Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([OH:4])=O.[CH:5](=[C:12]1/[CH2:13][O:14][C:15]2[C:20]([C:21]/1=O)=[CH:19][C:18]([F:23])=[CH:17][CH:16]=2)/[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.O.[NH2:25][NH2:26]>CCOC(C)=O.C([O-])(O)=O.[Na+]>[C:2]([N:25]1[CH:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:12]2[CH2:13][O:14][C:15]3[CH:16]=[CH:17][C:18]([F:23])=[CH:19][C:20]=3[C:21]2=[N:26]1)(=[O:4])[CH3:1]
Reactant: CC(=O)O
Reactant: NN
Reactant: O=C1/C(=C/c2ccccc2)COc2ccc(F)cc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=O)N1N=C2c3cc(F)ccc3OCC2C1c1ccccc1
Temperature: 175 °C

Procedure:
A 5 mL microwave tube was charged with 4 mL AcOH, 1-1 (0.50 g, 2 mmol), and hydrazine monohydrate (0.2 mL, 3.93 mmol). The tube was sealed and heated in a Personal Chemistry microwave apparatus for 15 min at 175° C. LC/MS analysis indicated two new products with the same molecular weight. The reaction was diluted with EtOAc and neutralized with 200 mL saturated aqueous NaHCO3. The organic layer was dried over MgSO4, filtered and concentrated. The remaining oil was absorbed onto silica gel and the diastereomers were separated on an Isco automated system affixed with a Biotage Flash 25(M) cartridge eluting at 20 mL/min with 15% EtOAc in hexane over 1 h. The diastereomer with the higher inhibitory activity (the cis) eluted second.
Reaction SMILES: [Cl-].[OH:2][NH3+:3].C(=O)([O-])[O-].[K+].[K+].[C:10]1([C:16](=[CH:19][CH2:20][CH3:21])[CH:17]=O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(O)C>[C:10]1([C:16](=[CH:19][CH2:20][CH3:21])[CH:17]=[N:3][OH:2])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: [NH3+]O
Reactant: CCC=C(C=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CCO
Product: CCC=C(C=NO)c1ccccc1
Reaction time: 2 h
Yield: 75.3 %

Procedure:
A mixture of hydroxylammonium chloride (10.84 g, 0.156 mol) and potassium carbonate (21.56 g, 156 mmol) in absolute ethanol (100 ml) was stirred for 2 h. The precipitated sodium chloride was filtered off and 2-phenyl-2-pentenal (5.00 g, 31 mmol) was added to the filtrate. The mixture was stirred at ambient temperature for 16 h. The solvent was evaporated in vacuo, the residue was crystallised from aqueous ethanol to give 4.09 g 2-phenyl-2-pentenal oxime.
Reaction SMILES: F[B-](F)(F)F.[CH3:6][O:7][C:8]1[C:17]2[O:16][CH2:15][O:14][CH2:13][C:12]=2[CH:11]=[C:10]([CH:18]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[N:33]=[C:32]([CH3:34])[O:31][N:30]=3)=[CH:25][CH:24]=2)[C:19]([NH2:21])=[S:20])[CH:9]=1.[C:35](=O)([O-])O.[Na+].C(OCC)(=O)C>C(#N)C>[CH3:35][S:20][C:19](=[NH:21])[CH:18]([C:10]1[CH:9]=[C:8]([O:7][CH3:6])[C:17]2[O:16][CH2:15][O:14][CH2:13][C:12]=2[CH:11]=1)[NH:22][C:23]1[CH:24]=[CH:25][C:26]([C:29]2[N:33]=[C:32]([CH3:34])[O:31][N:30]=2)=[CH:27][CH:28]=1
Reactant: COc1cc(C(Nc2ccc(-c3noc(C)n3)cc2)C(N)=S)cc2c1OCOC2
Reactant: O=C([O-])O
Agent: F[B-](F)(F)F
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COc1cc(C(Nc2ccc(-c3noc(C)n3)cc2)C(=N)SC)cc2c1OCOC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
After adding 10.6 g of Me3O+BF4− to a solution of 28.2 g of a crude product of 2-(8-methoxy-4H-benzo[1,3]dioxin-6-yl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylamino]thioacetamide in 100 ml of acetonitrile, the mixture was stirred at room temperature for 1 hour under a nitrogen atmosphere. Saturated aqueous sodium hydrogencarbonate was added to the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (27.2 g, crude product) as a light yellow solid.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:12]=[C:13]([O:15]C)[CH:14]=1)[O:6][C:7]1[NH:11][N:10]=[N:9][N:8]=1.[Cl-].[Al+3].[Cl-].[Cl-].C1C=CC=CC=1.O>CO>[OH:15][C:13]1[CH:12]=[C:5]([CH:4]=[C:3]([OH:2])[CH:14]=1)[O:6][C:7]1[NH:11][N:10]=[N:9][N:8]=1
Reactant: COc1cc(OC)cc(Oc2nnn[nH]2)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CO
Solvent: c1ccccc1
Solvent: O
Product: Oc1cc(O)cc(Oc2nnn[nH]2)c1

