 79%). 1H-NMR (300 MHz, CDCl3) δ 9.22 (s, 1H), 8.21 (d, 1H), 7.99 (d, 1H), 7.88 (dd, 1H), 7.25 (m, 2H), 6.84 (m, 2H), 6.38 (br s, 1H), 4.48 (heptet, 1H), 4.32-4.22 (m, 2H), 3.78-3.65 (m, 1H), 3.70 (s, 2H), 3.16 (td, 2H), 2.68 (q, 4H), 2.21-1.94 (m, 4H), 1.31 (d, 6H), 1.15 (t, 6H). LC/MS (ESI): calcd mass 499.3, found 500.5 (MH)+. A select fraction of this material was submitted for combustion analysis: Anal. Calcd for C30H37N5O2.0.18 water: C, 71.65; H, 7.49; N, 13.93. Found: C, 71.7; H, 7.55; N, 13.92.
Reaction SMILES: C[O:2][C:3](=[O:21])[CH:4]([CH2:19][Cl:20])[NH:5][C:6](=[O:18])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH:16]=[CH2:17])=[CH:10][CH:9]=1.[OH-].[Na+].Cl>CC(C)=O>[CH2:15]([O:14][C:11]1[CH:10]=[CH:9][C:8]([CH2:7][C:6]([NH:5][CH:4]([C:3]([OH:21])=[O:2])[CH2:19][Cl:20])=[O:18])=[CH:13][CH:12]=1)[CH:16]=[CH2:17]
Reactant: C=CCOc1ccc(CC(=O)NC(CCl)C(=O)OC)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: C=CCOc1ccc(CC(=O)NC(CCl)C(=O)O)cc1
Temperature: 40 °C
Yield: 94.2 %

Procedure:
4-Allyloxy-3-chloro-phenylacetyl-(DL)-alanine methyl ester (2.0 g) was suspended in acetone (20 ml). Aqueous sodium hydroxide (1 M, 8.0 ml) was added and the mixture was gently warmed to effect solution, and then heated to 40° C. for 20 min. After the solution has been cooled, the pH was adjusted to 2-3 using dilute hydrochloric acid (3 M) and the product was extracted with ethyl acetate (40 ml). The extract was dried (anhydrous sodium sulphate). The solvent was evaporated at reduced pressure to leave a solid residue (1.8 g); it had m.p. 120°-124° C. After recrystallisation from ethyl acetate/light petroleum (b.p. 60°-80° C.) the above-named product, (1.6 g), m.p. 123°-124° C. was obtained.
Reaction SMILES: F[C:2](F)(F)C(O)=O.C([Zn]CC)C.ICI.[I:16][C:17](=[CH2:37])[CH2:18][C@@H:19]([CH2:28][O:29][Si:30]([CH3:36])([CH3:35])[C:31]([CH3:34])([CH3:33])[CH3:32])[O:20][Si:21]([CH3:27])([CH3:26])[C:22]([CH3:25])([CH3:24])[CH3:23]>ClCCCl>[I:16][C:17]1([CH2:18][C@@H:19]([CH2:28][O:29][Si:30]([CH3:36])([CH3:35])[C:31]([CH3:34])([CH3:33])[CH3:32])[O:20][Si:21]([CH3:27])([CH3:26])[C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:2][CH2:37]1
Reactant: O=C(O)C(F)(F)F
Reactant: C=C(I)C[C@@H](CO[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Agent: CC[Zn]CC
Solvent: ClCCCl
Solvent: ICI
Product: CC(C)(C)[Si](C)(C)OC[C@H](CC1(I)CC1)O[Si](C)(C)C(C)(C)C
Reaction time: 0.58 h

Procedure:
Trifluoroacetic acid (8 eq) is added to a solution of diethyl zinc (16 eq) in DCE at 0° C. and stirred for 35 mins. Diiodomethane (8 eq) is added at 0° C., and the mixture stirred for an additional 20 min. A solution of (S)-5-(2-iodoallyl)-2,2,3,3,8,8,9,9-octamethyl-4,7-dioxa-3,8-disiladecane (1 eq) in DCE is added and the reaction stirred at room temperature overnight. The reaction is quenched by addition of a mixture of methanol and brine. After stirring for an additional hour, the mixture is concentrated under reduced pressure. The crude material is extracted with aqueous NH4Cl/CHCl3 and the organic layer washed with brine, dried (MgSO4) and concentrated under reduced pressure. The crude material is triturated in hexane and the solution filtered and evaporated to afford (S)-5-((1-iodocyclopropyl)methyl)-2,2,3,3,8,8,9,9-octamethyl-4,7-dioxa-3,8-disiladecane.
Reaction SMILES: Cl.[F:2][C:3]([F:17])([F:16])[CH2:4][N:5]=[C:6]([NH2:15])[NH:7][C:8]1[S:9][CH:10]=[C:11]([CH2:13]Cl)[N:12]=1.[OH-].[Na+].O.[SH:21][CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25]>CCO>[F:2][C:3]([F:17])([F:16])[CH2:4][N:5]=[C:6]([NH2:15])[NH:7][C:8]1[S:9][CH:10]=[C:11]([CH2:13][S:21][CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])[N:12]=1
Reactant: NC(=NCC(F)(F)F)Nc1nc(CCl)cs1
Reactant: COC(=O)CCS
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COC(=O)CCSCc1csc(NC(N)=NCC(F)(F)F)n1
Reaction time: 1 h

Procedure:
A mixture of 2-[2,2,2-trifluoroethyl]guanidino-4-chloromethylthiazole hydrochloride (4.6 g.) in EtOH (75 ml.) and methyl 3-mercaptopropionate (2.47 ml.) at 5° was treated dropwise with aqueous sodium hydroxide (1.8 g. in 15 ml. of water) over 10 minutes. The resulting solution was allowed to reach room temperature and was stirred for 1 hour. It was then poured into water and the precipitate filtered and crystallised from EtOH to give methyl 3-[2-(2-[2,2,2-trifluoroethyl]guanidino)thiazol-4-ylmethylthio]propionate (1.93 g), m.p. 96°-98°.
Reaction SMILES: [OH:1][C@:2]1([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Br:15])[CH:10]=2)[CH2:7][CH2:6][O:5][C@@H:4]([CH3:8])[CH2:3]1.[Si:16](Cl)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]>>[Si:16]([O:1][C@:2]1([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Br:15])[CH:10]=2)[CH2:7][CH2:6][O:5][C@@H:4]([CH3:8])[CH2:3]1)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C[C@H]1C[C@@](O)(c2cccc(Br)c2)CCO1
Product: C[C@H]1C[C@@](O[Si](C)(C)C(C)(C)C)(c2cccc(Br)c2)CCO1
Yield: 78 %

Procedure:
Using an analogous procedure to that described in the portion of Example 18 which is concerned with the preparation of starting materials, the 4-(3-bromophenyl)-2-methyltetrahydropyran so obtained was reacted with tert-butyldimethylsilyl chloride to give (2S,4R)-4-(tert-butyldimethylsilyloxy)-4-(3-bromophenyl)-2-methyltetrahydropyran in 78% yield as an oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][C:17]([OH:19])=O)[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH2:21]([NH2:28])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].CN(C)CCCN=C=NCC.OC1C2N=NNC=2C=CC=1>ClCCl.O>[C:1]([O:5][C:6](=[O:20])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][C:17]([NH:28][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:19])[N:15]=1)([CH3:8])[CH3:9])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCCCCCN
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CC(=O)O)cs1
Agent: CCN=C=NCCCN(C)C
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCl
Solvent: O
Product: CCCCCCCNC(=O)Cc1csc(SC(C)(C)C(=O)OC(C)(C)C)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 91.9 %

Procedure:
{2-[(2-tert-Butoxy-1,1-dimethyl-2-oxoethyl)thio]-1,3-thiazol-4-yl}acetic acid (25.0 g) synthesized in Example 3 and heptylamine (10.0 g) were dissolved in dichloromethane (250 mL), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (EDC) hydrochloride (18.0 g) and hydroxybenzotriazole (HOBT) monohydrate (16.6 g) were successively added thereto, and the mixture was stirred at room temperature for 5 hr. Water was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=2:1) to give the title compound (30.0 g) as a slightly yellow oil.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:13]=[C:14]([C:17]([CH3:20])([CH3:19])[CH3:18])[C:15]=1[OH:16])C=CC(O)=O)([CH3:4])([CH3:3])[CH3:2].[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[C:24]([N+:29]([O-:31])=[O:30])[CH:23]=1.[OH:32][C:33]1C2N=NNC=2C=[CH:35][CH:34]=1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C=O)C.C1COCC1>[CH3:20][C:17]([C:14]1[CH:13]=[C:7]([C:34](=[CH2:35])[C:33]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([OH:28])=[C:24]([N+:29]([O-:31])=[O:30])[CH:23]=2)=[O:32])[CH:6]=[C:5]([C:1]([CH3:2])([CH3:4])[CH3:3])[C:15]=1[OH:16])([CH3:18])[CH3:19]
Reactant: CC(C)(C)c1cc(C=CC(=O)O)cc(C(C)(C)C)c1O
Reactant: Nc1ccc(O)c([N+](=O)[O-])c1
Reactant: Oc1cccc2[nH]nnc12
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: C=C(C(=O)Nc1ccc(O)c([N+](=O)[O-])c1)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 73.9 %