Procedure:
A mixture of 38.3 g. of 5-(3,5-dimethoxyphenoxy)-1H-tetrazole, 68 g. of anhydrous aluminum chloride, and 400 ml. of benzene was heated under reflux for about one and one-half hours. A mixture of 150 ml. of water and 30 ml. of methanol was added slowly to the aluminum chloride mixture. The solution was then stirred and allowed to cool. The aqueous layer was separated and extracted with ethyl acetate. After the ethyl acetate was evaporated, the product was crystallized from water. The weight of the product obtained was 28.2 g. and its melting point was 191°-193° C. The following elemental analysis was obtained:
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[C:7]([CH2:9][CH3:10])[N:6]=[C:5]([NH:11][C:12]2[S:13][C:14]([C:17]#[N:18])=[CH:15][N:16]=2)[CH:4]=1.[Cl-].[CH3:20][NH:21][C:22]([N:24]1[CH2:29][CH2:28][NH2+:27][CH2:26][CH2:25]1)=[O:23].C(N(C(C)C)C(C)C)C>CS(C)=O.O>[C:17]([C:14]1[S:13][C:12]([NH:11][C:5]2[CH:4]=[C:3]([CH2:2][N:27]3[CH2:28][CH2:29][N:24]([C:22]([NH:21][CH3:20])=[O:23])[CH2:25][CH2:26]3)[CH:8]=[C:7]([CH2:9][CH3:10])[N:6]=2)=[N:16][CH:15]=1)#[N:18]
Reactant: CNC(=O)N1CC[NH2+]CC1
Reactant: CCc1cc(CCl)cc(Nc2ncc(C#N)s2)n1
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CS(C)=O
Product: CCc1cc(CN2CCN(C(=O)NC)CC2)cc(Nc2ncc(C#N)s2)n1
Reaction time: 24 h

Procedure:
2-{[4-(Chloromethyl)-6-ethylpyridin-2-yl]amino}-1,3-thiazole-5-carbonitrile (0.113 g, 0.41 mmol) was dissolved in 2 mL DMSO. 1-[(Methylamino)carbonyl]piperazin-4-ium chloride (0.146 g, 0.81 mmol) and N-ethyl-N,N-diisopropylamine (0.283 mL, 1.63 mmol) were added and the solution was stirred for 24 hours. The reaction was diluted with water and the resulting precipitate was filtered and washed with water. The precipitate was purified by flash column chromatography (gradient, 5-10% MeOH/CH2Cl2). The fractions containing the desired compound were concentrated to dryness to afford the desired product 12-4.
Reaction SMILES: C([N:3]([CH2:15][CH3:16])[C:4](=[O:14])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:6]=1C)C.C([Li])(C)(C)C.CCCCC.[N:27]1(C#N)[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>C1COCC1>[CH3:12][O:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[C:4]([OH:14])=[N:3][C:15]([N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1)=[CH:16]2
Reactant: CCN(CC)C(=O)c1ccc(OC)cc1C
Reactant: N#CN1CCOCC1
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: C1CCOC1
Product: COc1ccc2c(O)nc(N3CCOCC3)cc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 59.5 %

Procedure:
To a solution of N,N-diethyl-4-methoxy-2-methylbenzamide (500 mg, 2.259 mmol) in THF (5 ml) at −78° C. was added dropwise tert-butyllithium 1.7 M in pentane (2658 μl, 4.52 mmol) and the solution was stirred for 0.5 h before addition of morpholine-4-carbonitrile (253 mg, 2.259 mmol) in THF (5 ml). The resulting solution was warmed to rt and stirred for 16 h. The reaction mixture was quenched with water, neutralized with 1 N HCl. The precipitated solid was collected and washed with water to give 6-methoxy-3-morpholinoisoquinolin-1-ol (350 mg, 60% yield) as a solid after drying.
Reaction SMILES: [NH2:1][C:2]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:15])[C:7](=[O:8])[CH:6]=[CH:5][CH2:4][CH2:3]1.[OH:16][C:17]([CH2:19][CH2:20][CH2:21][CH2:22][C@H:23]1[C@@H:31]2[C@@H:26]([NH:27][C:28]([NH:30]2)=[O:29])[CH2:25][S:24]1)=O.Cl.CN(C)CCCN=C=NCC>CN(C)C=O>[C:17]([NH:1][C:2]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:15])[C:7](=[O:8])[CH:6]=[CH:5][CH2:4][CH2:3]1)(=[O:16])[CH2:19][CH2:20][CH2:21][CH2:22][C@H:23]1[C@@H:31]2[C@@H:26]([NH:27][C:28]([NH:30]2)=[O:29])[CH2:25][S:24]1
Reactant: O=C(O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Reactant: NC1(c2ccccc2Cl)CCC=CC1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: O=C(CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21)NC1(c2ccccc2Cl)CCC=CC1=O
Yield: 31.7 %

Procedure:
A solution of 6-amino-6-(2-chlorophenyl)-2-cyclohexen-1-one (50 mg, 0.23 mmol), (+)-biotin (56 mg, 0.23 mmol), hydroxybenzotdazole (31 mg, 0.23 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (66 mg, 0.35 mmol) in dimethylformamide (1 ml) was stirred at room temperature for 42 h. The reaction was partitioned between water and ethyl acetate, the organic phase was washed with water, brine, dried (Na2SO4), and the solvent removed by evaporation. Flash chromatography on silica gel eluted with 17:3 ethyl acetate / hexane afforded 6-biotinoylamino-6-(2-chlorophenyl)-2-cyclohexen-1-one (32.7 mg, 32%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH2:8][C:7](=O)[C:6]=2[CH:11]=1.[ClH:12].[NH:13]([C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1[C:17]([OH:19])=[O:18])N>C(O)C.O>[Cl:12][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]3[C:23]4[C:15](=[C:16]([C:17]([OH:19])=[O:18])[CH:20]=[CH:21][CH:22]=4)[NH:13][C:7]=3[C:6]=2[CH:11]=1
Reactant: Cl
Reactant: NNc1ccccc1C(=O)O
Reactant: O=C1COc2ccc(Br)cc21
Solvent: O
Solvent: CCO
Product: O=C(O)c1cccc2c1[nH]c1c3cc(Cl)ccc3oc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 66 %