Procedure:
1.78 g (6.4 mmoles) of 3,5-di-tert-butyl-4-hydroxycinnamic acid, 0.99 g (6.4 mmoles) of 4-amino-2-nitrophenol, previously diluted in 10 ml of DMF, 0.86 g (6.4 mmoles) of hydroxybenzotriazol and 1.32 g (6.4 mmoles) of dicyclohexylcarbodiimide are introduced into a 50 ml flask containing 10 ml of THF. The reaction medium is agitated for 15 hours at ambient temperature, the precipitate which appears is filtered and rinsed with ethyl acetate. After concentration of the solution under reduced pressure, the residue is diluted in 20 ml of ethyl acetate and the insoluble part is filtered again. The filtrate is washed with 20 ml of a saturated solution of sodium carbonate followed by 20 ml of water and 20 ml of a saturated solution of sodium chloride. After drying over sodium sulphate, the organic solution is filtered and concentrated to dryness under reduced pressure. The residue is purified on a silica column (eluant: heptane/ethyl acetate: 8/2). The pure fractions are collected and concentrated under vacuum to produce 1.95 g (47%) of the expected compound in the form of a yellow-orange powder. Melting point: 231-32° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[C:20](=[O:27])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[F:28][C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[C:20](=[O:27])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[C:33]2[CH:32]=[CH:31][CH:30]=[C:29]([F:28])[CH:34]=2)=[CH:4][CH:3]=1
Reactant: O=C1OC2(CCN(C(=O)c3c[nH]c4cc(Cl)ccc34)CC2)c2ccccc21
Reactant: OB(O)c1cccc(F)c1
Product: O=C1OC2(CCN(C(=O)c3cn(-c4cccc(F)c4)c4cc(Cl)ccc34)CC2)c2ccccc21

Procedure:
Following the general procedure VI as described above, the arylation of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one (prepared according to example 16 above) with commercially available 3-fluorophenylboronic acid gave the title compound. ES-MS m/e (%): 475.0 (M+H+).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:16]=[CH:15][C:7]([NH:8][C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])=[CH:6][CH:5]=1.C(N(CC)C(C)C)(C)C.Cl[CH2:27][O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>O1CCCC1.ClCCl>[CH2:29]([O:28][CH2:27][O:1][CH2:2][CH2:3][C:4]1[CH:16]=[CH:15][C:7]([NH:8][C:9](=[O:14])[C:10]([F:12])([F:13])[F:11])=[CH:6][CH:5]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: ClCOCc1ccccc1
Reactant: O=C(Nc1ccc(CCO)cc1)C(F)(F)F
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(CCOCOCc2ccccc2)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a stirred solution of 4′-(2-hydroxyethyl)-2,2,2-trifluoroacetanilide (5.9 g) in tetrahydrofuran (20 ml) and dichloromethane (20 ml) were added N,N-diisopropylethylamine (5.7 ml) and benzyl chloromethyl ether (3.9 ml) under ice-cooling, and the mixture was stirred for 24 hours at room temperature. The reaction mixture was poured into ice-water and extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous magnesium sulfate. Removal of the solvent under reduced pressure gave 4′-[2-(benzyloxymethoxy)ethyl]-2,2,2-trifluoroacetanilide (9.7 g).
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][C:9]([CH3:14])([CH3:13])[O:10]2)=[CH:5][CH:4]=1.B(Br)(Br)Br.C([O-])(O)=O.[Na+]>ClCCl>[CH3:13][C:9]1([CH3:14])[CH2:8][CH2:7][C:6]2[C:11](=[CH:12][C:3]([OH:2])=[CH:4][CH:5]=2)[O:10]1
Reactant: COc1ccc2c(c1)OC(C)(C)CC2
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC1(C)CCc2ccc(O)cc2O1
Temperature: 25 °C
Reaction time: 17 h
Yield: 41.7 %