Procedure:
To a solution of 5-chloro-3(2H)-benzofuranone (0.357 g, 2.12 mmol) [Ellingboe, J. et al. J. Med. Chem. 1992, 35 (7), 1176-1183] in ethanol (100 mL) was added a solution of 2-hydrazinobenzoic acid hydrochloride (0.800 g, 4.24 mmol) in deionized water (50 mL). The mixture was stirred for one hour at room temperature and then allowed to sit while cooled (0° C.). Vacuum filtration and drying in vacuo afforded 0.400 g (62%) of the title compound as a pale yellow solid: mp 190° C. (dec) which was used without further purification.
Reaction SMILES: [O-]CC.[Na+].[C:5](#[N:8])[CH:6]=[CH2:7].[CH2:9]([O:12][P:13]([CH:15]([O:20][CH2:21][CH2:22][CH3:23])[O:16][CH2:17][CH2:18][CH3:19])[OH:14])[CH2:10]C.C(O)(=O)C>C(O)C>[C:5]([CH2:6][CH2:7][P:13]([CH:15]([O:16][CH2:17][CH2:18][CH3:19])[O:20][CH2:21][CH2:22][CH3:23])(=[O:14])[O:12][CH2:9][CH3:10])#[N:8]
Reactant: C=CC#N
Reactant: CCCOC(OCCC)P(O)OCCC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CCCOC(OCCC)P(=O)(CCC#N)OCC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of sodium ethoxide in absolute ethanol (0.48 g of sodium metal in 15 ml of absolute ethanol) is cooled to 0° under nitrogen or argon. A solution of 2.72 g of acrylonitrile and 12.2 g of di-n-propyloxymethylphosphonous acid n-propylester in 50 ml of absolute ethanol is added at such a rate that the temperature does not exceed 5°. After the addition is completed, the solution is allowed to warm to room temperature and stirred overnight. After addition of 1.22 g of glacial acetic acid, the reaction mixture is concentrated in vacuo. The residue is partitioned between ethyl acetate and water and the organic phase separated. After drying over anhydrous magnesium sulphate the solvent is evaporated in vacuo to afford an oil. Chromatography on silica-gel yields ethyl 2-cyanoethyl(di-n-propyloxymethyl)phosphinate as a colourless oil.
Reaction SMILES: [CH:1]([Si:4](Cl)([CH:8]([CH3:10])[CH3:9])[CH:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2].[OH:12][CH2:13][C@@H:14]1[O:18][C:17]([CH3:20])([CH3:19])[O:16][C@@H:15]1[C@H:21]([OH:23])[CH3:22].N1C=CN=C1.C(OCC)(=O)C>CN(C)C=O.O>[CH3:20][C:17]1([CH3:19])[O:16][C@H:15]([C@H:21]([OH:23])[CH3:22])[C@H:14]([CH2:13][O:12][Si:4]([CH:8]([CH3:10])[CH3:9])([CH:5]([CH3:7])[CH3:6])[CH:1]([CH3:3])[CH3:2])[O:18]1
Reactant: C[C@@H](O)[C@H]1OC(C)(C)O[C@H]1CO
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)[Si](OC[C@@H]1OC(C)(C)O[C@@H]1[C@@H](C)O)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 23 h

Procedure:
4.46 mL of triisopropylsilyl chloride was added dropwise to a solution of 3.5 g of (1R)-1-((4R,5S)-5-(hydroxymethyl)-2,2-dimethyl-1,3-dioxolane-4-yl)ethan-1-ol and 1.63 g of imidazole in 50 mL of N,N-dimethylformamide in a nitrogen atmosphere at a temperature of 5° C. to 10° C., and the obtained mixture was then stirred at room temperature for 23 hours. Thereafter, ethyl acetate and water were added to the reaction mixture. The organic layer was fractionated, and it was washed with a saturated sodium chloride aqueous solution and was then dried over anhydrous magnesium sulfate. The solvent was distilled away under reduced pressure, so as to obtain 7.1 g of (1R)-1-((4R,5S)-2,2-dimethyl-5-(((tris(propan-2-yl)silyl)oxy)methyl)-1,3-dioxolane-4-yl)ethan-1-ol in the form of a colorless oily product.
Reaction SMILES: COC(C1C=C(OC2C=CC(S(C)(=O)=O)=CC=2)C=C2OC(C)CC=12)=O.[CH3:26][N:27]1[CH:31]=[CH:30][C:29]([NH:32][C:33]([C:35]2[CH:46]=[C:45]([OH:47])[C:38]3[CH2:39][CH:40]([CH2:42][O:43][CH3:44])[O:41][C:37]=3[CH:36]=2)=[O:34])=[N:28]1.[N:48]1([C:52]([C:54]2[CH:59]=[CH:58][C:57](F)=[CH:56][C:55]=2[F:61])=[O:53])[CH2:51][CH2:50][CH2:49]1>>[CH3:26][N:27]1[CH:31]=[CH:30][C:29]([NH:32][C:33]([C:35]2[CH:46]=[C:45]([O:47][C:57]3[CH:58]=[CH:59][C:54]([C:52]([N:48]4[CH2:51][CH2:50][CH2:49]4)=[O:53])=[C:55]([F:61])[CH:56]=3)[C:38]3[CH2:39][CH:40]([CH2:42][O:43][CH3:44])[O:41][C:37]=3[CH:36]=2)=[O:34])=[N:28]1
Reactant: COCC1Cc2c(O)cc(C(=O)Nc3ccn(C)n3)cc2O1
Reactant: O=C(c1ccc(F)cc1F)N1CCC1
Agent: COC(=O)c1cc(Oc2ccc(S(C)(=O)=O)cc2)cc2c1CC(C)O2
Product: COCC1Cc2c(Oc3ccc(C(=O)N4CCC4)c(F)c3)cc(C(=O)Nc3ccn(C)n3)cc2O1

Procedure:
The title compound was prepared in a similar manner as described for Intermediate 1f, from 4-hydroxy-2-methoxymethyl-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide (204d) and azetidin-1-yl-(2,4-difluoro-phenyl)-methanone. 1H NMR (400 MHz, CDCl3) δ 8.43 (s, 1 H) 7.54 (t, J=8.08 Hz, 1 H) 7.28 (d, J=2.27 Hz, 1 H) 7.13 (s, 1 H) 7.08 (s, 1 H) 6.81 (dd, J=8.59, 2.27 Hz, 1 H) 6.78 (d, J=2.02 Hz, 1 H) 6.68 (dd, J=11.12, 2.27 Hz, 1 H) 5.00-5.08 (m, 1 H) 4.22 (t, J=7.71 Hz, 2 H) 4.16 (t, J=7.71 Hz, 2 H) 3.81 (s, 3 H) 3.60 (d, J=5.05 Hz, 2 H) 3.43 (s, 3 H) 3.15 (dd, J=16.42, 9.60 Hz, 1 H) 2.92 (dd, J=16.42, 7.33 Hz, 1 H) 2.27-2.38 (m, 2 H); LCMS for C25H25FN4O5 m/z 481.00 (M+H)+.
Reaction SMILES: CCN(C(C)C)C(C)C.FC(F)(F)S(O[C:16]1[CH:17]=[CH:18][C:19]2[O:23][C:22]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)=[C:21]([C:31](=[O:34])[NH:32][CH3:33])[C:20]=2[CH:35]=1)(=O)=O.[CH3:38][C:39]1[O:43][C:42]([C:44]2[CH:45]=[C:46](B(O)O)[CH:47]=[CH:48][CH:49]=2)=[N:41][N:40]=1.O1CCOCC1>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.O>[F:30][C:27]1[CH:26]=[CH:25][C:24]([C:22]2[O:23][C:19]3[CH:18]=[CH:17][C:16]([C:46]4[CH:47]=[CH:48][CH:49]=[C:44]([C:42]5[O:43][C:39]([CH3:38])=[N:40][N:41]=5)[CH:45]=4)=[CH:35][C:20]=3[C:21]=2[C:31]([NH:32][CH3:33])=[O:34])=[CH:29][CH:28]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(OS(=O)(=O)C(F)(F)F)cc12
Reactant: Cc1nnc(-c2cccc(B(O)O)c2)o1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(-c4nnc(C)o4)c3)cc12
Temperature: 90 °C
Yield: 39 %

Procedure:
DIEA (50 μL, 0.288 mmol) was added to Pd(Ph3P)4 (6 mg, 4.79 μmol), 2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl trifluoromethanesulfonate (40 mg, 0.096 mmol), 3-(5-methyl-1,3,4-oxadiazol-2-yl)phenylboronic acid (29 mg, 0.144 mmol). Dioxane (799 μL) and water (160 μL) was added at rt. The reaction was heated to 90° C. overnight. The mixture was cooled and purified by prep HPLC to give the titled compound (16 mg, 37%). 1H NMR (500 MHz, DMSO-d6) δ ppm 8.49-8.56 (1H, m), 8.24 (1H, s), 7.98-8.05 (4H, m), 7.93 (1H, s), 7.79-7.83 (1H, m), 7.68-7.76 (2H, m), 7.41 (2H, t, J=8.70 Hz), 2.87 (3H, d, J=4.58 Hz), 2.62 (3H, s). LC-MS retention time: 1.41 min; m/z (MH−): 426. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge 5u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MS data was determined using a MICROMASS® Platform for LC in electrospray mode. Analytical HPLC method: Solvent A=5% CH3CN/95% H2O/0.1% TFA, Solvent B=95% CH3CN/5% H2O/0.1% TFA, Start % B=10, Final % B=100, Gradient time=15 min, Stop time=18 min, Flow Rate=1 ml/min. Column: Waters Sunfire C-18, 4.6×150 mm, 3.5 μm, Rt=12.96 min, purity=95%; Column: Waters XBridge phenyl column 4.6×150 mm, 3.5 μm, Rt=11.53 min, purity=94%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:24]([O-:26])=[O:25])=[C:6]([CH:23]=1)[O:7][CH:8]([CH2:20][CH2:21][CH3:22])[CH2:9][CH2:10][N:11](C)[C:12](=[O:18])[O:13]C(C)(C)C.N.[C:28](=[O:31])([OH:30])[O-].[Na+]>Cl.O1CCOCC1>[C:12]([OH:18])(=[O:13])[C:28]([OH:30])=[O:31].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:24]([O-:26])=[O:25])=[C:6]([CH:23]=1)[O:7][CH:8]([CH2:20][CH2:21][CH3:22])[CH2:9][CH2:10][NH:11][CH3:12]
Reactant: CCCC(CCN(C)C(=O)OC(C)(C)C)Oc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: O=C([O-])O
Agent: Cl
Agent: N
Agent: [Na+]
Solvent: C1COCCO1
Product: CCCC(CCNC)Oc1cc(Cl)ccc1[N+](=O)[O-]
Product: O=C(O)C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 71 %