Procedure:
To a stirred solution of 7-Methoxy-2,2-dimethyl-chroman (4.55 g, 23.7 mmol, from step 1) in anhydrous dichloromethane (50 mL) was added 1M BBr3 (72.86 mL, 47.4 mmol, 2.0 eq) via cannula over 10 min. The resulting dark brown solution was stirred at rt for 17 h. Saturated solution of NaHCO3 (50 mL) was added and extracted with CH2Cl2 (3×50 mL. The combined organic layers were dried over Na2SO4, filtered and evaporated. The residue was purified on silica gel (flash column chromatography) eluting with 5% ethyl acetate-hexane followed by 20% ethyl acetate-hexane to provide the desired product as white solid (1.76 g, 42%). 1H-NMR (CD3CN) δ 6.89 (d, J=8.5 Hz, 1H), 6.68 (broad, s, 1H, OH), 6.31 (dd, J=2.4, 8.5 Hz, 1H), 6.15 (d, J=2.4 Hz, 1H), 2.69 (t, 2H), 1.79 (t, 2H), 1.31 (s, 6H). MS LC-MS (MH+=179).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:26])[O:10][C:11]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[C:13]([N:18]2[N:22]=[C:21]([CH2:23][CH3:24])[C:20]([CH3:25])=[N:19]2)[CH:12]=3)=[CH:4][CH:3]=1.CN([CH:30]=[N:31][N:32]=[CH:33]N(C)C)C>CN(C)C=O.CC1C=CC(S(O)(=O)=O)=CC=1>[N:31]1[N:32]=[CH:33][N:1]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[C:9](=[O:26])[O:10][C:11]4[C:16]([CH:17]=3)=[CH:15][CH:14]=[C:13]([N:18]3[N:22]=[C:21]([CH2:23][CH3:24])[C:20]([CH3:25])=[N:19]3)[CH:12]=4)=[CH:4][CH:3]=2)[CH:30]=1
Reactant: CCc1nn(-c2ccc3cc(-c4ccc(N)cc4)c(=O)oc3c2)nc1C
Reactant: CN(C)C=NN=CN(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CN(C)C=O
Product: CCc1nn(-c2ccc3cc(-c4ccc(-n5cnnc5)cc4)c(=O)oc3c2)nc1C
Yield: 71.8 %

Procedure:
17.3 g (50.0 mmols) of 3-(4-aminophenyl)-7-(4-ethyl-5-methyl-2H-1,2,3-triazol-2-yl)-coumarin, 10.5 g (75.0 mmols) of 1,2-bis-(dimethylaminomethylene)-hydrazine and 200 mg of 4-methylbenzenesulphonic acid are refluxed in 40 ml of anhydrous dimethylformamide for 10 hours under an N2 atmosphere. A further 3.50 g (25.0 mmols) of 1,2-bis-(dimethylaminomethylene)-hydrazine are then added, and the mixture is refluxed for a further 10 hours. 16.1 g (81%) of pale yellow crystals are precipitated on cooling the mixture. Recrystallisation from dimethylformamide yields 14.3 g (72%) of 3-(4-(1,2,4-triazol-4-yl)-phenyl)-7-(4-ethyl-5-methyl-2H-1,2,3-triazol-2-yl)-coumarin in the form of small pale yellow crystals of melting point 321°-323° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[NH:5][C:6]1[S:7][C:8]2[C:14]([C:15]3[O:16][CH2:17][CH2:18][O:19][CH:20]=3)=[CH:13][CH:12]=[C:11]([O:21][CH3:22])[C:9]=2[N:10]=1)[CH3:2].[H][H]>O1CCOCC1.C(O)(=O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:23])[NH:5][C:6]1[S:7][C:8]2[C:14]([CH:15]3[CH2:20][O:19][CH2:18][CH2:17][O:16]3)=[CH:13][CH:12]=[C:11]([O:21][CH3:22])[C:9]=2[N:10]=1)[CH3:2]
Reactant: CCOC(=O)Nc1nc2c(OC)ccc(C3=COCCO3)c2s1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: CCOC(=O)Nc1nc2c(OC)ccc(C3COCCO3)c2s1
Yield: 62.1 %