Procedure:
[3-(5-chloro-2-nitrophenoxy)hexyl]methylcarbamic acid, 1,1-dimethylethyl ester (130 mg, 0.336 mmol) was dissolved in 4M hydrogen chloride in dioxane (10 ml). The resulting solution was stirred at room temperature for 3 h, then diluted with sodium bicarbonate solution containing ammonia and extracted three times with dichloromethane. The combined organic fractions were washed with brine then dried over magnesium sulphate. The solvent was evaporated and the residue dissolved in ethanol. To this solution was added oxalic acid in ethanol and the solvent evaporated. The residue was recrystallised from ethanol to give 90 mg (71%) of the title compound as a white solid.
Reaction SMILES: [N:1]#[C:2][NH2:3].[CH3:4][N:5]([C:12]1[S:13][C:14]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)=[N:15][N:16]=1)[C:6](=[O:11])[CH2:7][CH2:8]SC.C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1>C1COCC1>[C:2]([NH:3][CH2:8][CH2:7][C:6]([N:5]([CH3:4])[C:12]1[S:13][C:14]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)=[N:15][N:16]=1)=[O:11])#[N:1]
Reactant: N#CN
Reactant: CSCCC(=O)N(C)c1nnc(-c2cccnc2)s1
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: Ic1ccccc1
Product: CN(C(=O)CCNC#N)c1nnc(-c2cccnc2)s1
Temperature: -10 °C
Reaction time: 4 h
Yield: 29.1 %

Procedure:
Cyanamide (42 mg, 1.0 mmol) and N-methyl-3-methylsulfanyl-N-[5-(3-pyridyl)-1,3,4-thiadiazol-2-yl]propanamide (294 mg, 1.0 mmol) were suspended in THF and cooled in a −10° C. bath. Iodobenzene diacetate (322 mg, 1.0 mmol) was added and the resulting suspension was stirred at for 4 h. The reaction mixture was concentrated under reduced pressure and purified by reversed phase silica chromatography eluting with an aqueous acetonitrile mobile phase to yield a white solid (84 mg, 29%): mp 155-159° C.; 1H NMR (300 MHz, CDCl3) δ 9.15 (m, 1H), 8.72 (m, 1H), 8.35 (m, 1H), 7.45 (m, 1H), 4.70 (bs, 1H), 3.90 (s, 3H), 3.55 (m, 2H), 3.05 (m, 2H); ESIMS m/z 289 ([M+H]+).
Reaction SMILES: [F:1][C:2]1[C:9]([CH2:10]O)=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.O>O1CCCC1>[F:1][C:2]1[C:9]([CH3:10])=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:12]([F:13])([F:14])[F:15])[CH:3]=1
Reactant: N#Cc1cc(CO)c(F)cc1C(F)(F)F
Agent: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1cc(C#N)c(C(F)(F)F)cc1F
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 17.6 %

Procedure:
To a solution (10 mL) of 4-fluoro-5-(hydroxymethyl)-2-(trifluoromethyl)benzonitrile (545 mg) and triethylamine (0.862 mL) in tetrahydrofuran was added dropwise methanesulfonyl chloride (0.289 mL) at 0° C. After the dropwise addition, the mixture was stirred at room temperature for 1.5 hr, water was added to the mixture and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (20 mL) and sodium borohydride (400 mg) was added thereto. The reaction mixture was stirred for 1.5 hr and methanol (2.5 mL) was added thereto. The mixture was stirred for 30 min, and saturated aqueous sodium hydrogencarbonate was added thereto. The mixture was extracted with ethyl acetate, and the extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent: hexane-ethyl acetate=15:1→1:1) to give the title compound as a yellow oil (yield: 89 mg).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[Cl:13][C:14]1[CH:33]=[CH:32][C:17]([NH:18][C:19]2[C:28]3[C:23](=[CH:24][C:25]([OH:31])=[C:26]([O:29][CH3:30])[CH:27]=3)[N:22]=[CH:21][N:20]=2)=[C:16]([F:34])[CH:15]=1.[N:35]1([CH2:40][CH2:41]O)[CH:39]=[N:38][CH:37]=[N:36]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[ClH:13].[Cl:13][C:14]1[CH:33]=[CH:32][C:17]([NH:18][C:19]2[C:28]3[C:23](=[CH:24][C:25]([O:31][CH2:41][CH2:40][N:35]4[CH:39]=[N:38][CH:37]=[N:36]4)=[C:26]([O:29][CH3:30])[CH:27]=3)[N:22]=[CH:21][N:20]=2)=[C:16]([F:34])[CH:15]=1
Reactant: OCCn1cncn1
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCCn1cncn1
Product: Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 104.4 %

Procedure:
Diethyl azodicarboxylate (295 μl, 1.8 mmol) was added dropwise to a solution of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (300 mg, 0.93 mmol), (prepared as described for the starting material in Example 24), 2-(1,2,4-triazol-1-yl)ethanol (159 mg, 1.4 mmol), (Ann. Pharm. Fr. 1977, 35, 503-508), and triphenylphosphine (492 mg, 1.8 mmol) in methylene chloride (10 ml). The mixture was stirred for 2 hours at ambient temperature and further triphenylphosphine (246 mg, 0.9 mmol) and diethyl azodicarboxylate (147 μl, 0.9 mmol) were added. The mixture was stirred for 1 hour at ambient temperature and the resulting precipitate was collected by filtration, washed with methylene chloride and ether and dried under vacuum. This solid was suspended in methylene chloride/methanol and a 5M solution of hydrogen chloride in isopropanol (1.0 ml) was added. The volatiles were removed by evaporation, the residue was triturated with ether. The resulting solid was collected by filtration, washed with ether and dried under vacuum to give 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(1,2,4-triazol-1-yl)ethoxy)quinazoline hydrochloride (219 mg, 52%). m.p. 169-174° C. 1H NMR Spectrum: (DMSOd6) 3.99(s, 3H); 4.60(t, 2H); 4.74(t, 2H); 7.43(d, 1H); 7.45(s, 1H); 7.59(t, 1H); 7.67(dd, 1H); 8.06(s, 1H); 8.41(s, 1H); 8.68(s, 1H); 8.83(s, 1H) MS-ESI: 415 [MH]+
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[OH:9].[F:10][N+]1C(C(Cl)(Cl)Cl)=CC=CC=1Cl>ClC(Cl)CCl>[F:10][C:6]1[CH:7]=[C:2]([Cl:1])[C:3]([OH:9])=[C:4]([Cl:8])[CH:5]=1
Reactant: Oc1c(Cl)cccc1Cl
Reactant: F[n+]1c(Cl)cccc1C(Cl)(Cl)Cl
Solvent: ClCC(Cl)Cl
Product: Oc1c(Cl)cc(F)cc1Cl
Temperature: 55 °C

Procedure:
A mixture of 082 g of 2,6-dichlorophenol, 1.67 g of N-fluoro-2-chloro-6-(trichloromethyl) pyridinium rfluoroborate, and 40 ml of 1,1,2-trichloroethane was placed in a 100 ml 3-necked round bottomed flask equipped with a magnetic stirring bar, a thermometer, and a reflux condenser. The mixture was heated to 55° C. and allowed to react at that temperature for 8 hours under nitrogen. The mixture was then allowed to cool. Analysis by standardized gas-liquid chromatography using a mass spectrometer detector indicated that the title product was present in 24 percent conversion. The product identity was confirmed by its known 19F and 1H NMR spectra.