Procedure:
To a stirred solution of 12.0 g (35.7 mmol) [7-(5,6-dihydro-[1,4]dioxin-2-yl)-4-methoxy-benzothiazol-2-yl]-carbamic acid ethyl ester in 600 ml dioxane and 12 ml acetic acid was added 12 g of 10% palladium on charcoal and the mixture was then stirred for 48 h at room temperature under a 10 bar atmosphere of hydrogen. The mixture was then filtered, washing with dioxane, and the filtrate concentrated in vacuo. Flash chromatography (1/1 acetone/dichloromethane) followed by trituration in ether and hexane afforded 7.50 g (62%) (±)-(7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-yl)-carbamic acid ethyl ester as a white solid. ES-MS m/e (%): 339 (M+H+, 100).
Reaction SMILES: [C:1]([N:8]1C=CN=C1)([N:3]1[CH:7]=CN=[CH:4]1)=O.ON[C:15]([C:17]1[CH:25]=[CH:24][C:20]2[N:21]=[CH:22][NH:23][C:19]=2[CH:18]=1)=[NH:16].C([O-])(O)=[O:27].[Na+]>CN(C=O)C.O>[CH3:4][N:3]([CH:1]=[N:8][NH:16][C:15]([C:17]1[CH:25]=[CH:24][C:20]2[NH:21][CH:22]=[N:23][C:19]=2[CH:18]=1)=[O:27])[CH3:7]
Reactant: N=C(NO)c1ccc2nc[nH]c2c1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)C=NNC(=O)c1ccc2[nH]cnc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The respective carboxylic acid (1 eq.) was dissolved in DMF (5 ml), treated with carbonyldiimidazole (1 eq.) and stirred at room temperature for 1 h. N-Hydroxy-benzimidazol-5-carboxamidine (1 eq.) was added and the mixture was heated to 110° C. over night. After cooling to room temperature, the mixture was diluted with water until a precipitate was formed, basified by means of sat. NaHCO3-solution and extracted with EtOAc (3×25 ml). The combined organic layers were dried over Na2SO4, evaporated and the residue was purified by flash chromatography on silica using a CHCl3/MeOH gradient.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1.BrBr.[C:12](=O)(O)[O-].[Na+]>C(O)(=O)C.CCCCCC>[CH3:12][C:8]1[CH:7]=[CH:6][C:5]2[O:1][CH2:2][CH2:3][C:4]=2[CH:9]=1
Reactant: O=C([O-])O
Reactant: c1ccc2c(c1)CCO2
Agent: BrBr
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCCCCC
Product: Cc1ccc2c(c1)CCO2
Reaction time: 1 h
Yield: 28 %

Procedure:
To a chilled (10° C.) solution of 10 g (83 mmol) of 2,3-dihydrobenzofuran in 50 mL of acetic acid, 4 mL (78 mmol) of bromine in 6 mL of acetic acid was added dropwise over a 10 minute period. After 1 hour, the mixture was made basic by cautiously pouring the reaction mixture into saturated/solid aqueous sodium bicarbonate and stirring overnight. The mixture was then extracted with three 100 mL portions of EtOAc. The combined organic layers were washed with two 50 mL portions of saturated aqueous sodium bicarbonate, three 50 mL portions of brine, dried over magnesium sulfate, filtered, and concentrated to afford a yellow oil. The oil was diluted with hexane and passed through a pad (600 mL funnel) of silica gel eluting with hexane to afford a white solid which was diluted with cold (dry ice-acetone) hexane and collected by filtration to afford 4.7 g (28%) of the title compound as a white solid, m.p. 45° C.-48° C. The filtrate was concentrated to afford 5.1 g of 5-bromo-2,3-dihydrobenzofuran which was 70% pure.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]#[N:8].[OH-].[Na+].[N:11](OC)=[O:12]>CO>[OH:12][N:11]=[C:6]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)[C:7]#[N:8]
Reactant: CON=O
Reactant: N#CCc1cccs1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: N#CC(=NO)c1cccs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 26.8 %

Procedure:
As described under 3.1, 86 g (0.7 mol) of thiophene-2-acetonitrile are charged, with stirring and in the presence of 28 g (0.7 mol) of sodium hydroxide in 210 ml of methanol, with 0.7 mol of gaseous methyl nitrite at 0-5° C. over 4.5 hours. The ice bath is then removed and the brown solution is stirred overnight at room temperature. The solvent is distilled off and the residue is charged with water and toluene. The aqueous phase is separated, washed twice with ethyl acetate and acidified with conc. HCl. The aqueous phase is extracted twice with toluene, the extracts are washed with water and dried over magnesium sulfate. After filtration, the solvent is distilled off and the remaining brown solid is recrystallised from toluene, giving 28.6 g (39% of theory) of α-hydroxyiminothiophene-2-acetonitrile in the form of a beige solid having a melting point of 105-109° C. The 1H-NMR spectrum is consistent with the proposed structure.